Integration of Contrastenhanced. Multimodality Approach to Imaging of Nodules in a Cirrhotic Liver: How I Do It 1

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1 This copy is for personal use only. To order printed copies, contact Integration of Contrastenhanced US into a Multimodality Approach to Imaging of Nodules in a Cirrhotic Liver: How I Do It 1 Reviews and Commentary n How I Do It Patricia C. Jo, MD Hyun-Jung Jang, MD Peter N. Burns, PhD Kelly W. Burak, MD Tae Kyoung Kim, MD Stephanie R. Wilson, MD Accurate characterization of cirrhotic nodules and early diagnosis of hepatocellular carcinoma (HCC) are of vital importance. Currently, computed tomography (CT) and magnetic resonance (MR) imaging are standard modalities for the investigation of new nodules found at surveillance ultrasonography (US). This article describes the successful integration of contrast material enhanced US into a multimodality approach for diagnosis of HCC and its benefits in this population. The application of contrast-enhanced US immediately following surveillance US allows for prompt dynamic contrast-enhanced evaluation, removing the need for further imaging of benign lesions. Contrast-enhanced US also provides dynamic real-time assessment of tumor vascularity so that contrast enhancement can be identified regardless of its timing or duration, allowing for detection of arterial hypervascularity and portal venous washout. The purely intravascular nature of US contrast agents is valuable as the rapid washout of nonhepatocyte malignancies is highly contributory to their differentiation from HCC. The authors believe contrast-enhanced US provides complementary information to CT and MR imaging in the characterization of nodules in high-risk patients. q RSNA, 2017 Online supplemental material is available for this article. 1 From the Department of Radiology (P.C.J., S.R.W.) and Department of Medicine, Division of Gastroenterology (K.W.B., S.R.W.), Foothills Medical Centre, University of Calgary, St NW, Calgary, AB, Canada T2N 2T9; Department of Medical Imaging, Toronto General Hospital, University of Toronto, Toronto, Ont, Canada (H.J.J., T.K.K.); and Department of Imaging Research, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ont, Canada (P.N.B.). Received August 26, 2015; revision requested September 28; revision received January 6, 2016; accepted January 27; final version accepted February 3; final review by author, December 2. Address correspondence to S.R.W. ( stephanie.wilson@ahs.ca). q RSNA, 2017 Radiology: Volume 282: Number 2 February 2017 n radiology.rsna.org 317

2 Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide (1). The incidence and mortality of HCC continue to rise in Western and European countries (2 5). Historically, the incidence of HCC correlated with the geographic distribution of hepatitis B virus and hepatitis C virus infection. However, effective vaccination strategies and improved antiviral medications have substantially altered the incidence and mortality of HCC in Asian countries (6 9) and elsewhere. Today, alcohol and nonalcoholic fatty liver are of increasing importance. Regardless, Essentials nn Immediate characterization of benign liver lesions in a high-risk patient with contrast-enhanced US obviates referrals and further imaging, while reducing patient anxiety. nn Arterial phase hypervascularity without washout on CT or MR images, thought to represent vascular shunting or possibly hepatocellular carcinoma (HCC) variant without washout, may be resolved at contrast-enhanced US, as shunts generally do not show on contrast-enhanced US scans whereas an HCC will show a baseline nodule with appropriate vascular change. nn As contrast-enhanced US is a real-time dynamic scan, vascularity changes in liver nodules are shown, regardless of their timing or duration. nn The purely intravascular nature of microbubble contrast agents results in rapid strong washout of nonhepatocyte tumors such as cholangiocarcinoma, contributing to their accurate diagnosis and differentiation from HCC. nn Contrast-enhanced US benefits extend beyond nodule characterization and include evaluation of local treatment sites in the posttreatment liver and characterization of portal vein thrombosis. HCC develops almost exclusively in those with cirrhotic liver disease and approximately 4% 30% of those with cirrhosis will develop HCC (10). Arguments for HCC imaging surveillance are compelling. A well-defined risk group for HCC defines the screening population. Without surveillance, patients are usually diagnosed late in the course of the disease; advanced stages of HCC carry a dismal prognosis with few treatment options. Surveillance imaging allows for detection of small nodules at a time when potentially curative treatments can be offered. A retrospective study by Wong et al showed survival benefit for patients screened for HCC compared with those presenting with symptoms (11). Presumably, this is due to a greater number of patients undergoing potentially curative treatments such as liver resection or transplantation in the screened group. To date, the only randomized controlled trial looking at biannual screening with alpha fetoprotein and ultrasonography (US) showed a significant reduction in mortality (12). The recommended surveillance procedure is US imaging performed every 6 months. Once a suspicious new or growing nodule is detected, further work-up is performed with contrast material enhanced imaging. Currently, the Asian Pacific Association for the Study of the Liver, Canadian Association for the Study of the Liver, Italian Association for the Study of Liver, and Japanese Society of Hepatology include contrast-enhanced US in recommendations for diagnosis of HCC (13 16). Recently, the American College of Radiology introduced the Liver Imaging Reporting and Data System, or LI-RADS, contrast-enhanced US in August 2016 for standardization of reporting and management of HCC ( LIRADS). Practice guidelines by the American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), and United Network for Organ Sharing (UNOS) recommend dynamic contrast-enhanced computed tomography (CT) or magnetic resonance (MR) imaging only for evaluation of new nodules (17,18). Nonetheless, contrastenhanced US has been integrated into our HCC management practice for more than 10 years and has been an invaluable tool in the multimodality approach to characterization of cirrhotic nodules. During this time, we have been impressed by the unique advantages afforded by contrast-enhanced US that allow contributions to the management of HCC that are otherwise not possible. In this How I Do It article, we show the process by which we select cases for contrast-enhanced US, highlight the advantages, and provide explanations for their occurrence. Technique Contrast-enhanced US involves the use of microbubble contrast agents that allow detection of blood flow within the liver at the vascular perfusion level (19). The microbubbles consist of small spheres of a perfluorocarbon gas stabilized by a thin lipid shell. The microbubbles are approximately 3 5 mm in diameter, which is slightly smaller than a red blood cell but much larger than the molecules used in CT and MR imaging techniques. Given their relatively large size, they do not pass through the vascular endothelium into the interstitial space and are, therefore, purely intravascular. The contrast agent Definity (Lantheus Medical Imaging, Billerica, Mass) has been approved in Canada for liver imaging since 2002 and is now used in routine clinical practice at our institution. Lumason (Bracco Diagnostics, Monroe Township, NJ) has recently been approved for focal liver lesions in the United States and is approved Published online /radiol Radiology 2017; 282: Content codes: Abbreviations: AASLD = American Association for the Study of Liver Diseases EASL = European Association for the Study of the Liver FNH = focal nodular hyperplasia HCC = hepatocellular carcinoma ICC = intrahepatic cholangiocarcinoma Conflicts of interest are listed at the end of this article. 318 radiology.rsna.org n Radiology: Volume 282: Number 2 February 2017

3 in Europe and parts of Asia under the name SonoVue (Bracco Imaging, Milan Italy). Sonazoid (Daiichi-Sankyo, GE Tokyo, Japan), a microbubble agent with similar properties to Definity and SonoVue, also includes imaging in the hepatobiliary (Kupffer) phase and is approved today only in Japan. The 1.2-mL bottle of Definity is shaken in a vial shaker, activating the contrast agent and increasing the volume of bubbles to 1.8 ml. Intravenous access with a 22- or 24-gauge catheter in an antecubital vein is obtained and a three-way stopcock arrangement is used. Successful technique includes proper injection of the microbubbles, as the entire syringe of fragile bubbles can be destroyed if the bubbles are mishandled during their withdrawal from the vial or if pressure is applied against a closed stopcock. The contrast agent is injected intravenously by using established doses to a maximum of 10 ul/kg followed immediately by a saline flush. Generally, a liver study for focal mass evaluation might include two to four injections of 0.2 ml per injection. These are separated by an interval of several minutes for clearance of the bubbles from the field of view (Movie [online]). The equipment to perform contrast-enhanced US is not standard and requires specialized US capabilities, generally available on high-end systems. Dual-screen imaging is used for grayscale anatomic guidance alongside the contrast-only image. Specialized US software uses a subtraction technique called pulse inversion imaging to make the preinjection liver appear black. Low-mechanical-index imaging is used to induce a stable, nondisruptive oscillation of the microbubble, allowing preservation of the microbubble population for several minutes of scanning (20). The scanning technique required for contrast-enhanced US is not difficult, though there is a recognized learning curve for acquisition of the high skill level necessary to perform good examinations, especially on a cirrhotic liver. Patient position, breathing, and cooperation need to be established prior to injection. Contrast-enhanced US may be performed in most patients with quiet breathing. Failure of a contrast-enhanced US examination due to motion artifact is virtually unheard of. Evaluation in the sagittal plane is preferred so that the lesion remains in the field of view during quiet respiration. Evaluation begins with a thorough gray-scale US assessment for baseline nodules with targeted contrastenhanced US performed for suspicious nodules. The timer is started to coincide with the microbubble injection. Because of the very small volume of contrast agent per injection, this is best timed with the initiation of the saline flush. Cine loop storage begins after visualization of the first bubble in the field of view. The study requires continuous monitoring of the wash-in of contrast agent guaranteeing that peak arterial enhancement is always included in the movie file. Following this acquisition, intermittent brief insonation of the nodule is performed throughout the portal venous phase to preserve the bubble population until washout is demonstrated. If contrast enhancement is persistent throughout the portal venous phase, imaging continues into the late phase (up to 300 seconds) and in rare cases, imaging beyond 300 seconds may reveal very late washout. Depending on our level of suspicion, an additional small injection (0.2-mL aliquot) is performed with delayed imaging only for nodules with confirmed arterial hypervascularity but questionable washout. This is performed with short-interval scanning at 3, 4, and 5 minutes. As continuous US scanning destroys the microbubble population over time, short-interval scanning in the late phase only prevents bubble destruction and removes the possibility