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Advances in Clinical Radiology

Contrast-Enhanced Ultrasonography of the Abdomen

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      Keywords

      Key points

      • Contrast-enhanced ultrasonography (CEUS) is performed in dynamic real time with a purely intravascular contrast agent, providing high temporal resolution and sensitive detection of the ultrasonography contrast agent.
      • Characterization of focal masses within the liver and the kidney comprise 2 major applications.
      • CEUS is excellent to resolve indeterminate magnetic resonance or computed tomography scan in the liver and the kidney and elsewhere.
      • Ultrasonography contrast agents are very safe, have no nephrotoxicity, and their imaging requires no ionizing radiation.
      Video content accompanies this article at http://www.advancesinclinicalradiology.com.

      Introduction

      Since its clinical introduction in the 1970s, gray-scale ultrasonography (US) has provided incomparable noninvasive high-resolution evaluation of many organs throughout the body. The subsequent addition of Doppler, with color capability, transformed its usage by additionally showing vascular information about large blood vessels, generally with fast-moving blood. However, US with Doppler did not display blood flow at the capillary level, making imaging evaluations of organ perfusion impossible. Therefore, computed tomography (CT) and magnetic resonance (MR) scan gained a foothold in imaging of all soft tissue organs where the use of contrast-enhanced scans provided a means whereby tissue and tumor characterization were possible.
      Contrast-enhanced US (CEUS), as it is now known, was introduced to clinical practice around 2000, with the approval of second-generation microbubble contrast agents in Europe, Asia, and Canada. For the first time, US evaluation of blood flow at the capillary level was possible and original approvals everywhere were for characterization of focal liver masses [
      • Tang M.X.
      • Eckersley R.J.
      Nonlinear propagation of ultrasound through microbubble contrast agents and implications for imaging.
      ].
      Subsequent years have shown increasing applications of CEUS and it is now established for both liver mass characterization and detection, for renal mass evaluations, and for an unlimited number of growing indications for almost all of the accessible solid organs of the abdomen. This article comprises a brief introduction to microbubble contrast agents, their imaging techniques and safety, their applications in the liver and the kidney, and a brief overview of their most common usage in the abdomen in the adult population. In addition, pediatric indications are documented, which have rapidly evolved following the inclusion of children when the US Food and Drug Administration (FDA) first approved the use of a microbubble for imaging in the United States in April 2016.

      Microbubble Contrast Agents

      US contrast agents (UCAs) are tiny bubbles of a perfluoropropane gas with a supporting lipid shell, approximately the same size as a red blood cell. They are purely intravascular. Their behavior depends on their oscillation when exposed to a low-mechanical-index (MI) ultrasound field and their injection to the circulation greatly enhances the back scatter from blood, increasing its Doppler signal. Following injection, the bubbles are rapidly cleared from the body by the lungs.
      UCAs have an excellent safety record in millions of injections and provide less risk than examinations of similar value performed with either CT or MR contrast agents [
      • Piscaglia F.
      • Bolondi L.
      Italian Society for Ultrasound in Medicine and Biology (SIUMB) Study Group on Ultrasound Contrast Agents
      The safety of Sonovue in abdominal applications: retrospective analysis of 23188 investigations.
      ]. They show no nephrotoxicity and have no requirement for ionizing radiation.

      Technique for Contrast-Enhanced Ultrasonography

      UCAs require specialized imaging techniques that preserve the bubble population while detecting the oscillation of the microbubbles within a low-MI field, allowing incomparable contrast agent sensitivity and exceptional vessel resolution. CEUS is performed with contrast-specific software such as pulse inversion imaging, whereby 2 pulses are sent down each scan line with subtraction of the returning echoes [
      • Burns P.N.
      • Wilson S.R.
      • Simpson D.H.
      Pulse inversion imaging of liver blood flow: improved method for characterizing focal masses with microbubble contrast.
      ]. The background tissue, a linear reflector, sends back a wave that is a reflection of the insonating wave. Their subtraction, therefore, equals zero, totally removing the background signal. The result is a black image at the beginning of an imaging sequence for CEUS. The returning echoes from the oscillating microbubble contrast agents, by comparison, produce additive signals so that there is great augmentation of the Doppler signal from blood. The result of these sequences is the creation of an extremely sensitive microbubble-only image, with removal of the signals from the background tissues. The intensity of the signal on the image occurs in direct proportion to the volume of microbubbles within the region of interest. All high-end US systems now offer a contrast-specific software package with low-MI imaging and also a bubble tracking technique. This bubble tracking may involve a transient brief high-MI insonation, which destroys bubbles within the field of view, following which the refilling of the vessels may be tracked, improving their visualization [
      • Burns P.N.
      • Wilson S.R.
      • Hope Simpson D.
      • et al.
      Harmonic interval delay imaging: a new ultrasound contrast method for imaging the blood volume in the liver.
      ]. More detailed descriptions of the performance of CEUS are included in international guidelines [
      • Piscaglia F.
      • Nolsøe C.
      • Dietrich C.F.
      • et al.
      The EFSUMB guidelines and recommendations on the clinical practice of contrast enhanced ultrasound (CEUS): update 2011 on non-hepatic applications.
      ,
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • et al.
      Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver - update 2012.
      ].
      There are 2 constant technical aspects to the performance of CEUS that now contribute to its essential inclusion in the imaging of many abdominal solid organs. These aspects are, first, the performance of CEUS in dynamic real time allowing the assessment of tumor blood flow regardless of its timing or duration. Second, the use of a purely intravascular contrast agent is unique to CEUS and provides true vascular information about tumor and organ enhancement and washout.

      Liver contrast-enhanced ultrasonography

      CEUS of the liver has become the most popular and most successful application of CEUS [
      • Wilson S.R.
      • Burns P.N.
      • Kono Y.
      Liver contrast-enhanced ultrasound of focal liver masses: a success story.
      ]. CEUS is recognized as a first choice for diagnosis of masses found incidentally on US, and as a first-line or second-line modality for resolution of nodules from surveillance US for hepatocellular carcinoma (HCC). It is a major problem solver throughout the abdomen and shows excellent ability to resolve indeterminate observations on MR scans [
      • Hu J.
      • Bhanaya D.
      • Burak K.W.
      • et al.
      Resolution of indeterminate MRI with CEUS in patients at high risk for hepatocellular carcinoma.
      ]. CEUS is a major component of the Liver Reporting & Data System (LI-RADS) for CEUS, available on the American College of Radiology (ACR) Web site (https://www.acr.org/Clinical-Resources/Reporting-and-Data-Systems/LI-RADS/CEUS-LI-RADS-v2017).

