Major and ancillary magnetic resonance features of LI-RADS to assess HCC: an overview and update
© The Author(s). 2017
Received: 1 March 2017
Accepted: 21 April 2017
Published: 28 April 2017
Liver Imaging Reporting and Data System (LI-RADS) is a system for interpreting and reporting of imaging features on multidetector computed tomography (MDCT) and magnetic resonance (MR) studies in patients at risk for hepatocellular carcinoma (HCC). American College of Radiology (ACR) sustained the spread of LI-RADS to homogenizing the interpreting and reporting data of HCC patients. Diagnosis of HCC is due to the presence of major imaging features. Major features are imaging data used to categorize LI-RADS-3, LI-RADS-4, and LI-RADS-5 and include arterial-phase hyperenhancement, tumor diameter, washout appearance, capsule appearance and threshold growth. Ancillary are features that can be used to modify the LI-RADS classification. Ancillary features supporting malignancy (diffusion restriction, moderate T2 hyperintensity, T1 hypointensity on hapatospecifc phase) can be used to upgrade category by one or more categories, but not beyond LI-RADS-4. Our purpose is reporting an overview and update of major and ancillary MR imaging features in assessment of HCC.
Hepatocellular carcinoma (HCC) is one of the most common human solid malignancies worldwide [1, 2]. The most important risk factor for the development of HCC is liver cirrhosis, regardless of its etiology . Among patients with cirrhosis, those with chronic viral infection (hepatitis B and C) and high alcohol intake have the highest risks of HCC development. Imaging surveillance is a widely accepted tool that increases the likelihood of early detection of HCC and an accurate detection and characterization of focal liver nodule on patient at risk for HCC is mandatory since the management of HCC patients differs to other malignant or benign nodules . According to National Comprehensive Cancer Network (NCCN)  and the guidelines of European Association for the Study of the Liver (EASL) and American Association for the Study Liver Diseases (AASLD), diagnostic criteria, to characterize HCC, can only be applied to cirrhotic patients and should be based on the detection of the typical hallmark of HCC (hypervascular in the arterial phase with washout in the portal venous or delayed phases) . However, the current imaging-based criteria have several limitations, including the lack of established consensus regarding the exact definitions of imaging features, binary categorization (either definite or not definite HCC), and failure to address non-HCC malignancies and vascular invasion . Therefore American College of Radiology (ACR) sustained the spread of Liver Imaging Reporting and Data System (LI-RADS) to homogenizing the interpreting, reporting and data collection of HCC imaging . LI-RADS is a scheme for interpreting and reporting of imaging features on multidetector computed tomography (CT) and magnetic resonance (MR) studies in patients at risk for hepatocellular carcinoma (HCC) [5–7]. In the current (v. 2014) LI-RADS , the diagnosis of HCC is based on the presence of major imaging features. These are features used to categorize LI-RADS- category 3 (LR-3), LI-RADS- category 4 (LR-4), and LI-RADS- category 5 (LR-5) and include arterial-phase hyperenhancement, tumor diameter, washout appearance, capsule appearance, and threshold growth . Ancillary features are imaging features that can be used to change the LI-RADS category . Ancillary features favoring malignancy (diffusion restriction, moderate T2 hyperintensity, T1 hypointensity on hepatospecific phase) can upgrade category, but not beyond LR-4. In contrast, ancillary features favoring benignity can decrease category [5, 6].
As required in most clinical trials, MDCT presents the key imaging modality in the patient assessment. This is due to its wide availability, standardization, and ability to scan the whole abdomen and chest in one setting. MRI plays a role in HCC assessment of patients with contraindication to iodine contrast medium . However, considering the evidences on the accuracy of the various imaging modalities on HCC assessment , so as the guidelines of the European Society of Gastrointestinal and Abdominal Radiology (ESGAR) Working Group , MRI is the technique to choose in pre-treatment setting. It is a valuable diagnostic tool providing lesion morphological and functional data, thanks to hepatospecific contrast medium and DW sequences [11–14].