of false washout. After evaluation of target lesions, sweeps of the entire liver are performed in the portal venous phase to look for other regions of washout as a manifestation of malignancy that may not be evident at baseline. If a washout lesion is identified in the portal venous phase, evaluation for a baseline gray-scale nodule is performed along with another small injection to look for arterial hypervascularity. The additional injection may be performed on top of a washout lesion in the portal venous phase without waiting for clearance of bubbles to assess for arterial enhancement. Portal and hepatic vein evaluation is an essential component of US of an at risk liver because of the considerable implications of tumor thrombus in the veins. Contrast-enhanced US of the veins is performed when thrombus is identified on the baseline US scan or is suspected at prior imaging with CT or MR. Contrastenhanced US evaluation of portal vein thrombosis begins with focused imaging of the area in question. The presence of arterial hypervascularity or visualization of vessels within thrombus confirms malignant portal vein tumor thrombus. Meticulous technique is required to correlate any identified enhancement within a portal vein thrombus to the early arterial phase for confident determination of neovascularity within the tumor. Nonocclusive thrombus or recanalized chronic bland thrombus, alternately, may show later enhancement not within the arterial phase. Additional findings of disruption of the vessel wall or parenchymal invasion are also helpful (21,22). Washout of tumor thrombus may also be seen in the portal venous phase. In patients with prior treatment, baseline US and contrast-enhanced US target treatment sites looking for residual or recurrent tumor evidenced by classic hypervascularity and washout. As treatment of any liver progresses, we recognize decline in the quality of many US examinations as the heterogeneity of the parenchyma increases and often the acoustic accessibility of the liver deteriorates. In such cases, CT and MR are generally superior for global assessment of the treated liver. However, with these examinations, hypervascular regions may be indeterminate and US with contrast-enhanced US targeted at the CT or MR imaging abnormality is invaluable to select those amenable to further ablative or other therapies. Multiplicity of lesions is also a common scenario. The general view is that with the smaller field of view of US, a global perspective cannot be achieved. Radiology: Volume 282: Number 2 February 2017 n radiology.rsna.org 319

4 However, with a planned strategy, multiple lesions and treatment sites can be evaluated in the arterial and portal venous phase at contrast-enhanced US. Frequently, we evaluate three or even more nodules, each with a separate dedicated injection of contrast agent, to assess the enhancement characteristics of all nodules in question. Further, the portal venous and late phase features of many nodules can be assessed from a single injection as the observations are enduring and provide sufficient time to evaluate most, if not all, of the liver for washout following a single injection. Primary US Surveillance in High-Risk Patients At our institution, the majority of patients undergoing dynamic contrastenhanced imaging for characterization of cirrhotic nodules are from primary or posttreatment surveillance. The remainder are either symptomatic or have incidental nodules found at examinations performed for another reason. Regardless of presentation, almost all patients evaluated for a new suspicious nodule have initial imaging with US. Primary surveillance US is performed every 6 months. Surveillance US comprises a thorough gray-scale evaluation of the entire liver with positional variation in supine and left lateral decubitus positions. A standard low-frequency abdominal probe is used for sweeps of the entire liver in the transverse and sagittal planes. A high-frequency probe is also used to assess the superficial contour of the liver for subcapsular lesions. Gray-scale and color Doppler evaluation are performed of the portal and hepatic veins to ensure patency. Cirrhotic livers often have innumerable nodules that may be hypo-, iso-, or hyperechoic. Identification of a suspicious nodule is based on larger size or altered echogenicity compared with background liver (either hypoechoic or hyperechoic), well-circumscribed nodules that appear masslike, or nodules that cause an obvious contour abnormality on the liver surface. Overall, nodules are considered suspicious when they have an increase in size or conspicuity as compared with background liver. According to the AASLD guidelines, follow-up US at 3 months is recommended for suspicious nodules less than 1 cm in size. For patients with a nodule 1 cm or larger in size or one that has undergone interval growth, hepatology referral is recommended for further diagnostic work-up. Although contrast-enhanced CT and MR imaging are recommended under current AASLD and EASL guidelines, we believe that contrast-enhanced US should also be considered as an option for the first imaging test for the reasons that follow. Characterization of Cirrhotic Nodules from Surveillance US Noninvasive diagnosis of focal liver masses with contrast-enhanced US imaging is based on well-recognized enhancement patterns of known liver tumors (Fig 1). In this patient population, the imaging objective is correct noninvasive detection and diagnosis of HCC with correct exclusion of masses of other explanation. The evolution of HCC in a cirrhotic liver occurs by means of a stepwise process of hepatocarcinogenesis (23,24). In 1995, the International Working Party developed terminology to unify nomenclature for the spectrum of cirrhotic nodules (25). It ranges from the benign regenerative nodule, low- and high-grade dysplastic nodules, through to malignant HCC (25). Transition of the nodule is accompanied by gradual vascular