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Review Article

Contrast -Enhanced Ultrasound

State of the Art in North America

Barr, Richard G. MD, PhD∗,†; Wilson, Stephanie R. MD; Lyshchik, Andrej MD, PhD§; McCarville, Beth MD; Darge, Kassa MD; Grant, Edward MD#; Robbin, Michelle MD∗∗; Wilmann, Juergen Karl MD††; Chong, Wui K. MD‡‡; Fleischer, Arthur MD§§; Paltiel, Harriet J. MD∥∥

Author Information
doi: 10.1097/RUQ.0000000000000514
  • Free

Key Points

  1. Contrast-enhanced ultrasound (CEUS) allows cross-sectional imaging of the liver, kidneys, and multiple other solid and hollow viscera, providing excellent characterization of identified focal mass lesions.
  2. Performed with the injection of a microbubble contrast agent, CEUS provides a safe and readily available imaging technique that requires no ionizing radiation, making it appropriate for use in all ages, in those with renal insufficiency, and when a portable examination is needed.
  3. CEUS can be considered in abdominal imaging whenever blood flow information is of value to diagnosis.
  4. Dynamic real-time acquisition, thin slice thickness, superb background subtraction, and the use of a purely intravascular contrast agent are the most essential technical aspects of CEUS imaging, which distinguish it from both computed tomography and magnetic resonance scan.

Contrast-enhanced ultrasound (CEUS) has been used for a variety of applications in Europe, Canada, and Asia for many years. Medical imagers in these countries consider CEUS a unique technique requiring an important place in their imaging toolbox. Therefore, both the World Federation of Ultrasound in Medicine and Biology1,2 and the European Federation of Societies for Ultrasound in Medicine3 have published guidelines for appropriate use of CEUS.

There are 3 ultrasound contrast agents (UCAs) with Food and Drug Administration (FDA) approval available in the United States (Table 1).

TABLE 1
TABLE 1:
UCAs and Recommended Doses From Package Inserts
  1. Lumason (sulfur hexafluoride lipid-type A microspheres) injectable suspension, for intravenous (IV) or intravesical use; also known as SonoVue outside the United States (Bracco Diagnostics Inc, Monroe Township, New Jersey)
  2. Definity (perflutren lipid microspheres) Injectable Suspension (Lantheus Medical Imaging, Billerica, Massachusetts)
  3. Optison (perflutren protein-type A) Injectable Suspension (GE Healthcare, Malborough, Massachusetts)

After the long-awaited FDA approval of a microbubble for abdominal use in the United States in April 2016, the Society of Radiologists in Ultrasound convened a panel of specialists in CEUS to develop guidelines regarding the use of CEUS in noncardiac applications in both adult and pediatric patients. The panel met in Chicago, Illinois, on October 24–25, 2017, and drafted this document. The recommendations below are based on an analysis of the current literature and common practice strategies and are thought to represent a reasonable approach for both on-label and off-label use of CEUS.

The goals of the panel were to (a) detail the requirements for development of a CEUS program; (b) review UCA and their safety profile; (c) provide guidance on performance of CEUS examinations, interpretation of results, and reporting of the findings; (d) determine appropriate off-label indications for CEUS (in the long version online only); and (e) set an agenda for further research.

METHODS AND CONFERENCE PREPARATIONS

The comoderators of the conference (R.G.B. and H.J.P.) designed the schedule for the state-of-the-art conference and invited the speakers. The panel consisted of 2 comoderators and 8 additional speakers with expertise in CEUS. A summary of all talks and a list of relevant references were made available to the panelists before the meeting. Invited representatives interested in CEUS and industry were also in attendance.

Several panel members are on the advisory panels of ultrasound (US) contrast companies. Several panel members have research grants with equipment vendors. Final recommendations in this publication represent the consensus opinions of the panel members, none of whom have a financial interest in the technologies reviewed.

REQUIREMENTS FOR A CEUS PROGRAM

The successful implementation of a CEUS program requires a US scanner with contrast imaging software, UCA, IV access, and 2 sets of hands available for injection and performance of the CEUS imaging. Contrast-specific software, a low MI technique, including pulse inversion, power modulation, and combinations thereof, provides an excellent subtraction technique, which results in a microbubble-contrast image only.

Ultrasound contrast injections should comply with local departmental policies for consent, similar to those for computed tomography (CT) and magnetic resonance (MR) contrast agents. Today, this is generally verbal informed consent.

Features of US Equipment

Most US vendors have CEUS capable systems. These scanners have capability to continuously record information for intervals ranging from several seconds (generally approximately 20, for recording wash-in of a tumor) or up to several minutes (generally 2 or 3 for generation of time intensity curves for blood flow quantification). For tumor evaluations, routine acquisition of long clips is not generally advised, as the storage of large amounts of data is problematic and long intervals of scanning will always lead to some bubble destruction. Therefore, an acquisition of more manageable and shorter length is advised. In the Indications section hereinafter, a more detailed discussion of application-specific scanning is provided. Please refer to organ-specific protocols for detailed description of imaging techniques.

Scanning Protocol

For diagnostic CEUS images, an appropriate scanning protocol is required. The scanning protocol is detailed in the online version of this article, highlighting pitfalls. A brief summary of the steps in performing a CEUS study is listed in Table 2.

