Contrast-enhanced ultrasound (CEUS) has been used for a variety of applications in both Europe, Canada, and Asia for many years. Both the World Federation of Ultrasound in Medicine and Biology1,2 and the European Federation of Societies for Ultrasound in Medicine and Biology3 have published guidelines for appropriate use of this technique.
Ultrasound contrast agents (UCA) consist of microbubbles of heavy gas stabilized with a lipid, protein or lipoprotein shell. These agents vary in their gas content and shell structure. The bubbles are about the size of a red blood cell (1.5–2.5 μm) but large enough to prevent their extravasation to the interstitium after intravenous (IV) injection. They are, therefore, purely intravascular. They have a nonlinear response to low mechanical index (MI) ultrasound (US) and burst at high MI (>0.4). Contrast-enhanced ultrasound has several unique advantages compared with other contrast-enhanced imaging techniques, including the absence of renal or hepatic toxicity, no requirement for ionizing radiation, real-time assessment of vascularity, thin slice thickness, and excellent background tissue suppression (Table 1).
TABLE 1 -
Advantages of CEUS
|No renal or hepatic toxicity
||Can be safely used in patients with renal failure
|Real-time assessment of vascularity
||Can visualize all phases of enhancement at a high frame rate versus “snap shots” on MRI and CT. Best temporal Resolution in cross-sectional imaging.
|Contrast-only image—with excellent background
|Can see small amounts of enhancement which may be volume averaged on CT and MRI
|Narrow US beam
||Improved visualization of vascularity in small structures such as septations and mural nodules, improved spatial resolution
|No ionizing radiation
||Improved safety profile
|True vascular agents
||No extravasation of contrast into interstitium as CT and MRI may lead to improved quantification
||Allows for multiple injections
||Can be performed in ER, ICU, bedside
|Ability to perform examinations without sedation
||No need to sedate a child for CT or MRI
|Ability to perform examination in flexible positions
|No metal interference
||Can perform examination in patients unable to have an MRI; Less streak artifact than CT
|Work Flow improvement
||Immediate feed back
|Improved visualization of small amounts of contrast
||Able to detect small amounts of contrast that may not be identified on CECT or CEMRI
There are 3 UCA with FDA approval available in the United States (Table 2).
TABLE 2 -
Ultrasound Contrast Agents and Recommended Doses From Package Inserts
|-Characterization of FLLs in adult and pediatric patients.
-In ultrasonography of the urinary tract in pediatric patients for the evaluation of suspected or known vesicoureteral reflux
-To opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border in adult patients with suboptimal echocardiograms
|Ultrasonography of the liver
2.4 mL administered as an IV injection followed by 5 mL of 0.9% Sodium Chloride injection. A second dose can be administered if indicated
2 mL administered as an IV bolus injection followed by 5 mL of 0.9% Sodium
During a single examination, a second injection of 2 mL may be administered to prolong contrast enhancement.
|0.03 mL/kg administered as an IV injection followed by 5 mL of 0.9% Sodium Chloride injection. Do not exceed 2.4 mL per injection. A second dose can be administered if indicated.
For intravesical injection
|In patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border
||The recommended bolus dose for activated DEFINITY is 10 μL/kg of the activated product by IV bolus injection within 30–60 seconds, followed by a 10-mL saline flush. If necessary, a second 10 μL/kg dose followed by a second 10-mL saline flush may be administered 30 minutes after the first injection to prolong contrast enhancement.
The recommended infusion dose for activated DEFINITY is via an IV infusion of 1.3 mL added to 50 mL of preservative-free saline. The rate of infusion should be initiated at 4.0 mL/min, but titrated as necessary to achieve optimal image enhancement, not to exceed 10 mL/min.
Incremental dose amounts of 0.2–0.3 mL are suited for current ultrasound systems
|In patients with suboptimal echocardiograms to opacify the left ventricle and to improve the delineation of the left ventricular endocardial borders
||0.5 mL IV at a rate not exceeding 1 mL/s. If contrast enhancement is inadequate, may repeat dose in increments of 0.5 mL, up to 5 mL IV in a 10-min period. The maximum total dose should not exceed 8.7 mL in any 1 patient study
||Not FDA approved for any indication in the United States
||0.015 mL/kg when administered as a suspension liquid
The doses above are the doses recommended in the package insert. For some ultrasound equipment, lower doses may be appropriate. Dosage may vary based on the indication and ultrasound system used.