      Interpretation of Liver Contrast-Enhanced Ultrasonography

      Our algorithm for the interpretation of CEUS of focal liver masses is based on assessment of the enhancement of the mass relative to the adjacent liver as determined in the arterial phase (from 15 to 40 second), the portal venous phase (from 40 seconds to about 2 minutes), and then the late phase (from roughly 2 minutes to the end of useful contrast agent performance, usually after 5 minutes) [
      • Burrowes D.P.
      • Medellin A.
      • Harris A.C.
      • et al.
      Contrast-enhanced US approach to the diagnosis of focal liver masses.
      ,
      • Lyshchik A.
      • Kono Y.
      • Dietrich C.F.
      • et al.
      Contrast-enhanced ultrasound of the liver: technical and lexicon recommendations from the ACR CEUS LI-RADS working group.
      ].
      The first question posed during the characterization of a focal liver mass is whether the mass is malignant [
      • Wilson S.R.
      • Burns P.N.
      An algorithm for the diagnosis of focal liver masses using microbubble contrast-enhanced pulse-inversion sonography.
      ]. This question is answered most reliably by determining the enhancement of the mass in the portal venous and late phases looking for the observation of washout. This washout describes the decrease in the enhancement of a mass to less than that of the adjacent enhanced liver parenchyma following an initial enhancement of any type. This determination is a guideline only, and there are exceptions. Nonetheless, on every examination, the clinician must answer the question, “Is there washout?” (Fig. 1, Video 1) [
      • Bhayana D.
      • Kim T.K.
      • Jang H.J.
      • et al.
      Hypervascular liver masses on contrast-enhanced ultrasound: the importance of washout.
      ].
      Figure thumbnail gr1
      Fig. 1Klatskin tumor. A 67-year-old man presented with obstructive jaundice. Four axial images through the porta hepatis show a round focal large mass at the porta hepatis. There are dilated biliary ducts in the right and the left lobes. (A) Gray-scale image shows a homogeneous mass. (B) An image at the peak of the arterial phase enhancement, 8 seconds, shows there is mild hyperenhancement. (C) At 35 seconds, in the early portal venous phase, there is already washout of the mass. (D) At 2 minutes, in the late phase, the washout is marked, and the mass appears black. This enhancement pattern, with transient hypervascularity and rapid washout, is classic for cholangiocarcinoma. This figure corresponds with .
      Subsequently, specific diagnoses are determined. In broad, sweeping terms there are benign tumors and there are malignant tumors, the latter separated into those of hepatocellular origin and those of nonhepatocellular origin, including especially metastases and cholangiocarcinoma.
      Benign tumors, hemangioma and focal nodular hyperplasia (FNH), are characterized by a specific enhancement pattern in the arterial phase, most often associated with sustained enhancement in the portal venous and late phases [
      • Kim T.K.
      • Jang H.J.
      • Burns P.N.
      • et al.
      Focal nodular hyperplasia and hepatic adenoma: differentiation with low-mechanical-index contrast-enhanced sonography.
      ]. Their rapidly changing arterial enhancement patterns are better portrayed with real-time dynamic scans on US than they are on either CT or MR scans, where single images generally reflect the changes within an entire time frame.
      Hemangiomas are characterized by discontinuous globular enhancement with centripetal progression of enhancement. Their fill-in may be rapid or slow, and complete or incomplete, but, regardless, they generally show sustained enhancement relative to the adjacent liver without washout over time [
      • Dietrich C.F.
      • Mertens J.C.
      • Braden B.
      • et al.
      Contrast-enhanced ultrasound of histologically proven liver hemangiomas.
      ]. However, it is well recognized that hemangiomas may show infrequent washout after classic behavior in the arterial phase. FNH is characterized by arterial phase hyperenhancement with sustained enhancement, often with a central unenhanced scar (Fig. 2). Their arterial phase enhancement and filling show a stellate vessel morphology with centrifugal filling from the center of the tumor to the periphery (Video 2). Although there may be a single focus of centrality, more often the vessels may appear to arise from many central foci within the tumor. Use of a bubble tracking technique to enhance the appearance of these vessels is ideal and multiple high-MI bursts may show multiple refills of the tumor, something that is characteristic of this particular tumor. Hepatic adenomas are much less frequent than either hemangioma or FNH. In addition, there are multiple subtypes that complicate their clinical assessment and diagnosis. Nonetheless, if US is performed for characterization of an identified mass, their arterial phase characteristics on CEUS are not as constant, often complicated by the presence of obvious fat or hemorrhagic components. Further, their CEUS enhancement features are inconsistent. They may show simple benign features on CEUS of arterial phase hyperenhancement with no washout, or they may also show a suggestive arterial phase pattern that includes a hypervascular but heterogeneous mass with centripetal filling. In the portal venous phase, adenomas may show the expected sustained enhancement of a benign tumor, but may also show an exception to the enhancement rule with weak washout observed in the late phase in up to 50% of cases [
      • Albrecht T.
      • Hohmann J.
      • Oldenburg A.
      • et al.
      Detection and characterisation of liver metastases.
      ]. In these situations, differentiation of a hepatic adenoma from an HCC is reliant on demographic information, including the common history for adenoma of young women on long-term oral contraceptive use.
      Figure thumbnail gr2
      Fig. 2FNH. A 55-year-old asymptomatic man. Incidental discovery of a focal liver mass. (A) A power Doppler image shows a central isoechoic liver mass. There is stellate vascularity. (B) At 10 seconds, an early bubble tracking technique confirms the stellate vascularity. (C) At 40 seconds, the peak of arterial phase enhancement, the mass is homogeneous and hyperenhanced. (D) At 3 minutes, in the portal phase, the mass is still enhanced with a small central nonenhanced scar (arrows). Classic FNH. This condition is less common in male than in female patients. This figure corresponds with .
      CEUS is highly reliable to predict benign liver masses, and performance of CEUS at the time of incidental detection of a liver mass on routine sonography is a highly efficient method, removing patient anxiety and decreasing necessity for return visits to characterize a mass.
      Unlike benign tumors, malignant tumors are characterized, not by their enhancement in the arterial phase, which is highly variable, but by their washout, which refers to a decline in the enhancement of a nodule following its original enhancement. [
      • Bhayana D.
      • Kim T.K.
      • Jang H.J.
      • et al.
      Hypervascular liver masses on contrast-enhanced ultrasound: the importance of washout.
      ]. Washout is classified in 2 ways: according to its timing of occurrence and according to its intensity, when it is first shown. The timing may be early, occurring before 1 minute, or it may be late, first seen after 1 minute. Time zero coincides with the initiation of the saline flush following UCA injection. The intensity may be mild, in which case there are always bubbles remaining within the nodule (Fig. 3, Video 3), or it may be marked such that the nodule appears as a black or punched-out hole within the enhanced liver (Fig. 4, Video 4). Because washout intensity changes over time and becomes more marked, the designation of marked washout refers to those nodules that appear marked before 2 minutes following contrast injection. In general terms, washout that is rapid and marked is typical of nonhepatocellular carcinoma, whereas washout that is late and weak is typical of hepatocellular malignancies. This guideline is not absolute but is a helpful indicator.
      Figure thumbnail gr3
      Fig. 3HCC with dysmorphic vessels. A 54-year-old man with chronic hepatitis B virus infection and no cirrhosis. (A) A gray-scale image shows a heterogeneous liver mass. (B) At 10 seconds, a CEUS image taken with a bubble tracking technique shows dysmorphic tumor vessels (arrows) within the mass. (C) At 1 minute, the mass is isovascular and is barely visible against the enhanced liver parenchyma. (D) At 3 minutes, there is late weak washout. This lesion is LR-5, a classic HCC. This figure corresponds with .
      Figure thumbnail gr4
      Fig. 4Cholangiocarcinoma. A 67-year-old man with no risk factors for HCC. (A) A sagittal image of the left lobe of the liver shows a hypoechoic mass (arrows). (B) At the peak of arterial phase enhancement at 20 seconds, the mass is hyperenhanced. (C) At 50 seconds, there is weak washout. Some bubbles can still be identified within the mass, but the enhancement is less than the adjacent liver. (D) At 2 minutes, the mass now appears black and shows, therefore, marked washout. This mass is a nonhepatocellular malignancy. Biopsy shows cholangiocarcinoma. This figure corresponds with .