TABLE 2
TABLE 2:
Steps in Performing a CEUS Study

Safety

Ultrasound contrast agents have a strong safety profile in both pediatric and adult publications, with an adverse event rate less than that of modern CT and MR imaging (MRI) contrast agents.4,5

They are contraindicated for intra-arterial injection and in patients with a history of hypersensitivity to the agent or to any of the inactive ingredients of the UCA. Ultrasound contrast agents have no known renal toxicity in approved doses.

Indications

There are several advantages of CEUS, which are summarized in Table 3. Patients that are appropriate for CEUS are listed in Table 4. This document, based on literature review, provides the level of evidence (Table 5) for various clinical CEUS applications, including references to provide guidance.

TABLE 3
TABLE 3:
Advantages of CEUS
TABLE 4
TABLE 4:
Patients Who Are Appropriate for CEUS
TABLE 5
TABLE 5:
Level of Evidence for Various CEUS Applications*

Contrast-enhanced ultrasound provides an option for patient imaging in the United States, expanding the value of the integrated radiology offerings and should be part of the imaging solution provided by radiology. As per the Choosing Wisely Campaign, the need for an imaging option that does not involve ionizing radiation is desirable particularly for children and patients requiring serial or frequent testing due to oncologic/chronic disease.

LIVER CEUS

The performance of CEUS for focal liver lesion (FLL) characterization is one of the most successful applications for this technique. In a prospective multicenter trial with 1349 patients, there was no statistical significant difference between CEUS and spiral CT in liver tumor differentiation (malignant or benign) and tumor specification.6 In meta-analysis of 21 studies, for CEUS, sensitivity was 88% (95% confidence interval [CI], 87%–90%), specificity was 81% (95% CI, 79%–84%), and 38.62 (95% CI, 13.64%–109.35%) for diagnostic odds ratio, all were similar with no statistical difference from contrast-enhanced CT (CECT) or contrast-enhanced MRI.7

Recommended CEUS Use

  1. Characterization of FLLs in the noncirrhotic liver
    1. Incidentally found liver lesions on US
    2. Incompletely characterized lesions on noncontrast or contrast-enhanced CT or MRI
  2. Characterization of FLLs in the cirrhotic liver
    1. Assess nodules detected on surveillance US
    2. Assess Liver Imaging Reporting and Data System (LI-RADS) LR-3, LR-4, LR-5, or LR-M observations on prior CEUS CT or MRI
    3. Detect arterial phase hyperenhancement (APHE) when mistiming is suspected as the reason for its absence on prior CT or MRI
    4. Assess biopsied lesions with inconclusive histology
  3. Detection of metastases
  4. Vascular
    1. Determine hepatic artery, portal vein, and hepatic vein patency
    2. Assess transjugular intrahepatic portosystemic shunt patency
    3. Distinguish bland versus tumor hepatic/portal vein thrombus
  5. Interventional aids in known lesion detection/evaluation at the time of biopsy or therapy

CEUS PROTOCOL

To maximize benefits of real-time CEUS imaging and to preserve enough microbubbles to allow late contrast washout detection, the liver CEUS protocol is based on a combination of continuous imaging in the arterial phase (AP) and intermittent imaging in later phases.

IMAGING

  • It should be performed continuously on a preidentified nodule, from contrast injection until peak AP enhancement to characterize presence (yes or no), intensity (hyperenhancing, isoenhancing, hypoenhancing, or nonenhancing), pattern of AP hyperenhancement (diffuse, nodule-in-nodule, rim, peripheral discontinuous globular or stellate), and the direction of vascular filling (centrifugal or centripetal) with respect to adjacent normal liver.
  • Alternatively, continuous imaging could be extended beyond peak AP enhancement until 60 seconds after contrast injection to confirm the presence of early washout.
  • Subsequent imaging is intermittent (5–10 seconds every 30–60 seconds) to detect late washout and assess its degree.
  • This technique will minimize microbubble destruction until microbubbles are cleared completely from the circulation (usually 4–6 min after injection) and improve ability to detect late washout and assess its degree.
  • Sweeping the entire liver in the late phase can help to identify additional areas of abnormal enhancement, especially washout.
  • Injections can be repeated as needed including “on top” of a prior injection to assess vascularity of an identified area of washout.

IMAGE RECORDING

  • Time zero corresponds to the beginning of the saline flush injection.
  • Recording should be performed continuously from first bubble arrival through peak AP enhancement as a minimum requirement.
  • Optionally, cine loop recording can be continued beyond AP enhancement peak until 60 seconds after injection.

Recording of static images at 60 seconds and with each intermittent (every 30–60 seconds) acquisition thereafter is sufficient to document and evaluate the presence, timing, and degree of washout.8

CEUS IMAGE INTERPRETATION

Experience with the use of microbubble contrast agents for this indication has led to the recognition of multiple constant features, which lead to reliable differentiation of benign and malignant masses and also for the provision of their specific accurate diagnoses.

Washout and the Determination of Malignancy

A first step in the analysis of CEUS of a liver mass is determination of malignancy,9 best indicated by washout of contrast from a lesion after AP enhancement, whereby the mass becomes less enhanced than the adjacent liver parenchyma. Washout is shown to have a high predictive value for the determination of malignancy10,11 (Fig. 1).

FIGURE 1
FIGURE 1:
Washout of a nodule after AP enhancement is the most reliable predictor of malignancy. A liver tumor showed as a nodule on grayscale US (not shown). Left: at the peak of AP enhancement, the liver is mildly enhanced, whereas the nodule shows APHE. This reflects hypervascularity as compared with the liver. Right: at 4 minutes, the liver remains enhanced. The nodule shows washout such that it appears dark relative to the surrounding liver parenchyma. On CEUS, intensity and timing of washout differentiate hepatocellular from nonhepatocellular malignancy. Here, late weak washout is suggestive of HCC.

