CEUS LI-RADS: a pictorial review

Contrast-enhanced ultrasound (CEUS) greatly improved the diagnostic accuracy of US in the detection and characterization of focal liver lesions (FLLs), and it is suggested and often included in many international guidelines as an important diagnostic tool in the imaging work-up of cirrhotic patients at risk for developing hepatocellular carcinoma (HCC). In particular, CEUS Liver Imaging Reporting and Data System (LI-RADS) provides standardized terminology, interpretation, and reporting for the diagnosis of HCC. The aim of this pictorial essay is to illustrate CEUS features of nodules discovered at US in cirrhotic liver according to LI-RADS categorization.


Introduction
Worldwide HCC is reported to be the sixth most common tumor and the fourth cause of death related to cancer [1].
Cirrhotic patients are particularly considered a highrisk group for the onset of HCC, prompting several international scientific societies to publish guidelines recommending surveillance of adults with cirrhosis on the evidence of improved overall survival [2][3][4]. The recommended imaging surveillance tool for early detection of HCC is ultrasound (US), usually performed every 6 months [2,3]. Once a new nodule suspect for HCC is discovered in the liver of a cirrhotic patient, further imaging work-up with either computed tomography (CT) or magnetic resonance imaging (MRI) is usually recommended [2,3]. Both techniques require the intravenous administration of contrast media and difficulties may arise in patients with severe renal failure or allergies [5,6].
Contrast-enhanced US (CEUS) allows to assess noninvasively the contrast enhancement patterns of HCC, without the use of ionizing radiation and with a much higher temporal resolution than CT and MRI [7][8][9][10]. This unique feature of CEUS virtually eliminates the possibility of image acquisition mistiming, especially in the arterial phase [11]. Several studies have reported the improvement in diagnostic accuracy of CEUS in the detection and characterization of FLLs, including HCC [8][9][10][11]. CEUS has been also proved useful in the guidance and response assessment of therapeutic procedures [12][13][14][15][16][17][18].
CEUS examination is performed by injecting intravenously microbubble-based contrast agents (USCAs) consisting of flexible shells (e.g., phospholipids, liposomes) presenting a radius ranging from 1 to 10 μm, containing low solubility gases (e.g., perfluoropropane, perfluorocarbon, or sulphur hexafluoride) [19,20]. USCAs microbubbles pass through the lung capillary bed and they remain confined within the intravascular space. Although some USCAs may present a post-vascular phase in the liver and spleen, this phase is currently not taken in account for the characterization of HCC [21]. Approximately 20 min after the injection, the USCAs are completely eliminated: the gas diffuses into the blood and then exhaled via the pulmonary route, while the Monitor changes in enhancement pattern over time for selected CEUS LR-3 or CEUS LR-4 observations. Differentiate tumor in vein ("tumor thrombus") from bland thrombus. shell components are metabolized by the liver or filtered by the kidney [22]. USCAs are generally safe and well tolerated with a safety profile better than or similar to CT and MRI contrast media [23]. They are not nephrotoxic and may be used even in patients with severe renal failure, renal obstruction, or chronic obstructive pulmonary disease. Hence, there is no need of laboratory tests for assessing renal function before administering USCAs.
Currently, in many clinical settings, CEUS is recommended as pivotal imaging tool in the diagnostic workup of liver FLLs, including HCC, also considering its favorable cost-benefit ratio when compared with crosssectional imaging techniques [24][25][26][27]. In a recent metaanalysis, CEUS showed excellent diagnostic accuracy in differentiating malignant from benign FLLs with pooled sensitivity of 0.92, pooled specificity of 0.87, and diagnostic odds ratio of 104.20 respectively [21].
The CEUS cases presented in this paper were acquired by means of various ultrasound equipments: RS80A and RS85, (Samsung Medison, Co. Ltd.), iU22 (Philips Ultrasound, Bothell, Wash, USA), and MyLab Twice (Esaote, Genova, Italy). All of these units were provided with multifrequency convex array probes and contrastspecific imaging software.   and data collection for CEUS exams in patients at risk for developing HCC [28]. CEUS LI-RADS lexicon integrates with the previously released CT/MRI LI-RADS lexicons, and it is intended to allow the radiologists to (1) use consistent terminology, (2) reduce variability and mistakes in imaging interpretation, (3) promote communication with referring clinicians, and (4) facilitate research and quality assurance [29].