      Liver Metastases

      Metastatic liver disease is the most common hepatic malignancy in the world. The most common body cancers, those from the lung, breast, and colon, all involve the liver as their most common site of metastatic disease. Therefore, imaging the liver in search of metastatic disease is a common protocol procedure following treatment of a primary cancer, most often performed with portal venous phase CT imaging. The CEUS enhancement features are those of nonhepatocellular carcinoma with frequent transient arterial phase hypervascularity and then rapid marked washout (Fig. 5, Video 5). Arterial phase rim pattern enhancement is also frequent.
      Figure thumbnail gr5
      Fig. 5Cystic metastasis. (A) A portal venous phase CT image on a patient with prior pancreatic cancer resection shows an indeterminate low attenuation mass (arrow). (B) A gray-scale US image shows a cyst with a solid hypoechoic rim along 1 edge. (C) A CEUS image at 20 seconds shows enhancement of the liver. The solid rim of the cyst is slightly hypoenhanced relative to the liver. (D) There is rapid marked washout at 1 minute such that the entire complex mass now appears black. Rapid marked washout by 1 minute is classic for metastatic disease. This figure corresponds with .
      Although CEUS has been shown to be reliable for detection of metastatic disease [
      • Albrecht T.
      • Hohmann J.
      • Oldenburg A.
      • et al.
      Detection and characterisation of liver metastases.
      ], CEUS is not generally used as a routine technique for screening for metastases. Nonetheless, it is an excellent modality for resolution of indeterminate low-attenuation nodules, which are detected most often on screening CT scans and also in other situations.
      Metastatic disease on CEUS most often manifests as a transient hypervascular nodule, regardless of the tumor source. Following this hypervascularity, these nodules rapidly show washout that is generally complete and marked such that the tumors quickly appear as black holes within the enhanced parenchyma. Therefore, it follows that sweeping the liver as a continuous motion on CEUS in the portal venous phase in search of black holes has proved to be highly effective for metastatic disease detection. This thorough sweeping of the liver in both axial and sagittal planes should be performed routinely in any patient in whom there is detected or suspected malignant disease [
      • Albrecht T.
      • Blomley M.J.
      • Burns P.N.
      • et al.
      Improved detection of hepatic metastases with pulse-inversion US during the liver-specific phase of SHU 508A: multicenter study.
      ].

      Hepatocellular Carcinoma

      Liver nodules in patients at high risk for hepatocellular carcinoma

      HCC, a primary tumor of the liver hepatocytes, is a major health concern [
      • Rawla P.
      • Sunkara T.
      • Muralidharan P.
      • et al.
      Update in global trends and aetiology of hepatocellular carcinoma.
      ]. It is now the only solid organ cancer with an increasing incidence in the United States. HCC is associated with chronic liver disease and the current obesity epidemic, with its soaring rate of fatty liver, produces more cases yearly. The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing with obesity and this has become the most common cause of liver dysfunction worldwide. It will soon be the leading cause of both cirrhosis and HCC in many countries [
      • Younossi Z.M.
      Non-alcoholic fatty liver disease - A global public health perspective.
      ].
      Surveillance US performed every 6 months in high-risk patients is recommended by all major liver societies with the intention of detecting nodules while they are still small and amenable to therapy. However, HCC develops from a preexisting benign nodule in the liver by a process of hepatocarcinogenesis whereby a benign regenerative nodule enlarges with progressive atypia, eventually becoming a dysplastic nodule, and then showing a small focus of HCC within it and eventually total replacement of the nodule with cancerous tissue [
      • Sakamoto M.
      • Hirohashi S.
      • Shimosato Y.
      Early stages of multistep hepatocarcinogenesis: adenomatous hyperplasia and early hepatocellular carcinoma.
      ]. As these histologic changes are occurring, there are also changes in the nodule blood supply, with progressive destruction of the normal blood supply from the hepatic artery and portal vein while new abnormal arterial blood supply develops by the process of angiogenesis [
      • Matsui O.
      • Gabata T.
      • Kobayashi S.
      • et al.
      Imaging of multistep human hepatocarcinogenesis.
      ]. These vascular changes result in a great variation in the imaging features of nodules as they transform from benign nodules and eventually become full-blown HCC. Therefore, a classic HCC shows arterial phase hyperenhancement (APHE) with late and weak washout. However, HCC may be present in nodules without these classic features and there are a whole variety of benign and transitional nodules that may be seen as the nodules progress toward full-blown malignancy. Variations include no APHE and either isovascularity or hypovascularity in the arterial phase. The classic late weak washout may instead show no washout or rapid washout, whereby there is overlap with nonhepatocellular malignancies [
      • Jang H.J.
      • Kim T.K.
      • Burns P.N.
      • et al.
      Enhancement patterns of hepatocellular carcinoma at contrast-enhanced US: comparison with histologic differentiation.
      ]. The clinical magnitude of the HCC problem coupled with the challenges for noninvasive imaging for diagnosis have resulted in a great interest in liver mass imaging in radiology over the recent decades. On CEUS, the authors are aware of classic HCC and a wide variety of HCCs that have variations from the classic enhancement pattern. We are also aware that the precursor nodules to HCC show characteristic progression that may be well shown on dynamic serial CEUS.

      Intrahepatic Cholangiocarcinoma

      Intrahepatic cholangiocarcinoma (ICC) may occur in a normal liver but has an increased frequency of detection in patients with chronic liver disease, thereby overlapping with the same population at risk for HCC. ICC shows variable arterial phase enhancement ranging from hypovascularity through to hyperenhancement, which may additionally show a rim pattern. As with other nonhepatocellular malignancies, ICC shows rapid and marked washout (see Fig. 4, Video 4).

      Liver Reporting & Data System

      The recently introduced Liver Reporting & Data System (LI-RADS) for CEUS is available on the ACR Web site (https://www.acr.org/Clinical-Resources/Reporting-and-Data-Systems/LI-RADS/CEUS-LI-RADS-v2017). CEUS LI-RADS is a standardized system for technique, interpretation, reporting, and data collection for CEUS examinations in patients at risk for developing HCC. It includes an algorithm with multiple categories designed as a probabilistic scale for the likelihood of showing HCC from LR-1, a definitely benign nodule, through to LR-5, a confident HCC [
      • Wilson S.R.
      • Lyshchik A.
      • Piscaglia F.
      • et al.
      CEUS LI-RADS: algorithm, implementation, and key differences from CT/MRI.
      ].
      LR-5 nodules require 3 features: size greater than 1 cm, arterial phase hyperenhancement, and late and weak washout at greater than 1 minute. Strict adherence to these features in an at-risk patient provides a confident diagnosis of HCC, allowing treatment without biopsy. LI-RADS emphasizes specificity for LR-5, with an objective for diagnosis of HCC of as close to 100% as possible.
      Because of the complexity of the evolution of HCC, the malignant nodules along the path of hepatocarcinogenesis will not all meet the stringent criteria for LR-5 and may appear elsewhere in the LI-RADS algorithm, including LR-3, with intermediate probability of being HCC; LR-4, highly suspicious for HCC; and LR-TIV, to designate a nodule that shows additionally a soft tissue enhancing tumor within a vein. In addition, HCC may also appear outside of LR-5 within a specially created category to ensure that nonhepatocellular carcinomas have a category into which they are likely to fit; that is, LR-M, a probably or likely malignant nodule, without specificity for HCC. Within LR-M it is therefore expected to see cholangiocarcinoma, metastases, and also some HCCs that do not meet the stringent criteria for diagnosis of HCC.
      For LI-RADS, the end result is that virtually every nodule in LR-5 is HCC. HCC is also found in the neighboring categories of LR-3 and LR-4, and also within LR-M, along with many other malignancies [
      • Terzi E.
      • Iavarone M.
      • Pompili M.
      • et al.
      Contrast ultrasound LI-RADS LR-5 identifies hepatocellular carcinoma in cirrhosis in a multicenter retrospective study of 1,006 nodules.
      ]. Retrospective validation studies of CEUS LI-RADS for diagnosis of HCC within category LR-5 confirm the high specificity of LR-5 for diagnosis of HCC [
      • Terzi E.
      • Iavarone M.
      • Pompili M.
      • et al.
      Contrast ultrasound LI-RADS LR-5 identifies hepatocellular carcinoma in cirrhosis in a multicenter retrospective study of 1,006 nodules.
      ,
      • Makoyeva A.
      • Kim T.K.
      • Jang H.-J.
      Use of CEUS LI-RADS for the accurate diagnosis of nodules in patients at risk for hepatocellular carcinoma: a validation study.
      ]. They also show the benefit of LI-RADS for the categorization of ICC as LR-M, retaining the specificity of LR-5 but still diagnosing patients with significant malignant disease [
      • Leoni S.
      • Piscaglia F.
      • Granito A.
      • et al.
      Characterization of primary and recurrent nodules in liver cirrhosis using contrast-enhanced ultrasound: which vascular criteria should be adopted?.
      ]. Logistic regression analysis shows that late washout of contrast agent (>60 seconds) is the CEUS feature that most indicates HCC, and rapid washout of contrast agent (<60 seconds) is the CEUS feature that most indicates nonhepatocellular malignancy [
      • Leoni S.
      • Piscaglia F.
      • Granito A.
      • et al.
      Characterization of primary and recurrent nodules in liver cirrhosis using contrast-enhanced ultrasound: which vascular criteria should be adopted?.
      ].