Furthermore, washout timing and intensity are invaluable for the differentiation of hepatocellular (hepatocellular carcinoma [HCC]) and nonhepatocellular malignancy, including both metastases and cholangiocarcinoma. Hepatocellular carcinoma is characterized by washout that is late, occurring after 1 minute, and weak, whereas nonhepatocellular malignancy is characterized by rapid washout, occurring at less than 1 minute, which is often marked.

AP Enhancement

Benign tumors commonly encountered on CEUS examination include hemangioma and focal nodular hyperplasia (FNH). Both have highly suggestive enhancement patterns in the AP, optimally depicted by the real-time dynamic scanning afforded by CEUS.12

Hemangiomas are characterized by discontinuous peripheral globular enhancement with progressive centripetal enhancement over time. Focal nodular hyperplasia is a highly vascular tumor that is typically characterized by stellate vessel morphology with centrifugal filling (Fig. 2). Both FNH and hemangioma demonstrate sustained enhancement in the portal venous and late phases of enhancement, retaining contrast to the same degree as the adjacent liver parenchyma at 4 to 5 minutes after injection. Sustained enhancement is generally regarded as a benign enhancement feature.

FIGURE 2
FIGURE 2:
A 36-year-old asymptomatic woman. An incidental liver mass discovered at the time of pelvic ultrasound. A, A grayscale image of the right upper quadrant shows the liver and the kidney. The mass (arrow) is hypoechoic. B, At 10 seconds after microbubble injection, the mass shows a stellate vascular configuration. C, At 30 seconds, the mass is homogeneously enhanced greater than the adjacent liver. The kidney is also brightly enhanced. At 3 minutes, the mass is no longer visible, being isoenhancing with the adjacent liver. Sustained enhancement as here is consistent with a benign diagnosis.

Hepatic adenoma, a rare benign liver tumor, shows unpredictable grayscale and enhancement features that make its diagnosis a challenge. Fatty composition and complicating hemorrhage may alter baseline observations, and multiple subtypes have different enhancement features with only a percentage of lesions showing a suggestive centripetal filling pattern.13

In addition, adenoma is a benign exception to the washout rule in that approximately 50% of tumors show late weak washout, often making adenoma indistinguishable from HCC without clinical information.

The specific AP enhancement patterns characteristic of most benign tumors diagnosed on CEUS are not found in most malignant lesions where the AP enhancement features are more variable and nonspecific.14Metastases, the most common liver tumor, may demonstrate AP hyperenhancement, isoenhancement, or hypoenhancement, which may show a globular or rim pattern. Metastases, however, are not characterized by their AP enhancement patterns but by their rapid washout, generally occurring within 1 minute after contrast injection. Contrast-enhanced US features of other nonhepatocellular malignancies often overlap with those of metastases, as all tend to show rapid washout at less than 60 seconds. Classic HCC shows globular APHE. However, other liver nodules found in a cirrhotic liver may show AP variations, including no enhancement or isoenhancement.15

Regarding liver mass characterization, CEUS generally shows good agreement with CT and MRI, especially in the AP. However, discordance of CEUS imaging features with those on CT and/or MRI may be associated with the behavior of the purely intravascular contrast agents for CEUS showing washout in malignant masses, whereas CT and MR interstitial agents may instead show pseudoenhancement.8 This feature is found especially in cholangiocarcinoma.16

Contrast-Enhanced US LI-RADS

Contrast-enhanced US LI-RADS was recently developed under the direction of the American College of Radiology for the imaging, interpretation, reporting, and management of patients at risk for HCC. It supplements previously implemented LI-RADS for CT and MRI.17 The Liver Imaging Reporting and Data System provide an ordinal risk classification system for all observations on liver imaging. This positive advancement for liver imaging with US is fully described in the online version of this article.

Summary (Liver CEUS)

Contrast-enhanced US is invaluable for the characterization of both benign and malignant liver tumors. It improves the evaluation of liver masses and is a recognized modality for problem solving and for resolution of indeterminate masses identified on CT and MRI. Contrast-enhanced US features most relevant for liver imaging include dynamic real-time scanning, to show the specific features of benign tumors; purely intravascular contrast agents, showing true washout in cholangiocarcinoma; and a subtraction technique making US excellent for demonstration of both APHE and washout.

KIDNEY CEUS

Indeterminate renal masses are a common clinical problem. Although many renal masses are benign simple cysts and can be confidently diagnosed on routine grayscale imaging, CT or MRI, it is well recognized that many masses are indeterminate on CT/MR related to volume averaging, inability to use contrast agent, and thin septations. It is in this environment where CEUS plays a major role.

The Bosniak classification for CT and MRI has been recently revised.18 A Bosniak classification for CEUS has not been developed. The Bosniak classification is intended for cystic renal masses after infectious, inflammatory, vascular etiologies, 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.

Contrast-enhanced US has several advantages in renal mass characterization over other modalities. The UCA is not excreted in the collecting system allowing for improved visualization of the collecting system and differentiation of the medulla from the cortex. The UCA does not have renal toxicity and can be used in renal-impaired patients and in those with renal obstruction. Thin slice thickness improves characterization of septations and nodularity and detection of enhancement. Without the volume averaging seen in CT and MRI, real-time imaging detects enhancement that can be missed on “snapshot” images of CT and MRI. Contrast-enhanced US subtraction techniques remove the background soft tissue echoes with production of a contrast only image, allowing for visualization of enhancement in small structures such as septations or small mural nodules.