To standardize imaging technique among institutions, LI-RADS outlines technical requirements for MRI. Precontrast, arterial phase, portal venous phase, and delayed phase are all required for MRI with extracellular agents. Each phase contributes to characterization of LI-RADS major features. For MRI with hepatobiliary agents, a delay of 15–20 min for gadoxetic acid and a delay of 1 h for gadobenate dimeglumine consistently provide high-quality hepatobiliary phase imaging. In the setting of cirrhosis increasing the delay for hepatobiliary phase imaging to 30 min or more for gadoxetic acid and 2–3 h for gadobenate dimeglumine may improve parenchymal enhancement somewhat . Although the delayed phase cannot be used to evaluate washout appearance, it can be used to evaluate capsule appearance, a major feature of HCC. Also, the delayed phase and hepatobiliary phase can be used to evaluate hypointensity on both sequences; these are ancillary features favoring malignancy and so can be used to upgrade the category. Late arterial phase is strongly preferred over early arterial phase, as HCC enhancement usually is greater in the late than in the early phase, and some HCCs show hyperenhancement only in the late arterial phase . Unenhanced T1-weighted (T1-W) out of phase (OP)/in phase (IP) is required. T1-W OP/IP allows identification of fat and iron and is necessary for assessment of some ancillary features. T2-W sequences are required, improving distinction between solid and nonsolid lesions and are necessary for assessment of some ancillary LI-RADS features. DWI is suggested but not required .
Our purpose is reporting an overview and update of major and ancillary MR imaging features in assessment of HCC.
This overview and update is the result of autonomous studies without protocol and registration number.
Several electronic dataset were searched: PubMed (US National Library of Medicine, http://www.ncbi.nlm.nih.gov/pubmed), Scopus (Elsevier, http://www.scopus.com/), Web of Science (Thomson Reuters, http://apps.webofknowledge.com/) and Google Scholar (https://scholar.google.it/). The following search criteria have been used: “hepatocellular carcinoma” AND “diffusion magnetic resonance imaging” AND “characterization, “hepatocellular carcinoma” AND “dynamic contrast enhanced magnetic resonance imaging” AND “characterization, “hepatocellular carcinoma” AND “EOB-GD-DTPA contrast medium” AND “characterization, “hepatocellular carcinoma” AND “multimodal imaging” AND “characterization”. The search covered the years from January 2000 to January 2017. Moreover, the reference lists of the found papers were analysed for papers not indexed in the electronic databases.
All titles and abstracts were analysed and exclusively the studies reporting MRI, EOB-GD-DTPA MRI, DWI results in the characterization of HCC were retained.
The inclusion criteria were: clinical study evaluating MR assessment of HCC, clinical study evaluating functional MR imaging criteria in the assessment of patients with HCC, and clinical study evaluating DWI and EOB-GD-DTPA to assessing HCC patient. Articles published in the English language from January 2000 to January 2017 were included. Exclusion criteria were unavailability of full text, general overview articles and congress abstracts; studies with lesion higher than 20 mm. There was not define a minimum number of patients as an inclusion criteria.
Early diagnosis is a critical step in the management of HCC patients. The identification of the specific vascular profile characterized by contrast arterial uptake followed by washout in the venous phases has allowed defining the non-invasive diagnostic criteria for HCC according to AASLD and EASL-EORTC guidelines [4, 5]. The typical hallmark has 100% specificity when demonstrated on dynamic contrast study, both on CT than on MRI, in patients at high risk of HCC . However, arterial hyperehnancement and wash out appearance have a sensitivity rate of 50–60% in lesion smaller than 2 cm and thus a biopsy is still needed . The typical vascular profile is correlated to hemodynamic changes in nodule during hepatocarcinogenesis, and to understand the hemodynamics of HCC is important for the accurate diagnostic analysis, because there is an intense correlation between their hemodynamics and pathophysiology . Angiogenesis such as sinusoidal capillarization and unpaired arteries shows gradual increase during carcinogenesis from high-grade dysplastic nodule to classic hypervascular HCC. In accordance with this angiogenesis, the intranodular portal supply is decreased, whereas the intranodular arterial supply is first decreased during the early stage and then increased in parallel with increasing grade of malignancy of the lesion. On the other hand, the main drainage vessels of hepatocellular nodules change from hepatic veins to hepatic sinusoids and then to portal veins, mainly due to disappearance of the hepatic veins from the nodules . The nodule appearance on arterial phase relative, considering the intra-lesion arterial supply, can be categorized into four types. Type I when the nodule is isodense to the surrounding cirrhotic liver parenchyma, and it is due to the same intranodular arterial blood supply relative to the surrounding liver. Type II, when the nodule is hypodense to the surrounding cirrhotic liver parenchyma, indicating decreased arterial blood supply. Type III a part of the nodule demonstrating hyperdensity due a partially increased arterial supply and type IV entirely hyperdense indicating entirely increased arterial supply [16, 17]. These findings reveal the significant correlation or strong tendency between type I and low grade dysplastic nodule and early HCC, type II and high grade dysplastic nodule and early HCC, type III and well differentiated HCC and type IV and moderately or poorly differentiated HCC [16, 17]. Also in early HCC, there is not perinodular enhancement on portal or equilibrium phase of contrast study, but it is definite in hypervascular classical HCC.