- Lumason (sulfur hexafluoride lipid-type A microspheres) for injectable suspension, for IV use or intravesical use; also known as SonoVue outside of the United States (Bracco Diagnostics Inc., Monroe Township, NJ);
- Definity (perflutren lipid microspheres) injectable suspension (Lantheus Medical Imaging, Billerica MA);
- Optison (perflutren protein-type A) Injectable Suspension (GE Healthcare, Marlborough, MA).
At the time of this publication, Definity, Lumason, and Optison are approved for IV administration in adults undergoing echocardiography to improve visualization of the left ventricular cavity and the endocardial borders. In 2016, the FDA approved the use of Lumason for liver imaging in both children and adults, and for imaging of the pediatric urinary tract for evaluation of suspected or known vesicoureteral reflux (voiding urosonography). This milestone approval, after years of negotiations, is expected to accelerate the use of CEUS in North America. Importantly, there are many on- and off-label applications of UCA in wide use that can benefit patient care.4 To mention only the most common off-label usage, these include the characterization of renal solid and cystic masses, detection of solid organ injury in the setting of trauma, detection and characterization of endoleaks after abdominal aortic aneurysm (AAA) repair, quantification of wall inflammation in Crohn disease, differentiation of inflammatory masses as either abscess or phlegmon, and guidance and monitoring of US-guided interventions and ablative therapies. Despite widespread utilization in Europe and Asia, guidelines for the use of CEUS in North America have not been developed. Guidelines are needed for appropriate integration of CEUS within medical imaging and referral when this technique can be of benefit to patients. Additionally, appropriate guidelines are essential for regulatory and billing decisions.
Microbubble contrast agents (MBCA) for US are purely intravascular agents, and they do not have any interstitial phase. This is unlike contrast agents for computed tomography (CT) and magnetic resonance (MR) scan where there is a well-recognized interstitial phase, especially evident in malignant tumors with permeable vascular endothelium and a fibrous stroma where the contrast agent leaks into the interstitium, creating a type of pseudoenhancement in the late phase (LP). This produces a valuable discordance with MR scan of these tumors where washout is appropriately recognized in association with malignant tumors on CEUS only.5
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, IL on October 24 to 25, 2017, and drafted this document. The recommendations 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) define the requirements for development of a CEUS program; (b) review UCA and their safety profile; (c) provide guidance on performance of a CEUS examination; interpretation of the results, and reporting of the findings; (d) determine appropriate off-label indications for CEUS; and (e) establish 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 physician experts in CEUS. A summary of all talks and relevant references was available to the panelists before the meeting. Invited representatives interested in CEUS and the industry were also in attendance.
Several panel members are on the advisory panels of US contrast companies. Several panel members have research grants with equipment vendors. Final recommendations in this publication represent consensus opinions of the panel members, who do not 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 allows visualization of UCA using a low MI technique, including pulse inversion, power modulation, and combinations thereof. These US imaging sequences take advantage of the nonlinear responses of the microbubbles such that contrast agent-only imaging is implemented with complete subtraction of the background linear tissue. A detailed review of pulse sequences is beyond the scope of this work but can be found elsewhere.6 The CEUS imaging is performed according to specific protocols to dynamically evaluate all phases of contrast enhancement.
Ultrasound contrast injections should comply with the local department policies regarding contrast agents, similar to those for CT and MR contrast agents. Some institutions require the contrast agent to be placed on the hospital formulary, whereas others allow the radiology department to handle the ordering and storage of US contrast. Similarly, consent for contrast agent injections should parallel the departmental policy for CT/magnetic resonance imaging (MRI) imaging with contrast. Today, most departments have only an interview worksheet where pertinent information regarding potential contrast contraindications, including allergies, is reviewed with the patient before contrast administration with verbal consent: a standard precontrast injection screening form can be modified for CEUS.