Contrast-enhanced US alone has been successfully used to evaluate renal abnormalities.3,19–30 In a large CEUS series done for evaluation of indeterminate renal masses, the sensitivity was 100% (95% CI, 97.1%–100%) with a specificity of 95% (95% CI, 89.9%–98.0%), a positive predictive value of 91.5%, and a negative predictive value of 100%.29 Lesion classification based on CEUS enhancement patterns, presented in Table 6, shows a very strong association between benignancy and avascularity, whereas most vascular lesions regardless of complexity are malignant. Analysis of a large study of 1018 indeterminate renal masses on CT, MR, or unenhanced US found that the Bosniak classification does not correlate well with CEUS.31 In that study, it was found that appropriately two-thirds of Bosniak 3 lesions and a number of Bosniak 4 lesions could be classified as benign based on confirmed long-term follow-up.

TABLE 6
TABLE 6:
Renal Enhancement Patterns

Recommended CEUS Use

  • Characterization of indeterminate renal masses
  • Evaluation of renal parenchyma in patients with suspected renal abscess or infarction
  • Evaluation of renal transplants in patients with suspected renal vascular complications and renal infarcts

CEUS Kidney Protocol

Perform continuous recording from first arrival of a bubble in the field of view (FOV) to lesion characterization, which is usually less than 2 minutes. From the cine clips, still images can then be saved at the end of the study. Scanning the entire lesion to evaluate septations, mural nodules, and solid components particularly in indeterminate masses is required. Scanning the kidney for additional lesions is often possible. Initially, cortical phase enhancement of the renal cortex with little enhancement of the medullary pyramids is seen, followed by the nephrographic phase with enhancement of the entire kidney. The excretory phase shown on CT and MRI does not occur with CEUS, as the bubbles remain intravascular and are not excreted.

CEUS Image Interpretation

Benign Lesions

  • Benign cysts regardless of Bosniak classification show no contrast enhancement within the lesion. Indeed, any renal lesion that does not have enhancement can be confidently classified as benign (Fig. 3). Occasional individual bubbles can be identified traversing a septation, or there may be a constant flow of bubbles within a septation without nodularity. These are benign findings.29
  • Pseudotumors demonstrate an enhancement pattern identical to that of normal renal cortex in all enhancement phases with the presence of a central pyramid.
  • Angiomyolipomas usually show enhancement less than that of the renal cortex and often in a peripheral distribution. This contrasts with echogenic renal cell carcinomas (RCCs), which show uniform enhancement that is equal to or greater than normal renal cortex (unless there is central necrosis), and washout. Noncontrast CT or MRI is advised to confirm macroscopic fat in an angiomyolipoma.29 Any other cystic or solid mass with internal blood flow is considered malignant.
  • Pyelonephritis usually has decreased flow compared with normal renal cortex. Abscesses are avascular.
FIGURE 3
FIGURE 3:
Triphasic contrast-enhanced computed tomography images of a 68-year-old man who presented with renal masses demonstrates both a right and left upper pole low-attenuation renal masses: precontrast image (A), portal venous phase (B), and delayed phase (C). Both masses are similar on all 3 phases of contrast injection. However, on CEUS, the lesion in the right kidney markers demonstrated intense enhancement and quick wash out and was an RCC (D), whereas the lesion in the left kidney had no CEUS enhancement and was a benign cystic lesion (E). This case demonstrates the value of continuous real-time monitoring of the contrast enhancement in renal masses. Copied with permission from Barr RG. Is there a need to modify the Bosniak renal mass classification with the addition of contrast-enhanced sonography? J Ultrasound Med 2017;36:865–868.

Malignant Lesions

  • All malignant lesions show CEUS enhancement (Fig. 4). Renal cell carcinoma has several subtypes including conventional (clear cell; 70%), papillary (15%–20%), chromophobe (6%–11%), and collecting duct carcinoma (<1%). The classification of RCC into subtypes is important because of their different prognoses.32,33 If the subtype can be identified before surgery, it may change management. For example, an elderly patient with a papillary subtype may be watched instead of requiring surgery. Previous studies using CECT and MRI have found different enhancement patterns for the subtypes.34–36 On CECT, conventional RCC demonstrates stronger enhancement than nonconventional RCC in both the corticomedullary and excretory phases. Several small studies suggest that CEUS may also be able to differentiate between the subtypes of RCC, with papillary and chromophobe RCCs typically appearing less vascular than the adjacent enhancing renal parenchyma. Clear cell carcinoma, by comparison, appears hypervascular relative to the adjacent parenchyma.37,38
FIGURE 4
FIGURE 4:
A 77-year-old man with a history of left renal mass. Examination performed for follow-up study to assess interval growth. The B-mode image on the right demonstrates an exophytic renal mass (arrows). The CEUS image on the left shows the mass to be hyperenhancing to the renal cortex highly suggestive of an RCC.

Summary

Contrast-enhanced US of the kidney is a very useful diagnostic technique, substantially improving renal mass characterization on CT or MRI using the Bosniak criteria for complex renal cystic masses, thereby reducing the necessity for frequent follow-up examinations to resolve the nature of renal lesions. It is also useful for biopsy guidance of perfused tumors and can help assess for the presence of residual tumor after locoregional therapy.