changes characterized by loss of the normal portal venous and hepatic arterial blood supply and simultaneous development of neoplastic arteries (26,27). Regenerative nodules are either hypoechoic or hyperechoic relative to background liver parenchyma or may be isoechoic with a nodular contour on gray-scale US images. As they maintain the normal portal venous and arterial blood supply, it is expected that regenerative nodules enhance similarly to liver parenchyma with no hypervascularity or washout. Premalignant dysplastic nodules are variable in their enhancement and may be hypervascular, isovascular, or hypovascular, reflecting the spectrum of vascular changes in the transition of the nodule from low to highly dysplastic to well-differentiated HCC. However, we recognize that the nodule with transient hypovascularity before becoming isovascular may represent dysplastic nodule or welldifferentiated HCC (28,29), requiring biopsy for differentiation. There is recognized overlap in the imaging appearances of these entities for all modalities (30). Consistent with the evolution of HCC by hepatocarcinogenesis, the classic enhancement pattern of HCC is arterial phase hypervascularity and portal venous phase washout (26). However, in studies from contrast-enhanced CT, MR imaging, and US, there is recognition of variations in enhancement patterns, including no arterial hypervascularity and late, weak, or absent washout (23,28,31 33). Therefore, knowledge of the vascular changes that occur in association with this malignant transformation is the key to the noninvasive diagnosis of HCC. Immediate Characterization of Benign Clinically Unimportant Nodules Contrast-enhanced US can be used to accurately differentiate benign from malignant lesions, often with similar performance to that of CT and MR imaging (34,35). A study performed by Khalili et al (36) looking at new nodules in high-risk patients showed 78 of 138 (57%) nodules were immediately characterized as benign (eg, hemangiomas) or showed stability for at least 18 months. This suggests that many lesions that require additional evaluation have a benign etiology, which also includes benign cirrhotic nodules such as regenerative and dysplastic nodules. With contrast-enhanced US, benign masses show characteristic enhancement patterns in the arterial phase. The unique advantage of this technique not afforded by other imaging modalities is its ability to characterize the dynamic wash-in of contrast agents. Maximum intensity projection technique may be used to further improve characterization of vascular morphology and direction of intratumoral perfusion (37). As 320 radiology.rsna.org n Radiology: Volume 282: Number 2 February 2017

5 Figure 1 Figure 1: Schematic shows the typical enhancement patterns of common benign and malignant lesions in the cirrhotic liver. RN = regenerative nodule, DN = dysplastic nodule, AP = arterial phase, PVP = portal venous phase, LP = late phase. a result, contrast-enhanced US can accurately depict the classic enhancement characteristics of common benign liver lesions such as cavernous hemangioma and focal nodular hyperplasia (FNH) with high sensitivity and specificity (35). In a patient without risk factors for HCC, a diagnosis of hemangioma is generally accepted for small uniformly echogenic lesions seen on US images, whereas further dynamic imaging is required for patients with chronic liver disease or cirrhosis because dysplastic nodules and HCC can appear hyperechoic if there is abundant intranodular fat (26,38,39). On contrast-enhanced images, hemangiomas typically show nodular peripheral enhancement in the arterial phase and progressive centripetal enhancement in the portal venous phase. However, a variant of small hemangiomas, known as flash-filling hemangiomas, may show homogeneous arterial hypervascularity on CT or MR images, making differentiation from HCC challenging. Contrast-enhanced US, however, with real-time evaluation of the wash-in phase of contrast enhancement, allows for visualization of the peripheral nodules and the characteristic centripetal enhancement of both rapid- and slow-filling hemangiomas. This rapid filling is often best appreciated on a frame-by-frame review of a cine file of the wash-in of contrast material. FNH and FNH-like lesions have been described in cirrhotic livers; however, these remain an infrequent diagnosis in patients with chronic liver disease (40 42). With contrast-enhanced US, these lesions show characteristic stellate vascularity and centrifugal filling with a strong tendency of sustained enhancement (43). The characteristic arterial phase enhancing pattern of hemangioma and FNH can help differentiate these lesions from the variant of HCC that does not demonstrate washout. Wash-in of HCC at contrastenhanced US may show dysmorphic irregular vascular morphology or homogenous enhancement (28). Hepatocellular adenoma most commonly occurs in women with long-term oral contraceptive pill use and in those with glycogen storage disease. Its recognized increased association with HCC places affected patients in a surveillance population. Adenoma often demonstrate hypervascularity in the arterial phase and either demonstrate sustained enhancement or soft washout in the portal venous phase (35,43). Washout can be problematic in differentiating adenoma from HCC with any modality and history is of great importance in this instance. Biopsy may be required. Immediate characterization of a benign mass with contrast-enhanced US at the time of initial US surveillance can remove the requirement for further imaging with another modality, saving considerable resources and reducing patient anxiety (44). If a nodule cannot be confirmed as benign at Radiology: Volume 282: Number 2 February 2017 n radiology.rsna.org 321