It is necessary to have an US scanner with US contrast capability allowing performance of low MI harmonic imaging. Most US vendors have CEUS capable systems. The scanner should allow for recording of single images as well as multiimage acquisition of variable length: up to 1 minute for organ imaging and up to 2 to 3 minutes for generation of time-intensity curves (TIC) for quantification scans. For novices, review of a long cine clip (>30 seconds) may be particularly helpful to review a case. However, routine acquisition of such long clips is not generally advised, as the storage of large amounts of data is problematic. In addition, continuous insonation of large areas of vascular soft tissues will result in significant contrast agent degradation. This bubble destruction occurs especially in the near field and can be minimized with an acquisition of more manageable and shorter length. In the Indications section below, organ-specific scanning requirements are detailed. The following are the general guidelines:
Initial precontrast gray scale imaging is performed to localize the area of interest for CEUS evaluation, with storage of the best possible gray scale image for future review. Positioning the patient and transducer so that the lesion remains in the field of view (FOV) during breathing aids in the interpretation. Scanning in the long axis of the patient minimizes out of plane respiratory motion. When the lesion is deep (>10 cm from the skin surface), repositioning of the patient to decrease the distance of the lesion from the transducer improves image quality. For example, a deep liver lesion on a supine view may be much closer to the transducer when the patient is in a left lateral decubitus position and the transducer is placed in an intercostal space.
All UCAs require activation, which varies according to the agent selected. Intravenous access can be established before the examination or just before the injection. Sonographers, radiology technologists, and nurses can all be trained to start IV lines and decisions regarding which group(s) rests with the individual institution. A 20-gauge IV is preferred because smaller caliber needles may disrupt the bubbles. In children, a smaller gauge IV may be necessary. An antecubital vein, especially in the left arm, is generally the optimal choice. A central line can be used for contrast administration. The use of a 3-way stopcock facilitates the injection especially if multiple doses are to be administered. When using a stopcock, the UCA syringe should be attached to a port parallel to the IV line and the saline flush attached perpendicular to the IV line. This setup limits bubble destruction on the injection (Fig. 1). The contrast agent and saline are injected at approximately 1 mL/s. Recommended UCA doses, with variations for specific applications, are listed in Table 2. For each application in the Indications section, more details regarding advised dosage are given. The UCA injection is followed by 5 to 10 mL of normal saline. At injection, special care must always be taken to avoid pushing the UCA syringe against a closed stopcock, because this will instantly destroy all of the microbubbles.
The appropriate US transducer is selected according to the study indication. In general, all commercially available clinical UCA are optimized to resonate at 2.5 to 3.5 MHz. This usually matches the center frequency of standard abdominal curvilinear probes. The use of a higher frequency probe for superficial CEUS imaging results in a reduced bubble response and requires an increase (often doubling) of the UCA dose. Appropriate balancing of these factors requires experience for successful transducer selection and UCA dosing. Most contrast-enabled transducers permit selection of a range of frequencies. In larger patients or when using a higher-frequency probe, selection of the penetration mode setting may improve image quality.
To begin a CEUS examination, the contrast-specific mode should be activated. The use of a dual screen option is recommended for CEUS imaging. On 1 screen is a low MI gray scale image which allows for appropriate transducer placement over the region of interest (ROI). The contrast-only image appears on the second screen. In addition to a dual screen for correct localization of contrast enhancement or washout, a dual caliper or marker for assistance with simultaneous localization on each screen is essential, as is a clearly visible timer, showing the actual time from the start of the saline flush and also the time within a frozen clip, on replay.
Before the injection of the UCA, the gain on the contrast-only image should be adjusted so that there is minimal signal present in the image (ie, a nearly black screen). The B-mode gain adjusts the B-mode image for optimal viewing of the pathology. If TICs are going to be generated, the gain setting should remain constant during the imaging. The lesion is identified in the optimal patient position and imaging begun before contrast injection. Once the UCA is injected, it is immediately followed by the saline flush. The timer is activated at the beginning of the saline flush. Depending on the application, the image storage (cine clip) is started either at the beginning of the saline flush or upon visualization of the first bubble within the FOV. Recommendations for image storage are provided in the Indications section for each application.
If a second dose is required, waiting until the majority of the enhancement from the initial dose has dissipated (approximately 5 minutes) or stopping the contrast-specific software and using high MI imaging (most commonly color or Power Doppler) to remove existing bubbles can be used. Remember to return to low MI contrast-specific imaging before the second injection. Table 3 lists the steps to follow in performing a CEUS examination.