OTHER CEUS INDICATIONS

A review of the literature and expert recommendations for CEUS of bowel, spleen, pancreas, ovaries, testicles, breast, musculoskeletal, and vascular systems are included in the online version.

Interventional Oncology

Contrast-enhanced US can improve the sensitivity of US-guided tissue sampling in a variety of solid organs to 96% to 100%. It can guide biopsies of solid organ lesions identified on other imaging modalities not visible with conventional gray-scale US.39 Contrast-enhanced US substantially increases the adequacy and diagnostic yield of biopsies in sampling peripheral lung lesions with US guidance, predominantly by identification of nonnecrotic tumor areas to target and differentiating tumor from surrounding atelectasis.40 The interventional radiologist can also use CEUS to improve image guidance during percutaneous ablation treatments by improving tumor boundary visualization.3,41 Contrast-enhanced US is useful in early posttreatment assessment after ablation techniques and intraarterial chemotherapy/radiation therapy and may allow earlier evaluation of residual tumor than CT.42

Recommended CEUS Use

  • Imaging guidance for soft tissue biopsies and ablation
  • Assessment of tumor response after locoregional treatment

CEUS Protocol

When performing CEUS guidance for biopsies, several injections may be required. The first bolus injection is used to identify the target lesion and plan the procedural approach. It can also be used to locate the surrounding intrahepatic anatomical landmarks, plan a safe needle trajectory, adjust patient positioning, and review breathing instructions. It assists with the decision to biopsy when the lesion is enhanced, and the lesion demonstrates wash-out.

The second bolus is used to guide biopsy needle placement.

Procedure Guidance

For liver tumors, careful scanning in the both arterial and delayed phases of CEUS imaging is very beneficial in identifying target lesions which most often demonstrate APHE and delayed wash-out. The biopsy needle is usually clearly visible on both CEUS and reference B-mode images due to tissue motion in the vicinity of the needle tip, which generates harmonic signals, and the presence of air in the side notch of core biopsy needles, which appears as bright echogenic reflectors.43 When the target lesion is clearly visible after the second contrast agent injection, the biopsy needle is advanced into the target and tissue sampling is performed. Timing of needle placement will depend on the type of tumor being sampled. In large/partially necrotic tumors, sampling should be performed based on APHE of actively perfused, viable tumor components. In smaller lesions that are poorly identified on routine B-mode US, the biopsy is performed in the late phase of CEUS imaging, targeting areas of tumor wash-out surrounded by actively perfused, normal liver parenchyma.

Assessment of Tumor Response After Locoregional Treatment

Local recurrence and residual disease can be identified on CEUS by isoenhancement or hyperenhancement within or adjacent to the ablation defect. Granulation and scar tissue within or adjacent to the ablation cavity typically show substantially delayed and significantly less enhancement compared with the surrounding normal tissues.

Summary

Contrast-enhanced US is a powerful tool that can obviate the need for interventional procedures in select patients, where the benign nature of a previously indeterminate lesion can be definitely established with CEUS. Examples include a hemorrhagic or proteinaceous renal cyst, or a classic liver hemangioma in a patient with suspected liver metastasis. It is also useful for biopsy guidance of perfused tumors and can help assess for the presence of residual tumor after locoregional therapy.

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.38 Further studies are needed to determine if a CT or MRI Bosniak classification 3 lesion should have a 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 treatment in their evaluation. For cases where a renal lesion is detected on a 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.

PEDIATRIC CEUS

Intravascular Applications

The most common IV indications for UCA in children are FLLs (48%) and blunt abdominal trauma (37%).44 Focal lesions commonly diagnosed in children include hemangioma, FNH, focal fatty sparing, adenoma, and malignant tumor.45,46 These lesions have CEUS characteristics similar to those in adults.

The safety profile of IV Lumason in children resembles that in adults with very few (0.7%) minor, transient adverse events.44,47

Dosing

The approved dose for Lumason is 0.03 mL/kg with a maximum of 2.4 mL per injection. In practice, conspicuity of the lesion(s), depth of the area to be scanned, and transducer frequency require adjustment of the dose.

Scanning Protocol

As in adults, focal lesions are characterized according to early enhancement and delayed washout patterns. A video clip is obtained for the first minute after injection followed by static images or short clips obtained intermittently for approximately 5 minutes to detect early contrast washout from the lesion. Sweeping through an organ after complete enhancement is a screening method to detect lesions in suspected cases of blunt abdominal trauma.

Tips

Intravenous administration is best carried out using a peripheral line and can be performed through needles as small as 24G. Central lines can also be used.

Intravesical Applications

Indications for contrast-enhanced voiding urosonography (ceVUS) include suspected vesicoureteral reflux and/or urinary tract dilation. Studies have repeatedly demonstrated the higher sensitivity of ceVUS in the detection of reflux compared with voiding cystourethrography or direct radionuclide scintigraphy.48,49 Adverse events are rare and consist primarily of dysuria, transient macrohematuria, and abdominal discomfort, likely related to catheter placement.5

Dosing

The FDA-approved dose for Lumason is a 1-mL injection directly into the bladder. In practice, dose will vary according to what US equipment is used. With infusion, a 0.1% to 0.2% solution of Lumason in a 0.9% normal saline suspension is generally sufficient.