6 Figure 2 Figure 2: An occult lesion on CT and MR images is shown in a 56-year-old man with hepatitis B virus. (a) Surveillance US image shows a 1.6-cm nodule in the tip of the right lobe of the liver. Contrast-enhanced US images of the nodule demonstrate classic enhancement characteristics of HCC with (b) arterial hypervascularity (arrow) and (c) portal venous washout (arrow). (d) The patient underwent two subsequent gadolinium-enhanced MR examinations (arterial phase images shown) and one CT scan showing no nodule. At 6 months, MR imaging with a hepatobiliary contrast agent (gadoxetate disodium) was performed at our suggestion. This examination showed no nodule on precontrast images or arterial or portal venous phase postcontrast images. (e) The nodule only becomes apparent on the hepatobiliary phase (arrow). At liver resection, the nodule is moderately differentiated HCC. contrast-enhanced US, further work-up with CT or MR imaging is indicated. On the other hand, if a nodule is characteristically malignant at initial contrastenhanced US examination, then MR imaging and CT can be expedited for staging and treatment planning. Avoidance of Misregistration of Nodules A relatively infrequent but important problem that has been encountered in our practice is misregistration between modalities. This occurs when a suspicious nodule identified during screening US is not the same nodule that is evaluated on CT or MR images. This can become especially problematic in patients with innumerable nodules. Misinterpretation of a nodule on CT or MR images may have negative consequences if a nodule is characterized as benign but does not actually represent the new or growing index nodule on US images. This is avoidable by performance of contrast-enhanced US at the time of surveillance. CT and MR Imaging Occult Nodules Nodules may be occult at all imaging modalities. Reasons for this are uncertain but are likely related to the contrast resolution properties of the imaging modalities themselves. Contrastenhanced US is useful in this regard for the occasional situation in which a nodule at surveillance US is occult at CT or MR imaging. In situations in which the index nodule is not identified on CT and MR images, evaluation of the nodule with contrast-enhanced US is critical as it would not be appropriate to assume that the nodule is benign or does not exist because of a negative CT or MR imaging study. In our experience, some of these nodules prove to be HCC at 322 radiology.rsna.org n Radiology: Volume 282: Number 2 February 2017

7 Figure 3 Figure 3: Nodule-in-a-nodule lesion in a 66-year-old man with hepatitis C virus. (a) Gray-scale US image shows a nodule-in-a-nodule appearance of an echogenic nodule within a larger hypoechoic nodule, overall measuring 4.2 cm. (b) Contrast-enhanced US image shows arterial phase hypervascularity of the central echogenic nodule and hypovascularity of the surrounding nodule. (c) Portal venous phase image shows washout of the central echogenic nodule (arrowhead) and isovascularity of the outer nodule (arrow), consistent with HCC within a dysplastic nodule. (d, e) CT scans show (d) a fat-containing nodule only measuring 2.7 cm with arterial phase hypervascularity (arrow) and (e) portal venous phase washout (arrow). CT images do not show the surrounding dysplastic nodule resulting in size discordance. subsequent contrast-enhanced US imaging (Fig 2). Fusion imaging with US and contrast-enhanced US may also be helpful in identifying nodules and avoiding misregistration (45,46). Nodule in a Nodule Another potential benefit of performing contrast-enhanced US as the initial contrast-enhanced imaging examination is related to the entity of a nodule in a nodule, which represents a focus of HCC arising within a dysplastic nodule (47 49). Classically, the nodule-ina-nodule appearance is arterial phase hypervascularity and portal venous washout of the central nodule representing HCC, while the outer dysplastic nodule or well-differentiated HCC shows arterial hypovascularity and portal venous isovascularity. This imaging appearance can be shown on all modalities; however, in our experience, nodule-in-a-nodule appearance may be shown on a contrastenhanced US study while CT or MR imaging may not depict the central focus of HCC or the outer dysplastic nodule. When a small focus of arterial hypervascularity is identified within a dysplastic nodule on a contrast-enhanced US study, but CT or MR imaging does not demonstrate the small hypervascular focus, this may be attributable to the high contrast agent sensitivity of contrast-enhanced US. Alternatively, CT or MR may demonstrate the hypervascular HCC while not appreciating the surrounding dysplastic nodule on pre- or postcontrast images or both (Fig 3), similarly related to differences in contrast resolution and contrast agent sensitivity, respectively. Overall size of the mass is important in treatment planning, and in these cases, it would be prudent to treat both the HCC and the high-grade Radiology: Volume 282: Number 2 February 2017 n radiology.rsna.org 323

8 Figure 4 Figure 4: Our recommended integration of contrast-enhanced US (CEUS) into the AASLD guidelines for the diagnosis of HCC. Orange indicates AASLD guidelines for HCC management of a nodule found at surveillance US. Green indicates our integration of contrast-enhanced US and includes the observations, their subsequent diagnoses, and their management. There are several pathways to contrast-enhanced US: The essential pathways (solid green lines) are performed for negative or indeterminate nodules from CT or MR imaging, providing more noninvasive diagnoses prior to consideration of biopsy. The optional pathways (dotted green lines) show contrast-enhanced US performed as the initial imaging modality following nodule detection, obviously dependent on availability and expertise, and follow-up imaging of benign cirrhotic nodules. dysplastic nodule. In our institution, any nodule larger than 5 cm is contraindicated for radiofrequency ablation, with consideration of other treatment options for all lesions larger than 3 cm. Indeterminate CT or MR Findings In addition to immediate contrastenhanced US characterization of new nodules from surveillance US, contrastenhanced US is also helpful in evaluation of indeterminate masses on CT and MR images, and we have integrated contrast-enhanced US into the preexisiting AASLD guidelines for HCC diagnosis using a multimodality approach (Fig 4). There are two quite different situations that commonly result in an indeterminate CT or MR finding in our practice. First, CT or MR imaging may show vascularity change on postcontrast images without a corresponding nodule on baseline unenhanced CT or MR images, raising the possibility of a pseudolesion such as a vascular shunt. Alternatively, there may be an obvious concerning mass that does not demonstrate the classic enhancement features for HCC and is therefore indeterminate. 