TABLE 3 -
Steps in Performing a CEUS Study
|Perform standard B-mode examination and locate area of concern
|Identify the best patient position for the lesion to be nearer to the transducer and the lesion remains in the FOV during breathing
|Start IV (can be performed before starting the standard examination)
|Reposition the patient and identified the area of interest
|Activate the contrast agent
|Inject the UCA
|Inject the saline flush and at the same time begin the timer at the start of the saline injection
|Continue scanning and recording based on the application protocol
|If performing a liver study consider sweeping the liver in the delayed phase looking for areas of washout
|Review the case to determine of a second injection is required
|If a second dose is required using high MI technique destroy the majority of remaining bubbles
|Repeat injection as above
|Select images/clips to send to PACS
|When the study is complete remove IV
A very helpful additional injection technique includes injecting a second dose of contrast during the portal venous (PV) or LP imaging of the liver “on top” of the remaining parenchymal enhancement and often focused on a washout or black nodule. This allows for characterization of the washout regions that are frequently found on sweeps of the liver looking for baseline occult nodules with washout, by showing their enhancement pattern in the arterial phase (AP). This technique is invaluable especially when metastases are suspect.
Physician, Sonographer, and Nurse Training
The American Institute of Ultrasound in Medicine training guidelines for interpretation of abdominal US recognizes competence in CEUS after (a) documentation of 7 category 1 credits dedicated to contrast US and (b) clinical experience in performing at least 15 CEUS examinations within the previous 3 years. To maintain competence, the physician is required to complete 3 hours of category 1 credits specific to CEUS every 3 years.7 Numerous best practices articles can be found in the literature discussing both performance and interpretation of CEUS studies,2,3,8–11 with CME programs offered at multiple radiology and cardiology society meetings, as well as at individual institutions. A guide to image interpretation is provided in the Indications section for each application. It is of great value to visit a site with CEUS experience to observe a few CEUS cases before performing a first examination. Working with your UCA representative and your US system vendor are very helpful to improve success for optimal imaging.
Patient Selection and Imaging Considerations
Although no patient preparation is specifically required for the contrast examination, a standard 4-hour fast before an abdominal examination is usually helpful.
Table 4 lists those patients appropriate for CEUS evaluation.
TABLE 4 -
Patient That Are Appropriate for CEUS
|– Renal impaired patient requiring contrast
|– Patients with CT and/or MRI contrast allergy or other contraindication
|– CT or MRI do not answer clinical question or have conflicting results
|– When it is important to know that no enhancement is present – Contrast-only image (eg, post-RFA)
|– To decrease radiation dose (especially in pediatrics)
|– Portable examination needed
|– To decrease need of sedation for pediatric patients
Patient Scheduling and CEUS Workflow
Total room time for a routine CEUS examination is usually about 30 to 45 minutes, including placing the IV and contrast administration. The CEUS examinations may be performed by appropriately trained personnel, either a physician or a sonographer.
Ultrasound contrast agents are safe, with an adverse event rate similar to MRI contrast agents but less than iodinated contrast agents.12 A large retrospective investigation of more than 78,000 doses of Definity and Optison found a severe reaction rate of 0.01% (n = 8); half of these reactions (4 of 8) were considered anaphylactoid, and there were no deaths. Another large retrospective study evaluating the use of SonoVue in 23,188 subjects documented 29 adverse events, with only 2 considered serious.13 The majority of adverse events are nonanaphylactoid, mild, and likely physiologic in etiology, including symptoms, such as headache, a sensation of warmth or flushing, nausea, and altered taste. The majority of severe reactions are anaphylactoid, occurring within 30 minutes of administration, although typically occurring within 30 seconds.13 A review performed by the Society for Pediatric Radiology in conjunction with the International Contrast Ultrasound Society concluded that noncardiac applications of CEUS, including IV and intravesical administration, are safe, with side effects uncommon and typically minor.14 Minor adverse events include headache, backpain, and nausea/vomiting, reported in less than 1% of the patients.
Nonanaphylactoid adverse events are mild and transient, resolving spontaneously. As with all contrast agents, appropriate resuscitation equipment and trained personnel should be readily available at the time of injection in the event that an adverse reaction occurs.