      Variations Between Contrast-Enhanced Ultrasonography, Computed Tomography, and Magnetic Resonance Scans

      In addition to the benefits of dynamic real-time scan already documented, US is performed with purely intravascular microbubble contrast agents. These agents always reflect a purely vascular image and they reliably show washout in malignant tumors, especially in the liver but also elsewhere. By comparison, CT and MR contrast agents have a well-defined interstitial phase and, especially in the presence of tumors with permeable endothelium such as ICC and in the presence of abundant fibrosis, the contrast agents produce an image of pseudoenhancement as the contrast agent extravasates into the tissue interstitium. Recognition of these types of discordance is a helpful benefit of CEUS for interpretation of tumors, especially in the liver [
      • Wilson S.R.
      • Kim T.K.
      • Jang H.J.
      • et al.
      Enhancement patterns of focal liver masses: discordance between contrast-enhanced sonography and contrast-enhanced CT and MRI.
      ,
      • Burns P.N.
      • Wilson S.R.
      Focal liver masses: enhancement patterns on contrast-enhanced images--concordance of US scans with CT scans and MR images.
      ]. This discordance is especially frequently observed in ICC, where CEUS routinely shows rapid washout and MR scan regularly shows either sustained or increased enhancement.

      Liver Contrast-Enhanced Ultrasonography Today

      The FDA approval of a UCA for imaging in the United States and the inclusion of CEUS LI-RADS by the ACR, both within 2016, have greatly improved the adoption and inclusion of CEUS within liver imaging protocols. CEUS makes unique contributions related to superior temporal resolution with dynamic real-time imaging and the most reliable demonstration of washout in malignant tumors with the use of a purely intravascular contrast agent.

      Kidney contrast-enhanced ultrasonography

      More than one-half of patients more than 50 years of age have at least 1 renal mass. Up to 70% of these renal masses are discovered incidentally, during performance of imaging for an unrelated indication. Most renal masses are benign simple cysts and can be identified with US, CT, or MRI. However, most solid or cystic, contrast-enhancing renal masses, excluding inflammatory masses, vascular abnormalities, and pseudotumors, are malignant [
      • Silverman S.G.
      • Israel G.M.
      • Herts B.R.
      • et al.
      Management of the incidental renal mass.
      ]. However, there are a large number of complicated cystic lesions that range from clearly benign to clearly malignant.
      These lesions are classified using the Bosniak classification system [
      • Barr R.G.
      • Peterson C.
      • Hindi A.
      Evaluation of indeterminate renal masses with contrast-enhanced US: a diagnostic performance study.
      ], developed first for CT and then modified to include MR scan. The Bosniak classification now does not include CEUS [
      • Barr R.G.
      • Peterson C.
      • Hindi A.
      Evaluation of indeterminate renal masses with contrast-enhanced US: a diagnostic performance study.
      ].
      The Bosniak classification for CT and MRI has been recently revised [
      • Silverman S.G.
      • Pedrosa I.
      • Ellis J.H.
      • et al.
      Bosniak classification of cystic renal masses, version 2019: an update proposal and needs assessment.
      ]. A Bosniak classification for CEUS has not been developed. The Bosniak classification is intended for cystic renal masses after infectious, inflammatory, and vascular causes, and necrotic solid masses are excluded. The classification of cystic renal masses using the Bosniak classification should not be made on a noncontrast study. Therefore, in patients with contraindications for CT or MRI contrast, CEUS is the examination of choice for renal mass classification. Bosniak classification includes simple renal cysts as Bosniak 1 and malignant renal cysts as Bosniak 4, with increasing complexity in between.
      CEUS can characterize both simple and complicated cysts, as well as solid masses by providing information on kidney vascularity. Renal lesions without enhancement on CEUS, regardless of their complexity, are benign, whereas vascular lesions, regardless of complexity, are mostly malignant. CEUS has several advantages in renal mass characterization compared with other modalities:
      • 1.
        The UCA is not excreted in the collecting system, allowing improved visualization of the collecting system and differentiation of the medulla from the cortex.
      • 2.
        The UCA does not have renal toxicity and can be used in renal-impaired patients and in those with renal obstruction.
      • 3.
        Thin slice thickness improves characterization of septations and nodularity and detection of enhancement, without the volume averaging seen in CT and MRI.
      • 4.
        Real-time imaging detects enhancement that can be missed on snapshot images of CT and MRI.
      • 5.
        CEUS subtraction techniques remove the background soft tissue echoes with production of a contrast-only image, allowing visualization of enhancement in small structures such as septations or small mural nodules.
      Table 1 summarizes the CEUS enhancement patterns and the possible lesion types for each enhancement pattern.
      Table 1The left column describes the CEUS pattern. The middle column designates malignancy and the right column assigns an actual diagnosis.
      EnhancementBenign or MalignantType of Lesion
      NoneBenignSimple or complicated cyst
      Few bubbles or constant flow of bubbles in a fine septation (<1 mm) and no nodularityBenignComplicated cyst
      Enhancement equal to normal cortex on all enhancement phases with a less vascular medullary pyramidBenignFusion abnormality
      Echogenic mass with heterogeneous enhancement less than renal cortex
      CT or MRI advised to confirm macroscopic fat.
      BenignAngiomyolipoma
      Echogenic mass with homogeneous enhancement equal to or greater than normal renal cortex in the arterial phase
      If necrosis is present, an area of low enhancement may be seen centrally.
      MalignantEchogenic renal cell carcinoma
      Nonechogenic mass cystic or solid with enhancement of any typeMalignancy should be excludedRenal cell carcinoma

      Transitional cell carcinoma

      Oncocytoma

      Fat-poor angiomyolipoma

      Lymphoma

      Infected complicated cyst

      Pyelonephritis
      Should be used after infectious, inflammatory, and vascular causes are excluded.
      a CT or MRI advised to confirm macroscopic fat.
      b If necrosis is present, an area of low enhancement may be seen centrally.

      Normal Contrast-Enhanced Ultrasonography Renal Enhancement

      The normal kidney shows robust uniform enhancement of the cortex in the arterial phase on CEUS. UCAs are not excreted into the collecting system so there is no enhancement in the renal collecting system or renal pelvis. The medulla has less blood flow than the cortex and is easily visualized as a central pyramidal structure with less enhancement. In CT and MRI, excreted contrast enhances the medulla in the excretory phase, making differentiation between the medulla and cortex difficult.