Scanning Protocol

A catheter is placed into the bladder using standard sterile technique and the bladder emptied.50 With direct UCA injection, a 3-way stopcock is attached to the catheter, a 50-mL or larger syringe filled with normal saline is connected to the 90-degree port of the stopcock, and a syringe with UCA is attached to the 180-degree port. The bladder is slightly filled with normal saline followed by injection of the UCA. The syringe is removed from the 180-degree port and replaced with the tube connected to a bag of normal saline, which is then infused into the bladder. To facilitate homogenous distribution of UCA, a normal saline flush is given from the 90-degree port. In the infusion method, a solution is prepared by injecting 0.25 to 0.5 mL of Lumason into a 250-mL normal saline bag that is infused into the bladder. Bladder filling is continued until maximum bladder capacity is reached or the patient voids, whichever comes first.

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.51,52 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 cystourethrogram53 (Fig. 5).

FIGURE 5
FIGURE 5:
Contrast-enhanced voiding cystourethrogram of a 5-month-old shows grade IV reflux into the ureter and collecting system of the left kidney.

Tips

Baseline images of the kidneys should be obtained in contrast-specific dual mode for later comparison if reflux is suspected. It is best to use normal saline solution from plastic containers as glass containers may be vacuum sealed, which can lead to rapid diffusion of the microbubble gas into solution.54

Summary

Contrast-enhanced US is useful in the differential diagnosis of focal liver masses and detection of solid organ injury in trauma. Contrast-enhanced voiding urosonography is a sensitive method for diagnosis of reflux.

POTENTIAL FUTURE APPLICATIONS

Quantification

Noninvasive, quantitative measurement of tissue blood flow using diagnostic imaging methods is a rapidly expanding area of basic science and clinical investigation. Major areas of clinical research include assessment of tumor blood flow and measurement of bowel wall vascularity in inflammatory bowel disease. Assessment of tissue blood flow with CT and MRI requires the use of low-molecular-weight contrast agents that diffuse freely across the vascular membrane. Subsequently, quantification of tissue vascularity with these contrast agents requires complex, multicompartmental pharmacokinetic modeling. In addition, these modalities either expose the patient to the harmful effects of radiation or can require sedation. Contrast-enhanced has unique attributes that make it more compelling for measuring blood flow than other imaging modalities. Compared with dynamic CECT and MR, CEUS is relatively easy and quick to perform. Details on how to perform quantitative CEUS are presented in the online version.

Drug Delivery

In addition to diagnostic uses, US microbubbles can be used for therapeutic applications. Through a process called sonoporation, US microbubble-mediated cavitation generates transient or permanent pores in the walls of blood vessels, thereby enhancing imaging-guided delivery of therapeutics such as drugs or genes into the extravascular compartment.54 Cavitation is defined as the growing and shrinking response of microbubbles subjected to the alternating low- and high-pressure portions of the US wave.55 There are 2 types of cavitation: stable and inertial. Stable cavitation occurs at low acoustic pressure when microbubbles stably oscillate without collapsing in an acoustic field. Inertial cavitation occurs with higher acoustic pressures, where microbubbles violently grow and eventually collapse.

Dynamic microbubble motion along with fluid motion can exert mechanical forces on blood vessels. Energetic microbubble collapse results in secondary mechanical phenomena including liquid jetting and shockwaves.55 These cavitation-induced mechanical effects can lead to both short-term responses (e.g., cell morphology change) and extended bioeffects (e.g., temporal cell permeability changes and cell lysis), thereby enhancing the transmembrane transport and cellular uptake of therapeutic agents. Moreover, US microbubble-mediated drug delivery can potentially overcome disadvantages such as irreversible thermal damage to tissues (particularly the surrounding normal tissue) commonly associated with hyperthermia-mediated drug delivery.56 A review of the literature is presented in the online version.

LIMITATIONS OF CEUS

Contrast-enhanced US suffers from the same problems as noncontrast US, especially obesity and attenuation from fatty liver. Artifacts due to overlying bowel gas, poor acoustic windows, and a limited field of view compared with CT and MRI are also important. Although CEUS has the ability to view the enhancement pattern of a lesion at a high frame rate over an extended period, most often only one lesion (or adjacent lesions) can be assessed with one injection. However, multiple injections can be performed, as most CEUS agents stay in the vascular space and do not diffuse into the interstitial space and/or are not actively taken up by Kupffer cells.

CONCLUSIONS

Contrast-enhanced US is a safe, nonionizing imaging method that has many applications with sensitivities and specificities equal to or greater than CT and MRI. Use of dynamic real-time imaging, thin slice thickness, superb background suppression, and a purely intravascular microbubble contrast agent provide unique advantages that should make CEUS an essential tool in our imaging toolbox.