324 radiology.rsna.org n Radiology: Volume 282: Number 2 February 2017

9 Resolution of these nodules may be made by means of biopsy as recommended by the AASLD guidelines. In our institution, the choice of contrastenhanced US frequently provides noninvasive resolution. Pseudolesions Arterioportal venous shunts commonly develop in patients with cirrhosis and may or may not be associated with tumor such as HCC (50). On CT and MR images, nontumorous arterioportal venous shunts manifest as transient focal areas of arterial hypervascularity with no washout in the portal venous phase (50 53). As a result, the small subset of HCCs that do not show washout can be misinterpreted as vascular shunts. Conversely, vascular shunts may be misinterpreted as HCC on CT and MR images. This is usually not problematic with contrast-enhanced US, as these lesions are generally not appreciated. Although the explanation for this is not well understood, we hypothesize that small vascular shunts are not well seen at contrast-enhanced US due to its high contrast agent sensitivity resulting in very rapid visualization of the contrast agent filled arterial branches in the wash-in phase followed by early homogeneous parenchymal enhancement. On the other hand, the background liver shows minimal enhancement and remains relatively dark in the arterial phase on CT and MR images, allowing small early filling vascular shunts to be more easily perceived. Studies have shown that the majority of small early-enhancing lesions on CT or MR images without washout are stable or decrease in size on subsequent imaging studies; therefore, presumably these represent a benign entity rather than HCC (54 57). Thus, the isolated finding of arterial hypervascularity on CT or MR images is much less specific for HCC and is the reason why washout is essential to confirm HCC with these modalities. Arterial hypervascularity at contrast-enhanced US, however, without a typical wash-in pattern of previously discussed benign lesions, is highly specific for HCC with or without washout in a high-risk patient (29,58). Resolution of questionable vascular shunts on CT or MR images is one of the greatest strengths of contrastenhanced US as demonstration of a nodule on a baseline US study confirms the presence of a true lesion whereas lack of a corresponding baseline nodule at US is supportive evidence that the abnormality represents a pseudolesion. Absence of Arterial Phase Hypervascularity Accurate depiction of arterial phase hypervascularity is vital to distinguish HCC from dysplastic nodules, although there is considerable overlap between the two entities, as described above. Situations arise when there is identification of a nodule on precontrast CT or MR images without arterial phase vascularity. This should motivate other investigation such as contrast-enhanced US (Fig 5). In other instances, portal venous washout may be the only evidence of tumor presence at CT or MR imaging. CT studies have shown that tumor hypervascularity and conspicuity are best shown during the late arterial phase (approximately 35 seconds) when contrast material is seen within the portal veins with minimal enhancement of the hepatic parenchyma (59,60). With CT and MR imaging, timing of the late arterial phase is critical, and multiple techniques serve to optimize imaging at appropriate time points. Regardless of these techniques, these modalities rely heavily on uniform vascular kinetics among patients. However, perfusion abnormalities often exist in the cirrhotic population. Increased resistance in portal venous blood flow and the presence of vascular abnormalities, such as shunts and pseudoaneurysms, can alter transit time (50,61). Mistiming of arterial phase imaging at CT or MR imaging, whether due to failed bolus tracking or lack of individualization of fixed timed delays, may lead to arterial phase images being acquired too early or too late, thereby missing the peak arterial phase enhancement required to show arterial hypervascularity. Occasionally, arterial imaging is performed too early and the majority of contrast material is noted in the large arteries (ie, aorta and celiac axis) (Fig 6). The advantage of contrast-enhanced US, therefore, is the real-time continuous imaging that effectively removes timing as a source for misinterpretation. The second proposed explanation for lack of hypervascularity of a tumor on CT and MR images is related to differences in contrast agent sensitivity. These cases are distinguished from those due to timing of the contrast agent bolus when CT or MR contrast material is seen in the portal veins with minimal enhancement of the liver parenchyma, indicating that imaging has taken place in the appropriate late arterial phase. Contrast-enhanced US has high intrinsic sensitivity. The echo from a single resonant bubble is more than a thousand million times stronger than the echo from a red blood cell (19). Furthermore, the nonlinear acoustic signature of the microbubble echo allows for specialized US imaging techniques, such as pulse inversion, resulting in simultaneous suppression of echoes