      Benign Renal Masses

      Simple renal cyst

      A simple renal cyst is characterized by a thin or imperceptible wall and fluid content [
      • Siegel C.L.
      • McFarland E.G.
      • Brink J.A.
      • et al.
      CT of cystic renal masses: analysis of diagnostic performance and interobserver variation.
      ]. These cysts are typically asymptomatic, and no follow-up is necessary [
      • Siegel C.L.
      • McFarland E.G.
      • Brink J.A.
      • et al.
      CT of cystic renal masses: analysis of diagnostic performance and interobserver variation.
      ]. Simple cysts are nonenhancing, although thin walls (<2 mm) without irregularity may enhance on CEUS and are anechoic on gray-scale imaging. These lesions equate to Bosniak category 1.

      Pseudotumors

      A column of Bertin is a familiar pseudotumor composed of normal renal cortex interposed between the medullary pyramids. Pseudotumors have equal enhancement in all phases of enhancement to normal renal cortex and have the presence of a central medullary pyramid that has less enhancement than normal renal cortex [
      • Barr R.G.
      • Peterson C.
      • Hindi A.
      Evaluation of indeterminate renal masses with contrast-enhanced US: a diagnostic performance study.
      ] (Fig. 6). With the lack of excretion of the UCA, the difference between the vascularity of the cortex and medulla can easily be identified on all phases of enhancement, in contrast with CT and MRI.
      Figure thumbnail gr6
      Fig. 6Renal pseudotumor. A 31-year-old man with recent episode of gross hematuria. Outside US and CT suggested a contour abnormality versus a mass in the left kidney. Gray-scale imaging shows an isoechoic bulge at lateral aspect of left kidney (A, arrow). CEUS shows equal enhancement of the area of concern to the renal cortex in all phases of enhancement. Evenly spaced medullary pyramids are visualized, with a pyramid positioned within the pseudotumor (B, arrow).

      Pyelonephritis

      Imaging is usually not required for acute uncomplicated pyelonephritis. With complicating features such as acute papillary necrosis, renal abscess, or sepsis, a contrast imaging examination is required. In patients with impaired renal function, renal obstruction, or in pregnant women, CEUS is preferred because of its safety profile. Focal pyelonephritis may appear as a focal hypoechoic or echogenic area and may produce a masslike lesion mimicking a tumor. The area may be hypovascular on CEUS compared with adjacent normal kidney. CEUS shows an abscess as a central avascular defect with rim enhancement.

      Angiomyolipoma

      An angiomyolipoma (AML) is detected as a uniformly echogenic mass on B-mode US. AMLs display less heterogeneous enhancement than the normal renal cortex with a tendency to more peripheral distribution as the areas of fat show minimal enhancement [
      • Barr R.G.
      • Peterson C.
      • Hindi A.
      Evaluation of indeterminate renal masses with contrast-enhanced US: a diagnostic performance study.
      ]. Echogenic renal cell carcinoma (RCC) may be similar to AML on gray-scale scan but tends to have more marked uniform enhancement than the renal cortex in the arterial phase of CEUS. Fat-poor echogenic AML may have an appearance similar to an echogenic RCC at gray-scale scan. Obtaining an unenhanced CT or MRI scan to confirm macroscopic fat is recommended in AML (Fig. 7).
      Figure thumbnail gr7
      Fig. 7AML. A 72-year-old man with a history of renal mass. Gray-scale US shows well circumscribed hyperechoic mass with the appearance typical of AML (A, arrow). CEUS on the arterial phase shows a small amount of flow in a more globular pattern (not uniform enhancement) in the mass (B, arrow). This appearance is typical of an AML.

      Complex renal cysts on ultrasonography

      High-resolution US allows good visualization of the internal nature of complex renal cysts, showing both septations and nodularity. However, regardless of their gray-scale appearance, all cysts with no internal vascularity on CEUS are benign. Further, the appearance of single bubbles or a constant flow of thin bubbles without nodularity is a benign finding [
      • Barr R.G.
      • Peterson C.
      • Hindi A.
      Evaluation of indeterminate renal masses with contrast-enhanced US: a diagnostic performance study.
      ]. On CEUS, there is seemingly no value in detailed categorization of the baseline features.
      These features equate to Bosniak category 2 lesions, which are characterized by either thin, calcified walls or by single, thin (<2 mm) septations. Only in rare cases are Bosniak category 2 lesions found to be potentially malignant. A subset of Bosniak category 2 lesions characterized by thick calcifications of the walls or by thickened or enhanced septa are classified as Bosniak 2F and have an increased malignancy rate of approximately 5% [
      • Barr R.G.
      • Peterson C.
      • Hindi A.
      Evaluation of indeterminate renal masses with contrast-enhanced US: a diagnostic performance study.
      ].
      Bosniak category 3 lesions are characterized by multiple thick septations as well as by mural nodules. These lesions can be hyperdense when imaged using CT. Approximately half of all observed Bosniak 3 lesions were found to be benign and half malignant on CT or MRI [
      • Siegel C.L.
      • McFarland E.G.
      • Brink J.A.
      • et al.
      CT of cystic renal masses: analysis of diagnostic performance and interobserver variation.
      ,
      • Aronson S.
      • Blumenthal R.
      Perioperative renal dysfunction and cardiovascular anesthesia: concerns and controversies.
      ].
      On CEUS, Bosniak category 2, 2F, and 3 lesions from prior CT scan, which show no enhancement on CEUS, are all benign with a negative predictive value (NPV) of 100% in a large series [
      • Barr R.G.
      • Peterson C.
      • Hindi A.
      Evaluation of indeterminate renal masses with contrast-enhanced US: a diagnostic performance study.
      ] (Fig. 8).
      Figure thumbnail gr8
      Fig. 8CEUS shows no enhancement. A 74-year-old man on anticoagulant therapy with a remote history of hematuria presents with flank pain. On B-mode precontrast images, a hypoechoic mixed echogenic mass is seen in left kidney (A, arrows). The B-mode appearance is a Bosniak 4 lesion (without contrast). Postinjection images show no flow within the mass (B, arrows). This mass was thought to most likely represent a hemorrhagic renal cyst.
      On CEUS, all malignant cystic tumors show enhancement of the thickened wall, septations, or internal components of the mass with a positive predictive value of 95% [
      • Barr R.G.
      • Peterson C.
      • Hindi A.
      Evaluation of indeterminate renal masses with contrast-enhanced US: a diagnostic performance study.
      ]. These tumors correspond with Bosniak category 2, 2F, 3, and 4 malignant lesions. However, with the very high NPV of CEUS, biopsy or surgery is not required in nonenhancing lesions (Fig. 9).
      Figure thumbnail gr9
      Fig. 9Papillary RCC. This 69-year-old man presents with a history of prostate cancer and a renal mass seen on lumbar MRI examination. Gray-scale imaging shows a small, exophytic, 1.5-cm isoechoic mass (A, arrow). Marked enhancement can be seen after contrast injection, consistent with RCC (B, arrows). Dual screen display, with CEUS on the left and grayscale on the right, in the arterial phase, this mass enhanced uniformly but less than renal cortex and showed washout. This enhancement pattern is characteristic of papillary RCC.
      Bosniak category 4 lesions appear as a cystic mass with solid components on CT scan. If these are benign, they can easily be diagnosed as benign with CEUS because these masses have no enhancement. Solid components with enhancement have a very high probability of being malignant.
      Oncocytomas that are benign solid masses show enhancement on CEUS and are false-positive cases. Oncocytomas are often surgically removed because some pathologists do not classify them as benign unless the entire specimen is evaluated.
      Papillary RCC is often missed on CT and MRI because of low enhancement and contrast timing using these modalities. However, these vascular tumors can be readily identified using CEUS enhancement in the arterial phase because of the real-time scanning of CEUS compared with snapshots on CT and MRI.
      Echogenic RCCs usually show marked rapid enhancement more than renal cortex in the arterial phase and may show washout. They can be distinguished from AMLs because AMLs tend to have less enhancement than renal cortex in a heterogeneous pattern. CT or MRI is advised for AML to confirm macroscopic fat in the lesion because fat-poor AMLs may have a similar appearance to RCC.