REFERENCES

1. Claudon M, Dietrich CF, Choi BI, et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver—update 2012. Ultrasound Med Biol. 2013;39(2):187–210.
2. Claudon M, Dietrich CF, Choi BI, et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver—update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM. Ultrasound Med Biol. 2013;39(2):187–210.
3. Piscaglia F, Nolsøe C, Dietrich C, et al. The EFSUMB guidelines and recommendations on the clinical practice of contrast enhanced ultrasound (CEUS): update 2011 on non-hepatic applications. Ultraschall Med. 2012;33(1):33–59.
4. Piscaglia F, Bolondi L. The safety of Sonovue in abdominal applications: retrospective analysis of 23188 investigations. Ultrasound Med Biol. 2006;32(9):1369–1375.
5. Darge K, Papadopoulou F, Ntoulia A, et al. Safety of contrast-enhanced ultrasound in children for non-cardiac applications: a review by the Society for Pediatric Radiology (SPR) and the International Contrast Ultrasound Society (ICUS). Pediatr Radiol. 2013;43(9):1063–1073.
6. Seitz K, Strobel D, Bernatik T, et al. Contrast-enhanced ultrasound (CEUS) for the characterization of focal liver lesions—prospective comparison in clinical practice: CEUS vs. CT (DEGUM multicenter trial). Parts of this manuscript were presented at the Ultrasound Dreilandertreffen 2008, Davos. Ultraschall Med. 2009;30(4):383–389.
7. Guang Y, Xie L, Ding H, et al. Diagnosis value of focal liver lesions with SonoVue(R)-enhanced ultrasound compared with contrast-enhanced computed tomography and contrast-enhanced MRI: a meta-analysis. J Cancer Res Clin Oncol. 2011;137(11):1595–1605.
8. Lyshchik A, Kono Y, Dietrich CF, et al. Contrast-enhanced ultrasound of the liver: technical and lexicon recommendations from the ACR CEUS LI-RADS Working Group. Abdom Radiol (NY). 2018;43(4):861–879.
9. Burns PN, Wilson SR, Simpson DH. Pulse inversion imaging of liver blood flow: improved method for characterizing focal masses with microbubble contrast. Invest Radiol. 2000;35(1):58–71.
10. Wilson SR, Burns PN. An algorithm for the diagnosis of focal liver masses using microbubble contrast-enhanced pulse-inversion sonography. AJR Am J Roentgenol. 2006;186(5):1401–1412.
11. Burns PN, Wilson SR. Focal liver masses: enhancement patterns on contrast-enhanced images–concordance of US scans with CT scans and MR images. Radiology. 2007;242(1):162–174.
12. Kim TK, Jang HJ, Burns PN, et al. Focal nodular hyperplasia and hepatic adenoma: differentiation with low-mechanical-index contrast-enhanced sonography. AJR Am J Roentgenol. 2008;190(1):58–66.
13. Dietrich CF, Tannapfel A, Jang HJ, et al. Ultrasound imaging of hepatocellular adenoma using the new histology classification. Ultrasound Med Biol. 2019;45(1):1–10.
14. Durot I, Wilson SR, Willmann JK. Contrast-enhanced ultrasound of malignant liver lesions. Abdom Radiol (NY). 2017.
15. Jang HJ, Kim TK, Burns PN, et al. Enhancement patterns of hepatocellular carcinoma at contrast-enhanced US: comparison with histologic differentiation. Radiology. 2007;244(3):898–906.
16. Wilson SR, Kim TK, Jang HJ, et al. Enhancement patterns of focal liver masses: discordance between contrast-enhanced sonography and contrast-enhanced CT and MRI. AJR Am J Roentgenol. 2007;189(1):W7–W12.
17. Available from: www.acr.org/Quality-Safety/Resources/LIRADS. Accessed February 2, 2020.
18. Silverman SG, Pedrosa I, Ellis JH, et al. Bosniak classification of cystic renal masses, version 2019: an update proposal and needs assessment. Radiology. 2019;292(2):475–488.
19. Ascenti G, Mazziotti S, Zimbaro G, et al. Complex cystic renal masses: characterization with contrast-enhanced US. Radiology. 2007;243(1):158–165.
20. Clevert DA, Minaifar N, Weckbach S, et al. Multislice computed tomography versus contrast-enhanced ultrasound in evaluation of complex cystic renal masses using the Bosniak classification system. Clin Hemorheol Microcirc. 2008;39(1–4):171–178.
21. Correas JM, Claudon M, Tranquart F, et al. The kidney: imaging with microbubble contrast agents. Ultrasound Q. 2006;22(1):53–66.
22. Ignee A, Straub B, Brix D, et al. The value of contrast enhanced ultrasound (CEUS) in the characterisation of patients with renal masses. Clin Hemorheol Microcirc. 2010;46(4):275–290.
23. Mazziotti S, Zimbaro F, Pandolfo A, et al. Usefulness of contrast-enhanced ultrasonography in the diagnosis of renal pseudotumors. Abdom Imaging. 2010;35(2):241–245.
24. Park BK, Kim B, Kim SH, et al. Assessment of cystic renal masses based on Bosniak classification: comparison of CT and contrast-enhanced US. Eur J Radiol. 2007;61(2):310–314.
25. Quaia E, Bertolotto M, Cioffi V, et al. Comparison of contrast-enhanced sonography with unenhanced sonography and contrast-enhanced CT in the diagnosis of malignancy in complex cystic renal masses. AJR Am J Roentgenol. 2008;191(4):1239–1249.
26. Robbin ML, Lockhart ME, Barr RG. Renal imaging with ultrasound contrast: current status. Radiol Clin North Am. 2003;41(5):963–978.
27. Sanchez K, Barr RG. Contrast-enhanced ultrasound detection and treatment guidance in a renal transplant patient with renal cell carcinoma. Ultrasound Q. 2009;25(4):171–173.