Ultrasound contrast agents are contraindicated for intraarterial injection and in patients with a history of hypersensitivity to the agent or to any of the inactive ingredients of the UCA. The Black Box Warning has identical language on all the commercially available UCAs. Ultrasound contrast agents are not contraindicated but should be used with caution in patients with an unstable cardiopulmonary condition (eg, acute myocardial infarction, unstable congestive heart failure) as the risk for a serious cardiopulmonary reaction may be increased. However, a study15 of 1513 hospitalized patients with pulmonary hypertension showed that adverse reactions to the UCA Definity were very rare (0.002%).
Ultrasound contrast agents have no known renal toxicity in approved doses. Two publications describe the use of CEUS in pregnancy without any adverse fetal effect.16,17 There are no data on the presence of UCAs in human milk, the effects on the breastfed infant, or the effects on milk production. Optison contains human albumin, a derivative of human blood, and may confer a theoretical risk of viral or prion infection; additionally, it may not be used in patients with religious or ethical objections to the intravascular receipt of human blood products.
CODING AND REIMBURSEMENT
Category 1 CPT codes for noncardiac CEUS were implemented on January 1, 2019. The codes are defined as “for reporting ultrasound, targeted dynamic microbubble sonographic contrast characterization (noncardiac).” 76978 is used for evaluation of an initial lesion and 76979 for subsequent injection for additional lesions. The new codes are add-on, that is, they can be combined with existing US codes if a precontrast examination is performed. They are organ and agent agnostic, that is, they can be used to image any organ, and any UCA can be used. Injection code C96374 cannot be used with the CAT 1 codes. Additionally, UCA benefit from supplemental reimbursement through Q codes. Q codes are pass-through codes that can be billed for Medicare patients in an outpatient setting. The code for Lumason is Q9950, for Optison Q9956, and for Definity Q9957. The code for Lumason was extended until September 3, 2020. The billing unit for a Q9950 is 1 mL, with 5 billing units per vial.
In a physician office or independent imaging centers (ie, Independent Diagnostic Testing Facility), Lumason, and other contrast agents are reimbursed according to the Medicare Fee for Service Part B drugs price list which is adjusted quarterly. Providers in all care settings should work with their billing department to ensure that commercial (ie, non-Medicare) insurers have new procedure codes and contrast coding in their contracts with an agreed upon price for either a bundled procedure or separate payment for the procedure and contrast.
Since January 1, 2017, CMS requires that when billing for separately payable drugs in single dose vials/packages—the JW modifier must be used to indicate the amount that is not administered to the patient (for Hospital Outpatient Prospective Payment System and Independent Diagnostic Testing Facility/physician office).
Table 5 lists the appropriate coding for CEUS.
CPT codes (as of 4-2-2020) for CEUS.
*APC 5571. Level I imaging with contrast. There is no technical reimbursement for 79679 (subsequent injection) under HOPPS.
HOPPS, Hospital Outpatient Prospective Payment System.
The FDA provides information regarding “off-label” and investigational use of marketed drugs, biologics, and medical devices.18 It states “the physicians use legally available drugs and devices according to their best knowledge and judgment. If the physician uses a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medicine evidence, and to maintain records of the product's use and effect.” Use of a marketed product in this manner when the intent is the “practice of medicine” does not require the submission of an investigational new drug application, investigational device exemption, or review by an institutional review board.
However, the institution at which the product will be used may, under its own authority, require institutional review board review and other institutional oversight,18 The FDA approval of the 3 UCA for at least 1 indication confirms the safety of these agents. As the administration and distribution of these agents in the body is independent of the organ being evaluated, the safety of these agents remains the same regardless of the application.
In this document, based on literature review, the panel provides the level of evidence (Table 6) for various clinical CEUS applications of these agents, including references to provide guidance. At the time of this publication, although all 3 CEUS contrast agents have FDA approval for echocardiography, only 1 LUMASON is also approved for liver imaging in both children and adults and for imaging of the pediatric urinary tract for evaluation of suspected or known vesicoureteral reflux (voiding ultrasonography).
TABLE 6 -
Level of Evidence for Various CEUS Applications*
||Level of Evidence
||Characterization of FLLs
||Detection of FLLs
||Guidance/assessment of ablative procedures
||Characterization of indeterminate renal masses
||Guidance/assessment of ablative procedures
||Assessment of lesions
||Assessment of lesions
||Assessment for fibrosis/inflammation in IBD
||Characterization of testicular lesions
||Characterization of ovarian lesions
||Assessment of lesions
||Assessment of lesions
||Assessment for endoleaks
||Detection of PCa
*Based on expert opinion and review of the literature using the Oxford Classification Level of Evidence.