      Transitional cell carcinoma

      Transitional cell carcinoma (TCC) is most commonly found in the bladder, although less commonly TCC can be found in the renal pelvis or ureter. TCCs account for approximately 95% of all malignant tumors in the epithelial lining of the urinary tract [
      • Vikram R.
      • Sandler C.M.
      • Ng C.S.
      Imaging and staging of transitional cell carcinoma: part 2, upper urinary tract.
      ,
      • Vikram R.
      • Sandler C.M.
      • Ng C.S.
      Imaging and staging of transitional cell carcinoma: part 1, lower urinary tract.
      ]. TCC is known for a high rate of recurrence, as well as multifocality [
      • Vikram R.
      • Sandler C.M.
      • Ng C.S.
      Imaging and staging of transitional cell carcinoma: part 2, upper urinary tract.
      ,
      • Vikram R.
      • Sandler C.M.
      • Ng C.S.
      Imaging and staging of transitional cell carcinoma: part 1, lower urinary tract.
      ].
      On CEUS, TCCs show enhancement and location within the epithelial lining of the urinary tract, including the renal pelvis ureters, and the bladder. It is their location that suggests the diagnosis.

      Lymphoma

      Renal lymphoma typically occurs as part of multisystemic lymphoma or because of recurrence of a tumor. Imaging often reveals multiple hypodense masses [
      • Urban B.A.
      • Fishman E.K.
      Renal lymphoma: CT patterns with emphasis on helical CT.
      ]. Almost half of all cases of renal lymphoma are discovered at autopsy, whereas approximately 5% of cases are detected using CT [
      • Urban B.A.
      • Fishman E.K.
      Renal lymphoma: CT patterns with emphasis on helical CT.
      ].
      On CEUS, these lesions show enhancement and are difficult to distinguish from RCCs. Adenopathy in other locations or a perinephric mass may be a clue to the diagnosis, but biopsy is usually required to make the diagnosis.

      Monitoring of interventional procedures

      CEUS can be used to monitor interventional procedures such as radiofrequency ablation (RFA) or cryoablation [
      • Lackey 2nd, L.
      • Peterson C.
      • Barr R.G.
      Contrast-enhanced ultrasound-guided radiofrequency ablation of renal tumors.
      ]. It can improve the accuracy of biopsies, allowing areas of necrosis (no enhancement) to be avoided. CEUS monitoring of RFA or cryoablation can be performed at the time of the procedure, to access whether adequate ablation has occurred, and during additional procedures if needed at the same setting. With enhancement lasting about 5 minutes, multiple injections can be given during a procedure [
      • Lackey 2nd, L.
      • Peterson C.
      • Barr R.G.
      Contrast-enhanced ultrasound-guided radiofrequency ablation of renal tumors.
      ,
      • Bansal S.
      • Gui J.
      • Merrill C.
      • et al.
      Contrast-enhanced US in local ablative therapy and secondary surveillance for hepatocellular carcinoma.
      ].

      Renal contrast-enhanced ultrasonography today

      CEUS is a very sensitive and specific imaging modality for characterization of renal masses. It has improved accuracy compared with CT and MRI because of its thin slice thickness (no volume averaging), real-time assessment of vascularity (identifying areas of enhancement that can be missed during contrast timing on CT or MRI), and superb background tissue suppression (allowing superior detection of small amounts of enhancement). With an NPV of 100%, benign lesions can be diagnosed with high certainty [
      • Barr R.G.
      • Peterson C.
      • Hindi A.
      Evaluation of indeterminate renal masses with contrast-enhanced US: a diagnostic performance study.
      ]. The ability to use multiple injections is helpful in performing biopsies and procedures.
      A Bosniak classification for CEUS has not been developed. However, the new Bosniak classification for CT and MRI [
      • Silverman S.G.
      • Pedrosa I.
      • Ellis J.H.
      • et al.
      Bosniak classification of cystic renal masses, version 2019: an update proposal and needs assessment.
      ] can be modified to incorporate CEUS. The definitions of septa number, wall and septa thickness, wall and septa irregularity from nodules, and calcifications can all be applied to US, although US may detect more septations and nodularity. With a much thinner slice thickness, measurements of septations may be slightly different than with CT or MRI but this should not substantially affect the classification. What is different is the probability of malignancy for some classifications, especially for Bosniak III and IV lesions, because CEUS has been shown to be more sensitive and specific in characterizing these lesions [
      • Barr R.G.
      • Peterson C.
      • Hindi A.
      Evaluation of indeterminate renal masses with contrast-enhanced US: a diagnostic performance study.
      ,
      • Barr R.G.
      Is there a need to modify the Bosniak renal mass classification with the addition of contrast-enhanced sonography?.
      ]. For Bosniak classification 3 lesions, approximately 50% are benign and 50% are malignant on CT or MRI [
      • Silverman S.G.
      • Pedrosa I.
      • Ellis J.H.
      • et al.
      Bosniak classification of cystic renal masses, version 2019: an update proposal and needs assessment.
      ]. However, in a large single-center study using CEUS to characterize indeterminate renal masses, CEUS was able to characterize the lesion as benign or malignant with greater than 95% accuracy [
      • Barr R.G.
      • Peterson C.
      • Hindi A.
      Evaluation of indeterminate renal masses with contrast-enhanced US: a diagnostic performance study.
      ,
      • Barr R.G.
      Is there a need to modify the Bosniak renal mass classification with the addition of contrast-enhanced sonography?.
      ] in appropriately triaging patients to follow-up or intervention, thereby eliminating the need for many biopsies or surgeries.
      The new Bosniak classification using CT or MRI requires the use of contrast. Based on the current literature, CEUS should have higher accuracy in characterizing a lesion as benign or malignant, especially for Bosniak category 3 lesions [
      • Barr R.G.
      Is there a need to modify the Bosniak renal mass classification with the addition of contrast-enhanced sonography?.
      ]. Further studies are needed to determine whether a CT or MRI Bosniak classification 3 lesion should have CEUS to improve characterization of the lesion to avoid unnecessary biopsy or surgery.
      For those cases where CT or MRI contrast is contraindicated, CEUS is the examination of choice. For renal lesions that do not fulfill the criteria for the use of the Bosniak classification, including solid lesions, CEUS has been shown to have high sensitivity and specificity for characterization of these masses and should be considered as a first-line study in their evaluation. For cases where a renal lesion is detected on CT or MRI where a renal mass protocol has not been used and the lesion needs further evaluation, CEUS can characterize these lesions with high accuracy without the need for radiation or high cost. CEUS is not included in the original or the recently revised Bosniak classification, but, until a CEUS Bosniak classification is devised, CEUS requires no such classification for excellent differentiation of malignant tumors, and diagnosis of benign and malignant renal masses.

      Contrast-enhanced ultrasonography beyond the liver and the kidney

      In any circumstance in which blood flow information may contribute to answers in radiology, a choice to use CEUS is reasonable. Following are brief descriptions of some of the further applications.