During hepatocarcinogenesis multi-step changes of drainage vessels and peritumoral enhancement occurred. In dysplastic nodules or early HCCs, the main drainage route from the tumor is intranodular or perinodular hepatic vein. However, because hepatic veins disappear from the tumor during very early stage of hepatocarcinogenesis, drainage vessels change to hepatic sinusoids. This drainage was well visualized in the late phase of contrast studies. Histological examination revealed continuity between a tumor sinusoid and a portal venule in the pseudocapsule (encapsulated HCC) or surrounding hepatic sinusoids (HCC without pseudocapsule). In moderately differentiated HCC with pseudocapsule formation, the communication between tumor sinusoids and the surrounding hepatic sinusoids are also blocked, and then, the portal venules in the pseudo-capsule finally become the main drainage vessel from the tumor. In accordance with the changes of the drainage vessels, thin to thick corona enhancement appears surrounding the tumor. Corona enhancement is thicker in encapsulated HCC and thin in HCC without pseudocapsule .
Arterial phase hyperenhancement
Arterial phase hyperenhancement is an essential prerequisite for definitely HCC (LR-5), but it is non-specific. In fact considering the hepatocarcinogenesis this feature may be not present, so as it may be observed in benign entities such as dysplastic nodules and arterio-portal shunts [1, 2]. Holland et al. showed, in proven HCC patients, that the majority (93%) of hypervascular lesions on arterial phase that were not detected on T2-W and portal and/or equilibrium phase of contrast study were non-neoplastic . Conversely, Kim et coworkers  demonstrated that the most significant findings associated with HCC, in nodules smaller than 20 mm, were arterial phase hypernhancement. Ehman et al. demonstrated that arterial hypenhancement was the most commonly observed major criterion on 159 (86%) of 184 proven HCC, and was seen slightly more frequently at CT vs. MRI (87 vs. 86%, p = 1.00). Between the two readers, there was agreement on arterial phase characteristics in 156 (95%) cases (κ = 0.75) . Conversely Burrel et al.  showed that sensitivity of MR was superior to CT to detect HCC (58/76 [76%] versus 43/70 [61%], respectively). Sensitivity of MR for detection of additional nodules decreased with size (>20 mm: 6/6 [100%]; 10–20 mm: 16/19 [84%]; <10 mm: 7/22 [32%]) and was superior to CT for nodules 10 to 20 mm (84 vs. 47%). Non specific hypervascular nodules >5 mm at MR were HCC in two thirds of the cases . Special attention must be given to perfusion alterations, common condition in cirrhotic livers that may be false positive. These are areas of arterial hyperenhancement most frequently caused by arterioportal shunts [22, 23]. These alterations are usually peripheral, wedge shaped, and isointense relative to the surrounding parenchyma on T1- and T2-W MR images, and can be confidently characterized as LR-1. Perfusion alterations can also be nodular and it is difficult to distinguish from a true lesion [18, 23]. Areas of nodular arterial hyperenhancement seen exclusively during the arterial phase are more appropriately categorized as LR-2 [13, 18], but if corresponding others observations (eg, hyperintensity T2 signal or restricted diffusion) should be categorized as either LR-3 or LR-4 depending on its size and nonvascular features. Some areas of perfusion alteration can occur secondary to focal liver lesions, including HCC .
Capsule appearance is defined as a peripheral rim of smooth hyperenhancement in the portal or delayed phase (Fig. 3). The rim of enhancement is not always a true tumor capsule, but may represent a pseudocapsule corresponding to fibrous tissue and dilated sinusoids around a nodule [16, 17, 28]. Anis and coworkers showed as the capsule appearance has a high positive predictive value for HCC in at-risk patients . Dioguardi Burgio et al.  showed as hyperintense capsule was present either on portal phase in 11/46 and in 24/25 HCCs imaged with gadoxetic acid and gadobenate dimeglumine-enhanced MR imaging, respectively (24 vs. 96%). A hypointense capsule appearance was present on hepatobiliary phase in 8/46 and 0/22 HCCs evaluated with gadoxetic acid and gadobenate dimeglumine-enhanced MR imaging, respectively (17 vs. 0%) . Conversely to Dioguardi Burgio et al. that analyzed two different contrast media, Zhang et al.  compared diagnostic accuracy of CT and MRI to predicting of malignancy and showed that CT against MR produced false-negative findings of pseudo-capsule by 42.9% with an underestimated LI-RADS score by 16.9% for LR- 3, 37.3% for LR- 4, and 8.5% for LR- 5. CT produced significantly lower accuracy (54.3 versus 67.8%) and sensitivity (31.6 versus 71.1%) than MRI in the prediction of malignancy . Also Corwin et al.  compared the diagnostic accuracy of CT respected to MR to grading LI-RADS. The most important finding of this study was that nearly half (42%) of observations were significantly upgraded on MRI compared with CT, and approximately one third of upgrades were to category 4, 5, or 5 V. The most common reason for the upgrade by MRI was the visualization of arterial hyperenhancement or a delayed enhancing capsule not seen on CT . It is clear that these features should be correctly identified since they are major features on LI-RADS.