from tissue (62). The result of this technique is the very high intrinsic contrast between blood and tissue on a contrast-enhanced US image. Absence of Portal Venous Phase Washout In our experience, the most common finding resulting in an indeterminate CT or MR study in our multidisciplinary rounds is a nodule with arterial hypervascularity but no washout (Fig 7). There is abundant variation in the timing of washout in the portal venous and delayed phases. A study looking at the pattern of enhancement of 112 histologically proven HCCs at contrastenhanced US (28) showed the classic enhancement pattern of arterial phase hypervascularity (74 of 77, 96%) and portal venous washout within 90 seconds (72 of 74, 97%) in the majority of moderately differentiated HCC. However, well-differentiated and poorly differentiated HCCs accounted for the majority of atypical enhancement patterns where 25 of 97 (26%) showed washout between 91 and 180 seconds and 21 of 97 (22%) showed late washout between 180 and 300 seconds. Seven of nine (78%) HCCs that showed Radiology: Volume 282: Number 2 February 2017 n radiology.rsna.org 325

10 Figure 5 Figure 5: Absence of arterial phase enhancement at MR imaging in a 39-year-old man with hepatitis B virus and a 3.5-cm mass found at surveillance US. (a) MR image shows a T1-weighted hypointense (arrows) and slightly T2-weighted hypointense (not shown) mass in segment III of the liver. (b) The mass is hypovascular relative to liver parenchyma on the arterial phase MR image (arrows) and remains hypovascular in the portal venous and late phases (not shown). The marked T1-weighted hypointensity and lack of arterial hypervascularity are unusual for HCC; therefore, the mass was reported as indeterminate. Biopsy was recommended. (c) The mass (arrow) is shown on baseline US image. (d,e) Contrast-enhanced US images demonstrate (d) arterial phase hypervascularity (arrow) and (e) late portal venous phase washout (arrow), classic for HCC. After liver resection, the mass is confirmed as moderately differentiated HCC. isoenhancement or persistent hyperenhancement (ie, no washout) were welldifferentiated HCCs. Cholangiocarcinoma In addition to HCC, there is strong evidence that those with cirrhosis and chronic hepatitis C infection are at increased risk for intrahepatic cholangiocarcinoma (ICC), a nonhepatocyte tumor (63,64); mortality rates associated with ICC are increasing (65 67). Differentiation of HCC from ICC is important as a diagnosis of ICC substantially alters treatment and prognosis. Contrast-enhanced US of ICC, as compared with HCC, shows considerable differences in enhancement in both the arterial and portal venous phases, with the former tumor frequently characterized by rim enhancement and rapid strong washout typically before 1 minute, similar to other nonhepatocyte tumors (68 71). HCC, on the other hand, shows arterial phase hyperenhancement followed by slow weak washout. The largest studies looking at the enhancement characteristics of ICC on CT and MR images have typically shown stable or progressive enhancement with no washout in the portal venous phase (72 76). Iodine and gadolinium contrast agents for CT and MR imaging, respectively, are similar in that they diffuse through the vascular endothelium into the tissue interstitium, resulting in the so-called interstitial or equilibrium phase (77 79). The angiogenic tumor vascular endothelium is well known to be hyperpermeable (80), allowing CT and MR contrast agents to diffuse more rapidly into the tumor interstitium, so that washout can be masked in the portal venous phase by interstitial contrast material. 326 radiology.rsna.org n Radiology: Volume 282: Number 2 February 2017

11 Figure 6 Figure 6: Mistiming of arterial phase CT scanning in a 49-year-old man with hepatitis C virus cirrhosis with mass found at surveillance US. (a) Arterial phase CT image with fixed time delay at 35 seconds shows the majority of contrast within the abdominal aorta and celiac axis. No mass is identified in the arterial phase. (b) On the portal venous phase image, there is faint washout of a mass (arrow) measuring 2 cm, resulting in an indeterminate CT. There is a corresponding mass at baseline US, not shown. (c) Contrast-enhanced US shows homogeneous arterial enhancement on image obtained at 20 seconds and washout at 3.5 minutes (not shown). This confirms HCC and demonstrates the advantage of the real-time scanning technique. The mass is biopsy-proven welldifferentiated HCC. There has been controversy around the use of contrast-enhanced US for evaluation of cirrhotic nodules owing to suggestion that HCC enhances similarly to ICC on contrast-enhanced US studies (73). In our experience, progressive or stable enhancement of a mass on CT or MR studies and the discordant finding of rapid washout on contrast-enhanced US studies are highly suggestive of ICC and highlight the additive benefit of a multimodality approach. Nevertheless, biopsy is recommended for all nodules with atypical enhancement characteristics for HCC. Posttreatment Surveillance Following liver resection or local ablative procedures for HCC management, such as radiofrequency ablation or percutaneous ethanol injection, the patient transitions to posttreatment surveillance to assess for tumor recurrence or new tumor development (81). These procedures are performed with the intention of local cure of small early HCCs, although patients remain at risk for recurrence due to their underlying liver disease. Seventy percent of patients will have tumor recurrence within 5 years of surgical resection or radiofrequency ablation (82). Our posttreatment surveillance program includes MR imaging and contrast-enhanced US. MR imaging is performed 1 month after treatment and contrastenhanced US is performed at 3 months. MR imaging and contrast-enhanced US are then alternated every 3 months so that patients are screened with each modality every 6 months for the first 2 