      Pancreas Contrast-Enhanced Ultrasonography

      Although neither US nor CEUS are widely used for the evaluation of pancreatic disorder in North America, there is sufficient evidence that pancreatic tumors do show differentiating enhancement patterns and CEUS can help with characterization of pancreatic adenocarcinoma. Pancreatic neoplasms include both cystic and solid tumors, the former all showing enhancement of their septations and nodularity in either a microcystic or macrocystic pattern. Solid tumors include hypoenhancing adenocarcinoma (Fig. 10, Video 6) compared with striking hyperenhancing neuroendocrine tumors. As with malignant tumors elsewhere, washout is a feature of malignant disease. Infrequent metastatic RCC may involve the pancreas, creating an appearance highly similar to a neuroendocrine tumor on gray-scale imaging and also CEUS. History is most helpful. Intraductal papillary mucinous neoplasia is well evaluated with CEUS, and detection of enhancing nodules within the dilated main or side branches indicates malignancy.
      Figure thumbnail gr10
      Fig. 10Pancreatic adenocarcinoma. On surveillance US performed on a 62-year-old man with inflammatory bowel disease (IBD), (A) there is an incidentally discovered pancreatic mass obstructing the pancreatic duct within the pancreatic body and tail (arrow). (B) At the peak of arterial phase enhancement, the mass is hypoenhanced (arrow). (C) The mass in the portal venous phase, still hypoenhanced relative to the parenchyma (arrow). This persistent hypoenhancement is classic for adenocarcinoma. Neither CT nor MR scan confirmed the presence of this mass. It was confirmed at surgical exploration. This figure corresponds with .
      CEUS assists in differentiation of cancer from inflammatory pancreatic masses, and in the differentiation of cystic tumors from benign pseudocysts. Transient vascularity of inflammatory masses associated with autoimmune pancreatitis and acute pancreatitis are suggestive. Masses associated with acute pancreatitis are aided by their clinical information. Pancreatic pseudocysts tend to be virtually bubble free on CEUS, regardless of the apparent complexity on gray-scale examination [
      • D'Onofrio M.
      • Zamboni G.
      • Faccioli N.
      • et al.
      Ultrasonography of the pancreas. 4. Contrast-enhanced imaging.
      ].

      Spleen Contrast-Enhanced Ultrasonography

      Splenic focal masses are much less frequently encountered than are focal liver masses, and their pathologic confirmation is also far less common. Nonetheless, CEUS is valuable to show the vascular patterns of tumors and, as in the liver, is invaluable to guide biopsy. Further, both splenic mass detection and lesion characterization are improved with CEUS [
      • Omar A.
      • Freeman S.
      Contrast-enhanced ultrasound of the spleen.
      ].
      Correlation with all available imaging is helpful to determine whether an identified masslike disorder is new and also whether it is growing. Although lacking good published confirmation, hyperenhancing splenic masses with rapid marked washout are concerning and should be biopsied (Fig. 11, Video 7). They may correlate with lymphoma deposits and also splenic metastases. Use of PET scan may confirm significance. In contrast, benign tumors such as hemangiomas may occur in the spleen, showing hyperenhancement with no washout.
      Figure thumbnail gr11
      Fig. 11Splenic tumor. A 65-year-old man with a remote liver transplant for cirrhosis with HCC. Surveillance US scan. (A) There is a focal hypoechoic round mass within the spleen. (B) At the peak of arterial phase enhancement, the mass is heterogeneous and slightly hyperenhanced (arrows). (C) At 50 seconds, the mass is completely black. This rapid and marked washout suggests malignancy and motivated PET scan. (D) PET scan confirms hypermetabolic activity (arrow). This mass is B-cell lymphoma. This figure corresponds with .
      Splenic infarction refers to a peripheral zone of the spleen without normal arterial perfusion. This condition may occur as a consequence of trauma, pancreatic neoplasm, or inflammation and may occur as a complication of splenomegaly from myeloproliferative disease.
      Splenic cysts may be developmental or acquired as a consequence of sepsis or trauma. Internal complexity and septations are insignificant if avascular [
      • Omar A.
      • Freeman S.
      Contrast-enhanced ultrasound of the spleen.
      ].

      Gastrointestinal Tract Contrast-Enhanced Ultrasonography

      In practical terms, the use of CEUS in the bowel is largely devoted to the assessment of the vascularity of the bowel in inflammatory bowel disease (IBD) as a reflection of active inflammation (Fig. 12, Video 8). US gray-scale assessment of the bowel in IBD shows mural thickening, perienteric inflammatory fat, and signal on color Doppler as inflammatory indicators. To show mural perfusion at the capillary level, CEUS is performed at the site of maximal wall abnormality, with subjective and objective quantification of the mural blood flow [
      • Medellin-Kowalewski A.
      • Wilkens R.
      • Wilson A.
      • et al.
      Quantitative contrast-enhanced ultrasound parameters in Crohn disease: their role in disease activity determination with ultrasound.
      ].
      Figure thumbnail gr12
      Fig. 12CEUS in IBD. A 31-year-old man with acute onset of colitis and new diagnosis of Crohn disease. All images show the affected left colon in long axis. (A) A gray-scale image shows mural thickening to more than 1 cm with luminal apposition. (B) A color Doppler image shows profuse mural vascularity. (C) A CEUS image at the peak of arterial phase enhancement shows transmural enhancement of the bowel wall. (D) Regions of interest are placed within the enhanced wall and generate time-intensity curves, 1 of which shows a high peak enhancement of 25 dB, consistent with severe active inflammation. This figure corresponds with .
      CEUS is performed by collecting raw data from a region of interest with maintenance of the probe over the segment of abnormal bowel for 2 minutes. The CEUS subjective evaluation estimates transmural blood flow and also identifies a comb sign reflecting vascularization of the mesentery. From this dataset, a time-intensity curve is generated by placement of regions of interest within the enhanced bowel wall. The peak enhancement, time to peak, and area under the curve are calculated [
      • Greis C.
      Quantitative evaluation of microvascular blood flow by contrast-enhanced ultrasound (CEUS).
      ].
      Studies show correlation of endoscopic activity assessments with estimations of activity on CEUS, and our study integrated CEUS data into a grading method based on gray-scale and color Doppler evaluations [
      • Ripolles T.
      • Rausell N.
      • Paredes J.M.
      • et al.
      Effectiveness of contrast-enhanced ultrasound for characterisation of intestinal inflammation in Crohn's disease: a comparison with surgical histopathology analysis.
      ]. Further, bowel CEUS and bowel wall point shear wave elastography are valuable biomarkers for characterization of strictures in Crohn disease as chronic or inflammatory [
      • Lu C.
      • Gui X.
      • Chen W.
      • et al.
      Ultrasound shear wave elastography and contrast enhancement: effective biomarkers in Crohn's disease strictures.
      ].
      Other applications for CEUS in the bowel include characterization of inflammatory masses as fluid-containing abscesses, as distinct from many inflammatory masses without drainable pus [
      • Ripolles T.
      • Martinez-Perez M.J.
      • Paredes J.M.
      • et al.
      Contrast-enhanced ultrasound in the differentiation between phlegmon and abscess in Crohn's disease and other abdominal conditions.
      ], and identified masses within the bowel lumen, bowel wall (Fig. 13, Video 9), and the supporting mesentery can be characterized with CEUS.
      Figure thumbnail gr13
      Fig. 13Bowel mass. A 50-year-old woman with an incidental tumor found within distal ileum at screening colonoscopy. US performed to assess for possible residual tumor. (A) A gray-scale image of the terminal ileum shows a very black mass (arrow) within the wall of the ileum, which shows a layered appearance. (B) At the peak of arterial phase enhancement, the mass is hyperenhanced (arrow). (C) At 2 minutes, the mass shows washout and appears hypoechoic relative to the rest of the bowel (arrow). This mass is malignant neuroendocrine tumor with characteristic gray-scale appearance and CEUS enhancement. This figure corresponds with .