CEUS LI-RADS CEUS LI-RADS system
Noteworthy, although FLL characterization features using CEUS are similar to those of multiphasic CT and/ or MRI, there are still important differences between these techniques, regarding both features and characterization algorithm [30]. CEUS LI-RADS is Baseline US image (a) shows a hyperechoic oval-shaped area sized 2.8 cm in the segment IV in a fatty liver (arrow). At CEUS in the extended portal venous phase (b), the area is constantly isoechoic with respect to the surrounding liver parenchyma, as well as throughout the vascular study (arrow) intended for the use with purely intravascular microbubble contrast agents-such as Lumason® (in USA)/Sono-Vue® (outside USA) and Definity® (in USA, Canada)/ Luminity® (outside USA, Canada)-which affects washout and "capsule" characterization [11,31,32]. Actually, CEUS washout is true washout. On the other hands, CEUS does not depict "capsule"; hence, "capsule" is not a CEUS major feature. CEUS usually does not depict vascular pseudo-lesions such as arterioportal shunts, a frequent cause of diagnostic confusion on CT and MRI: as consequence, any CEUS enhancing observation is a true lesion [33].
Of note, the use of a combined blood pool and Kupffer cell agent (Sonazoid®) is not contemplated in FLL characterization using CEUS LI-RADS [28].
When is CEUS LI-RADS categorization system indicated?
CEUS LI-RADS must be applied only in patients at high risk for developing HCC (cirrhosis, chronic hepatitis B, current or prior HCC, adult liver transplant candidates, and recipients after transplant). CEUS LI-RADS must not be applied to patients without the abovementioned risk factors or < 18 years old. Table 1 lists the man indications of CEUS LI-RADS in patients at high risk for HCC [28].

CEUS LI-RADS reporting and categories
According to CEUS LI-RADS criteria, the two major features of HCC are (1) arterial phase enhancement (not rim or globular peripheral) and (2) washout. Not surprisingly, CEUS sensitivity in the observation of arterial hypervascularity from nodules in liver cirrhosis has been showed to be significantly higher than that of CT/MRI [34][35][36].

Washout
Washout is defined as a reduction in enhancement in whole or in part in comparison with the liver resulting in hypoenhancement. This latter may begin during or after arterial phase. Furthermore, CEUS characterization of washout requires assessment of its onset (late vs. early) and degree (mild vs. marked), not just its presence. Actually, early (< 60 s) and/or marked washout is a major feature for LR-M [37]. On the other hand, late (≥ 60 s) and mild washout is a major feature for HCC [38].
The degree of washout is defined "mild" when the nodule enhances less than liver, but not some enhancement persists. If this persistent enhancement disappears after 2 min, the degree of washout is still considered mild, even if the nodule eventually becomes "punchedout." On the other hand, the degree of washout is defined "marked" when the nodule lacks of any contrast enhancement within 2 min after contrast injection: the observation appears black or "punched out." The ancillary imaging features can be taken into account for category adjustment when category classification is not definite and, as stated by ACR, they can be The presence of patent veins or the presence of thrombosis must be assessed as well [28]. Currently, there are eight CEUS LI-RADS diagnostic categories with related imaging work-up suggestions (Fig. 1). In particular, categories from 1 to 5 include nodules with increasing probability of malignancy. Of note, a one-toone correspondence between such categories and histologic progression or grade of cirrhosis-associated nodules does not exist [39]. As consequence, no cirrhotic nodule is included in LR-1 and many HCCs might be categorized LR-4 or lower. The LR categorization impact on the imaging workup options as well, as described in Table 2.