years. The rationale for this is based on studies showing that approximately 50% of tumor recurrence following surgical resection occurs within the first 2 years and this may be distinct to later recurrence, which reflects the development of de novo HCC in the setting of cirrhosis (83,84). After the first 2 years, we alternate the scans every 6 months, until the 5-year mark when, if patients remain recurrence free, they are returned to US surveillance every 6 months. Pitfalls of Contrast-enhanced US The limitations of contrast-enhanced US often parallel those of standard US, including difficulty in obese and very large patients as well as penetration problems in those with fatty livers and deep lesions at greater than 10 cm depth from the transducer crystal. The subdiaphragmatic liver is a recognized potential blind area, aggravated further by large patient size. While acknowledging these potential shortcomings, US with contrast-enhanced US does exceptionally well in the majority of our patient population. Patients with very cirrhotic heterogeneous livers on gray-scale US studies can be challenging to evaluate. The response to contrast-enhanced US is somewhat unpredictable in these patients, but many livers become homogeneous in all phases of enhancement, removing concern and requirement to refer on to another modality. An important artifact to be aware of in the interpretation of contrastenhanced US is pseudoenhancement from nonlinear artifact occurring in echogenic objects that are deep in location (85). This is particularly important when evaluating deep nodules or post radiofrequency ablation treatment sites for viable vascularized tumor. Oscillating microbubbles create nonlinear harmonic echoes that are used to image vessels and suppress the echo Radiology: Volume 282: Number 2 February 2017 n radiology.rsna.org 327

12 Figure 7 Figure 7: Questionable pseudolesion in a 64-year-old man with hepatitis B virus. (a) MR image shows no nodule on precontrast T1- and T2-weighted images and a small focus of enhancement in the arterial phase (arrow). (b) No corresponding washout is identified in the portal venous or delayed (shown) phases. This was reported as indeterminate but favored to represent a vascular shunt. (c) Gray-scale US image shows a baseline nodule, essentially excluding the possibility of vascular shunt. (d,e) Contrast-enhanced US images show (d) arterial phase hypervascularity of the nodule and (e) washout, beginning at 3.5 minutes and remaining weak until 6 minutes, confirming that the MR-indeterminate nodule represents HCC. from background tissue using pulse inversion. However, the presence of oscillating microbubbles in vascularized tissue between the transducer and the object of interest creates nonlinear echoes that can give the appearance of enhancement of a deep echogenic lesion relative to background tissue. With regards to treatment sites, this pseudoenhancement typically occurs in the late portal venous phase, progresses over time, and is nonmarginal in location (85). Additionally, in our experience, there may be incomplete suppression of echoes from tissue that is echogenic at baseline grayscale US, resulting in apparent hypervascularity. This pseudoenhancement is seen most often in fatty lesions or severely fatty livers that are echogenic at baseline US. This may falsely mask washout of a fatty lesion or falsely suggest washout of a lesion in a fatty liver. Summary In this article, we discuss the integration of contrast-enhanced US into the multimodality approach for evaluation of nodules in high-risk patients for HCC. As the majority of patients being evaluated for a suspicious nodule undergo initial imaging with US, contrast-enhanced US can provide an immediate one-stop method for confirmatory imaging diagnosis. This can reduce unnecessary referrals and further imaging for benign lesions, including regenerative and dysplastic nodules. Contrast-enhanced US is also invaluable in providing resolution for indeterminate nodules on CT and MR images, especially for the very common situation in which pseudolesions and HCC are concurrently being considered. We believe contrast-enhanced US should be the next imaging step for all CT- and MR-indeterminate nodules before biopsy is undertaken. Acknowledgments: We acknowledge the contributions of Dr Hojun Yu for preparation of the schematic of enhancement patterns of cirrhotic nodules at contrast-enhanced US and the Telehealth services at the Foothills Medical Centre for preparation of the movie. Disclosures of Conflicts of Interest: P.C.J. disclosed no relevant relationships. H.J.J. disclosed no relevant relationships. P.N.B. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: Scientific advisory boards to Supersonic Imagine and Philips Ultrasound. Other relationships: disclosed no relevant relationships. K.W.B. Activities related to the present article: disclosed no relevant relationships. Activities 328 radiology.rsna.org n Radiology: Volume 282: Number 2 February 2017

13 not related to the present article: grants from Bayer, Oncozyme, and Lupin for clinical trials; honoraria for speaking from Astellas, Bayer, and Gilead; personal fees for Advisory boards from Astellas, Gilead, Novartis, BTG International, Lupin, AbbVie, and Merck. Other relationships: disclosed no relevant relationships. T.K.K. disclosed no relevant relationships. S.R.W. disclosed no relevant relationships. References 1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN Int J Cancer 2015;136(5): E359 E Altekruse SF, Henley SJ, Cucinelli JE, Mc- Glynn KA. Changing hepatocellular carcinoma incidence and liver cancer mortality rates in the United States. Am J Gastroenterol 2014;109(4): Bosetti C, Levi F, Boffetta P, Lucchini F, Negri E, La Vecchia C. Trends in mortality from hepatocellular carcinoma in Europe, Hepatology 2008;48(1): elsaadany S, Tepper M, Mao Y, Semenciw R, Giulivi A. 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