28. Tamai H, Takiguchi Y, Oka M, et al. Contrast-enhanced ultrasonography in the diagnosis of solid renal tumors. J Ultrasound Med. 2005;24(12):1635–1640.
29. Barr RG, Peterson C, Hindi A. Evaluation of indeterminate renal masses with contrast-enhanced US: a diagnostic performance study. Radiology. 2014;271(1):133–142.
30. Zarzour JG, Lockhart ME, West J, et al. Contrast-enhanced ultrasound classification of previously indeterminate renal lesions. J Ultrasound Med. 2017;36(9):1819–1827.
31. Tomich J, Grove Nigro K, Barr RG. Primary angiosarcoma of the breast: a case report and review of the literature. Ultrasound Q. 2017;33(1):46–48.
32. Kim JK, Kim TK, Ahn HJ, et al. Differentiation of subtypes of renal cell carcinoma on helical CT scans. AJR Am J Roentgenol. 2002;178(6):1499–1506.
33. Low G, Huang G, Fu W, et al. Review of renal cell carcinoma and its common subtypes in radiology. World J Radiol. 2016;8(5):484–500.
34. Egbert ND, Caoili EM, Cohan RH, et al. Differentiation of papillary renal cell carcinoma subtypes on CT and MRI. AJR Am J Roentgenol. 2013;201(2):347–355.
35. Sun MR, Ngo L, Genega EM, et al. Renal cell carcinoma: dynamic contrast-enhanced MR imaging for differentiation of tumor subtypes–correlation with pathologic findings. Radiology. 2009;250(3):793–802.
36. Hotker AM, Mazaheri Y, Wibmer A, et al. Differentiation of clear cell renal cell carcinoma from other renal cortical tumors by use of a quantitative multiparametric MRI approach. AJR Am J Roentgenol. 2017;208(3):W85–W91.
37. Xue LY, Lu Q, Huang BJ, et al. Differentiation of subtypes of renal cell carcinoma with contrast-enhanced ultrasonography. Clin Hemorheol Microcirc. 2016;63(4):361–371.
38. Sun D, Wei C, Li Y, et al. Contrast-enhanced ultrasonography with quantitative analysis allows differentiation of renal tumor histotypes. Sci Rep. 2016;6:35081.
39. Yoon SH, Lee KH, Kim SY, et al. Real-time contrast-enhanced ultrasound-guided biopsy of focal hepatic lesions not localised on B-mode ultrasound. Eur Radiol. 2010;20(8):2047–2056.
40. Cao BS, Wu JH, Li XL, et al. Sonographically guided transthoracic biopsy of peripheral lung and mediastinal lesions. J Ultrasound Med. 2011;30(11):1479–1490.
41. Madsen HH, Rasmussen F. Contrast-enhanced ultrasound in oncology. Cancer Imaging. 2011;11(1A):S167–S173.
42. Eisenbrey JR, Sridharan A, Liu JB, et al. Recent experiences and advances in contrast-enhanced subharmonic ultrasound. Biomed Res Int. 2015;2015:640397.
43. Schlottmann K, Klebl F, Zorger N, et al. Contrast-enhanced ultrasound allows for interventions of hepatic lesions which are invisible on convential B-mode. Z Gastroenterol. 2004;42(4):303–310.
44. Yusuf GT, Sellars ME, Deganello A, et al. Retrospective analysis of the safety and cost implications of pediatric contrast-enhanced ultrasound at a single center. AJR Am J Roentgenol. 2017;208(2):446–452.
45. Jacob J, Deganello A, Sellars ME, et al. Contrast enhanced ultrasound (CEUS) characterization of grey-scale sonographic indeterminate focal liver lesions in pediatric practice. Ultraschall Med. 2013;34(6):529–540.
46. Anupindi SA, Biko DM, Ntoulia A, et al. Contrast-enhanced US assessment of focal liver lesions in children. Radiographics. 2017;37(6):1632–1647.
47. Torres A, Koskinen SK, Gjertsen H, et al. Contrast-enhanced ultrasound using sulfur hexafluoride is safe in the pediatric setting. Acta Radiol. 2017;58(11):1395–1399.
48. Darge K. Voiding urosonography with US contrast agents for the diagnosis of vesicoureteric reflux in children. II. Comparison with radiological examinations. Pediatr Radiol. 2008;38(1):54–63; quiz 126-7.
49. European Society of Radiology (ESR). ECR 2012 Book of Abstracts—B—Scientific Sessions. Insights Imaging 2012;3(suppl 1):135–363.
50. Darge K. Voiding urosonography with ultrasound contrast agents for the diagnosis of vesicoureteric reflux in children. I. Procedure. Pediatr Radiol. 2008;38(1):40–53.
51. 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. Pediatr Radiol. 2012;42(6):660–667.
52. Berrocal T, Gaya F, Arjonilla A. Vesicoureteral reflux: can the urethra be adequately assessed by using contrast-enhanced voiding US of the bladder?Radiology. 2005;234(1):235–241.
53. Darge K, Troeger J. Vesicoureteral reflux grading in contrast-enhanced voiding urosonography. Eur J Radiol. 2002;43(2):122–128.
54. Darge K, Bruchelt W, Roessling G, et al. Interaction of normal saline solution with ultrasound contrast medium: significant implication for sonographic diagnosis of vesicoureteral reflux. Eur Radiol. 2003;13(1):213–218.
55. Lentacker I, Sanders NN. Drug loaded microbubble design for ultrasound triggered delivery. Soft Matter. 2009;5(11):2161–2170.
56. Overgaard J. The current and potential role of hyperthermia in radiotherapy. Int J Radiat Oncol Biol Phys. 1989;16(3):535–549.
Keywords:

ultrasound contrast; ultrasound contrast agents; liver masses; kidney masses; lesion characterization; safety; CEUS = contrast-enhanced ultrasound; UCA = ultrasound contrast agent; FLL = focal liver lesion; APHE = arterial phase hyperenhancement; AP = arterial phase; FNH = focal nodular hyperplasia

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