How to apply CEUS LI-R-RADS system?
If after the injection of microbubble contrast agent, any observation results not assessable due to image degradation or omission, CEUS LR-NC (not categorizable) must be used. In this case, information about the cause technical limitations or artifacts should be reported and further work-up advice should be also provided, such as repeat CEUS or perform alternative imaging modality (i.e., CT and/or MRI) within 3 months (Table 2).
CEUS LR-1 and 2 categories include definitely and probably benign observations, respectively: in particular, LR-1 includes three main observation types: (1) cyst, (2) hemangioma, (3) fat deposition/sparing. A liver cyst is defined, as elsewhere in the body, as an anechoic lesion with increased posterior acoustic through transmission showing no contrast enhancement in any phase. Although simple cysts are easily detected and characterized even without the use of any contrast agent, CEUS may be of particular value in the characterization of more complex appearing lesions on B-mode US, showing their complete avascularity (Fig. 2) [8,15]. Hemangioma is often recognized as a hyperechoic lesion, but it may present variable echogenicity on B-mode US [40]. CEUS easily depicts a typical peripheral globular enhancement in arterial phase followed by progressive centripetal fillin and iso-or hyperenhancement in portal venous and late phase (Fig. 3) [41,42]. The filling may be complete or partial depending on lesion size and/or the presence of mixoid or fibrotic degeneration [43]. Hepatic fat deposition/sparing is defined as nonmasslike, nonspherical, hyper/hypoechoic area of parenchyma in a characteristic location for fat deposition/sparing. Characteristic areas include liver parenchyma nearby the gallbladder and anterior to the right portal vein in segment 4. Hepatic fat deposition/sparing shows isoenhancement to the liver in all phases [44][45][46]. If the hyper/hypoechoic area is not in a characteristic location for fat deposition/sparing, categorize as CEUS LR-2 (see below) (Fig. 4). In case of detection of isoenhancing nodule at CEUS, observation should undergo CEUS LR-2 classification if solid nodule < 10 mm (Fig. 5), whereas if isoenhancing nodule is ≥ 10 mm, it should be categorized as CEUS LR-3 (see below). On the other hand, LR-3 nodules with interval size stability for more than 2 years can return to LR-2. These small nodules are probably typical regenerative or lowgrade dysplastic nodules [47]. Any isoenhancing observation of any size, nonmasslike and without typical appearance of hepatic fat deposition or fat sparing, should be also categorized as LR-2 (Fig. 6).
Any nodule not showing any APHE nor washout must be categorized as CEUS LR-3 regardless of size (Fig. 7). A nodule smaller than 2 cm, without any APHE but showing late and mild washout, should be also assigned to CEUS LR-3 category. On the other hand, any nodule larger than 2 cm, without any APHE but showing late and mild washout, must be assigned to CEUS LR-4 category.
Nodules showing APHE (not rim or peripheral globular) without washout of any type should be categorized, depending on size, as CEUS LR-3 (when the nodule is smaller than 10 mm) or CEUS LR-4 (≥ 10 mm) respectively (Fig. 8). At the same time, nodules showing APHE (not rim or peripheral globular) but presenting with late and mild washout should be categorized, depending on size, as CEUS LR-4 (when the nodule is smaller than 10 mm) or CEUS LR-5 (≥ 10 mm) respectively (Fig. 9).
In LR-M category, any nodule of any size should be included, which may show any of the following criteria [55-60]: 1. Rim APHE: "ring-like" APHE in which enhancement is most evident at the periphery of the nodule (Fig. 10); 2. Early (< 60 s) washout: temporally defined subtype of washout in which onset is within 60 s from contrast injection. Usually marked in degree (Fig. 11); 3. Marked washout.
At CEUS, the vast majority of malignant nodules typically show washout, including liver metastases, intrahepatic cholangiocarcinoma (ICC), and other tumors with  [61][62][63][64][65]. Hence, to maintain specificity for HCC, CEUS characterization of washout requires assessment of its "onset" and "degree," not just its presence. As consequence, observations with late and mild washout may be categorized as CEUS LR-3, LR-4, or LR-5. Nodules with early or marked washout should be categorized LR-M. ICC may be typically included in this category in a cirrhotic liver.
Finally CEUS LR-TIV (definite tumor in vein) includes observation of enhancing tissue within a vein, independently from the detection of a coexisting liver tumor. Tumoral invasion of veins must be differentiated from bland thrombus [66]. To this purpose, the arrival time of microbubble contrast agent to the vein helps to distinguish tumor in vein from bland thrombus [67]: Bland thrombus shows lack of vascularization (Fig. 13). The proximity with any liver mass may help in etiology definition. In particular, if TIV is contiguous or associated with any LI-RADS 4 or 5 lesions, tumor in vein is probably or definitely attributable to HCC, whereas if TIV is near LR-M, it is probably due to non-HCC malignancy. If no masses are detected, etiology is undetermined.

HCC and CEUS LI-RADS: final considerations
CEUS is currently recommended as an adjunct tool in the imaging work-up of HCC, either in the LI-RADS lexicon or in other international guidelines, with encouraging results also in terms of cost-benefit analysis [24,68,69]. Of note, there is still lack of consensus among different Scientific Societies regarding the precise role of CEUS in the diagnostic algorithm for the characterization of HCC. On one hand, various scientific societies, including ACR and Japanese, Italian, German, and British, suggest the use of CEUS in the diagnostic algorithm of HCC in their guidelines (www.webaisf.org, www.drg.de, and www.nice.org.uk, respectively). In the latest version of European Association for Study of Liver (EASL) guidelines on the management of HCC, CEUS is also considered a diagnostic tool for HCC as well as CT and MRI [68]. On the other hand, other Korean and American Societies, such as the Korean Liver Cancer Study Group, the American Association for the Study of Liver Diseases, and the Organ Procurement and Transplantation Network, suggest the use of CT and MR only [68,69]. Further refinement may allow a desirable and better uniformity in international guidelines.