Hypointense signal on hepatobiliary phase
Other ancillary features (intalesional fat, corona enhancement, mosaic architecture and iron sparing in iron overloaded)
MR imaging diagnosis of HCC is based mainly on assessment of vascularity, capsule appearance, and signal intensity in the hepatobiliary phase. MR imaging also permit assessment of ancillary imaging features, that can be divided into those that favor the diagnosis of HCC specifically (intralesional fat, corona enhancement, nodule-in-nodule architecture, and mosaic architecture) and those that favor the diagnosis of malignancy but are not specific for HCC (mild-moderate T2 hyperintensity, restricted diffusion, and lesional iron sparing) [5–7, 81].
Intralesional fat is the presence of lipid within a nodule in higher concentration than in the hepatic parenchyma . This feature can be detected at MR by observing signal loss on out-of-phase compared with in-phase T1-weighted GRE images. In a patient at risk for HCC, the detection of intralesional fat in a solid nodule raises concern for malignancy or premalignancy. In fact, this feature does not establish the diagnosis of HCC, however, as the differential diagnosis includes high-grade dysplastic nodule and occasionally low-grade dysplastic nodule .
Corona enhancement is a feature of hypervascular, progressed HCC and refers to enhancement of the venous drainage area in the peritumoral parenchyma . It is as a rim (“corona”) of enhancement around a progressed, hypervascular HCC in the late arterial phase or early portal venous phase, with fading to isoenhancement at subsequent phases. This feature begins a few seconds after tumor enhancement, so that corona and tumor enhancement may appear to overlap. This overlap may cause the tumor to appear larger than it really is. Its presence helps to differentiate small hypervascular HCCs from pseudolesions, however it is not a feature of early HCC [16, 82].
Mosaic architecture refers to the presence within a mass of randomly distributed internal nodules differing in enhancement, intensity, often separated by fibrous septa. This feature is characteristic of large HCCs and reflects the mosaic configuration observed at pathologic evaluation. It is unusual in tumors other than HCC .
Lesional iron sparing refers to relative paucity of iron in a solid mass compared with that of background iron-overloaded liver. This feature raises concern for premalignancy or malignancy because high-grade dysplastic nodules and HCCs characteristically are iron “resistant”. However it is not specific for high-grade dysplastic nodule or HCC, but other non-HCC malignancies may have this appearance .
Early diagnosis is a critical step in the management of HCC patients. The identification of the specific vascular profile characterized by contrast arterial uptake followed by washout in the venous phases has 100% specificity when demonstrated on dynamic contrast study, in patients at high risk of HCC. Although the arterial phase hyperenhancement is an essential prerequisite for definitely HCC, it is not sufficient for LR-5 categorization. Hypointensity on hepatospecific phase and wash-out appearance are the most relevant diagnostic sign for differentiating low-risk from high-risk nodules in patients at risk for HCC. Therefore the use of EOB-GD-DTPA should be considered in this category of patients. The capsule appearance, T2-W hyperintensity and restricted diffusion have a high positive predictive value for HCC and may be associated to other imaging features for LIRADS characterization.
The authors are grateful to Alessandra Trocino, librarian at the National Cancer Institute of Naples, Italy. Moreover, for the collaboration, authors are grateful to Maria Bruno, Laura Galeani, Rita Guarino, Leandro Eto and Assunta Zazzaro.
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Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
VG conceived of the study, and participated in its design, coordination and drafting of the manuscript. RF participated in the studies collection and drafted the manuscript. AA, OC, FF, ML, RP, FI, AP participated in the studies collection. All authors read and approved the final manuscript.
The authors have no conflict of interest to be disclosed. The authors confirm that the article is not under consideration for publication elsewhere. Each author has participated sufficiently to take public responsibility for the manuscript content.
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