      Endovascular Aortic Repair

      Endovascular insertion of a covered graft for treatment of abdominal aortic aneurysm is now a popular treatment of choice [
      • Chaikof E.L.
      • Mutrie C.
      • Kasirajan K.
      • et al.
      Endovascular repair for diverse pathologies of the thoracic aorta: an initial decade of experience.
      ]. However, marked improvement in survival is accompanied by an endoleak rate of 20% to 50%, mandating annual surveillance of all grafts looking for aneurysm growth or evidence of leak.
      Leaks are classified according to their assumed source of sac pressurization.
      • Type I endoleaks are seal failures between the graft and the native aorta at the proximal (type IA) or distal (type IB) ends [
        • Chaer R.A.
        • Avgerinos E.
        Endoleak following endovascular aortic repair.
        ] (Fig. 14, Video 10).
        Figure thumbnail gr14
        Fig. 14Endovascular aortic repair surveillance. CT surveillance scan following endovascular aortic repair shows (A), coronal and (B) axial images of the graft. There is a large collection of contrast agent (arrows) accumulated within the aortic sac. (C) CEUS long axis and (D) CEUS axial images show the same accumulation of contrast adjacent to the graft, best shown on the axial view. This concordant result shows a type 2 leak on both examinations. This figure corresponds with . Ao, aorta.
      • Type II endoleaks occur because of retrograde filling of excluded aneurysm sac from collateral flow in the lumbar of inferior mesenteric artery [
        • Chaer R.A.
        • Avgerinos E.
        Endoleak following endovascular aortic repair.
        ].
      • Type III endoleaks occur through gaps between components of the graft or, much less commonly, tears in the graft material [
        • Chaer R.A.
        • Avgerinos E.
        Endoleak following endovascular aortic repair.
        ].
      • Type IV endoleaks occur because of porosity of graft wall material [
        • Chaer R.A.
        • Avgerinos E.
        Endoleak following endovascular aortic repair.
        ].
      • Type V endoleaks are diagnosed in patients with aneurysm sac expansion without a definite perfusion source.
      Lifelong annual surveillance of patients treated with endovascular aortic repair [
      • Chaikof E.L.
      • Brewster D.C.
      • Dalman R.L.
      • et al.
      SVS practice guidelines for the care of patients with an abdominal aortic aneurysm: executive summary.
      ] is recommended. Because the endoleaks are often asymptomatic, early recognition is critical for appropriate patient management.
      Systematic reviews and meta-analyses show a comparable diagnostic accuracy of CEUS and CT angiography (CTA) in the diagnosis and classification of endoleaks [
      • Mirza T.A.
      • Karthikesalingam A.
      • Jackson D.
      • et al.
      Duplex ultrasound and contrast-enhanced ultrasound versus computed tomography for the detection of endoleak after EVAR: systematic review and bivariate meta-analysis.
      ,
      • Karthikesalingam A.
      • Al-Jundi W.
      • Jackson D.
      • et al.
      Systematic review and meta-analysis of duplex ultrasonography, contrast-enhanced ultrasonography or computed tomography for surveillance after endovascular aneurysm repair.
      ,
      • Sun C.
      • Lin S.
      • Zhao L.
      • et al.
      A meta-analysis of ultrasound imaging in diagnosis of endoleak among patients after endovascular abdominal aortic aneurysm repair.
      ,
      • Guo Q.
      • Zhao J.
      • Huang B.
      • et al.
      A systematic review of ultrasound or magnetic resonance imaging compared with computed tomography for endoleak detection and aneurysm diameter measurement after endovascular aneurysm repair.
      ]. The 2011 European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) practice guidelines suggest that CEUS may be more suited for characterization of endoleaks than CTA [
      • Piscaglia F.
      • Nolsøe C.
      • Dietrich C.F.
      • et al.
      The EFSUMB guidelines and recommendations on the clinical practice of contrast enhanced ultrasound (CEUS): update 2011 on non-hepatic applications.
      ]. This technique includes no requirement for ionizing radiation and no risk of nephrotoxicity.

      Pediatric Contrast-Enhanced Ultrasonography

      There is mounting evidence of the usefulness of CEUS in children in many areas, primarily as an imaging technique that reduces exposure to radiation, requires no iodinated contrast medium, and possesses the patient-friendly circumstances of US [
      • Sidhu P.S.
      • Cantisani V.
      • Deganello A.
      • et al.
      Role of contrast-enhanced ultrasound (CEUS) in paediatric practice: an EFSUMB position statement.
      ]. The safety profile of UCA for children is comparable with the excellent safety records shown in adults [
      • Mao M.
      • Xia B.
      • Chen W.
      • et al.
      The safety and effectiveness of intravenous contrast-enhanced sonography in chinese children-a single center and prospective study in China.
      ].
      Scanning and injection techniques for UCA are similar to those in adults with appropriate reduction of dose and peripheral line access related to patient size and age. Imaging techniques are also similar. Intravascular interpretation reflects the similarity of the disorders between the populations.
      Intravascular applications include surveillance following blunt abdominal trauma, with solid organ injury, and characterization and detection of liver masses, focal fatty sparing, adenoma, and malignant tumor [
      • Anupindi S.A.
      • Biko D.M.
      • Ntoulia A.
      • et al.
      Contrast-enhanced US assessment of focal liver lesions in children.
      ].
      Intravesical applications assessing for reflux comprise another major application for pediatric CEUS. Scans are performed with direct injection of UCA into the bladder, with subsequent imaging showing any refluxed contrast within the upper urinary tracts. Multiple studies show the higher sensitivity of contrast-enhanced voiding urosonography (ceVUS) in the detection of reflux compared with voiding cystourethrography or direct radionuclide scintigraphy. Adverse events are rare, and consist primarily of dysuria, transient macrohematuria, and abdominal discomfort, likely related to catheter placement [
      • Darge K.
      Voiding urosonography with ultrasound contrast agents for the diagnosis of vesicoureteric reflux in children. I. Procedure.
      ].
      Imaging is performed with the patient supine, prone, or in a decubitus position. The kidneys are alternately scanned while intermittently monitoring the bladder during filling and voiding. During voiding, the urethra can be scanned from either a suprapubic or transperineal approach [
      • Duran C.
      • del Riego J.
      • Riera L.
      • et al.
      Voiding urosonography including urethrosonography: high-quality examinations with an optimised procedure using a second-generation US contrast agent.
      ,
      • Berrocal T.
      • Gaya F.
      • Arjonilla A.
      Vesicoureteral reflux: can the urethra be adequately assessed by using contrast-enhanced voiding US of the bladder?.
      ]. Reflux is diagnosed when microbubbles are detected in a ureter and/or the pelvocalyceal system. Grading of reflux by ceVUS is similar to the 5-point international grading system used for voiding cystourethrogram.

      Contrast-Enhanced Ultrasonography in Interventional Radiology

      CEUS is a valuable addition to US for the guidance of interventional procedures, greatly facilitating the ability to see the target, whether it be for percutaneous biopsy or ablation of tumors; for example, within the liver or kidney. Monitoring response to therapy is a further developing role for CEUS.

      Summary

      There is compelling evidence that CEUS of both the liver and the kidney is an invaluable addition to other cross-sectional imaging techniques. This article presents additional evidence of the growing applications for CEUS throughout the abdomen.

      Supplementary data

      References

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