Contrast-enhanced ultrasound provides an option for patient imaging in the United States, expanding the value of the integrated radiology offering 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, patients requiring serial or frequent testing due to oncologic/chronic disease needs.
Lastly, “an inherent advantage of CEUS of the liver is the opportunity to assess the contrast enhancement patterns in real time, with a much higher temporal resolution than is possible with other imaging modalities, so the enhancement dynamics of the lesions can be studied. There is no need to predefine scan time points or to perform bolus tracking. Additional CEUS benefits include the excellent tolerance and safety profiles of contrast agents allowing for their repeated administration in the same session if needed.”2
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.18 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 (DOR), all were similar with no statistical difference from contrast-enhanced CT (CECT) or CEMRI.19
Although CEUS is in wide use for the last 2 decades in Asia, Europe, and Canada, characterization of focal liver masses in the United States is related exclusively to the use of the contrast agent Lumason (Bracco Diagnostics Inc.) approved for this indication in March 2016. Characterization is based on enhancement features, for an identified mass or nodule, in the AP and the PV phase (PVP)/LP of contrast enhancement.20 These features are generally similar to those for the noninvasive diagnosis of liver masses on CT and MR scan.21
Recommended CEUS Use
- Characterization of FLLs in the noncirrhotic liver.
- Incidentally found liver lesions on US,
- Incompletely characterized lesions on noncontrast or CECT or MRI.
- Characterization of FLLs in the cirrhotic liver.22
- Assess nodules detected on surveillance US;
- Assess Liver Imaging Reporting and Data System (LI-RADS) LR-3, LR-4, LR-5, or LR-M observations on prior CECT or MRI;
- Detect AP hyperenhancement (APHE) when mistiming is suspected as the reason for its absence on prior CT or MRI;
- Assess biopsied lesions with inconclusive histology.
- Detection of metastases
- Determine hepatic artery, portal vein, and hepatic vein patency,
- Assess transjugular intrahepatic portosystemic shunt (TIPS) patency,
- Distinguish bland versus tumor hepatic/portal vein thrombus,
- Interventional aid in known lesion detection/evaluation at the time of biopsy or therapy.
To maximize benefits of real-time CEUS imaging and to preserve enough microbubbles to allow detection of late contrast washout, the liver CEUS protocol is based on a combination of continuous imaging in the AP and intermittent imaging in later phases.23
- A nodule should be identified and maintained within the FOV for the entire injection to show its enhancement changes with time
- Should be performed continuously of the washin of the preidentified nodule, from contrast injection until peak AP enhancement to characterize presence(yes or no), intensity (hyper, iso, hypo, or nonenhancing), pattern of APHE, (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
- Alternately, 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 minutes after injection) and improve ability to detect late washout and assess its degree.
- Sweeping the entire liver in the portal/LP 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.
- 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.
- To obtain still images of contrast washin and peak arterial phase enhancement, extract during replay of the acquired multiframe file.
Recording of static images at 60 seconds and with each intermittent acquisition thereafter (every 30–60 seconds) is sufficient to document and evaluate the presence, timing, and degree of washout.
- Dependence on transducer, instrumentation, and body habitus.
- In general, for the majority of adult patients a dose of 1.5 to 2.4 mL Lumason; Definity 0.2 to 0.4 mL; and Optison, where limited experience prevents accurate commentary about liver lesion characterization. Repeat injections may be required for study of multiple lesion
- At the time of injection, the image should be virtually black, with just 1 click separating the black image from one with background noise.
- Utilize the shortest distance from the transducer crystal to the lesion to optimize the study. Consider supine and LLD patient positions and also subcostal and intercostal transducer placement.
- Imaging in the long axis of the patient will reduce out of plane images due to respiration. Practice breathing with the patient utilizing either quiet breathing or breath suspension in neutral position. Avoid full suspended inspiration.
- Use a large flush volume of 10 cc to obtain optimal enhancement in the AP.
Fundamentals for Interpretation of CEUS of Focal Liver Disease
Experience with the use of MBCA for liver mass characterization 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.24 All interpretations recognize that the intensity of enhancement on a CEUS examination is in direct proportion to the volume of microbubbles within a ROI and enhancement levels are always compared with the adjacent and enhancing liver parenchyma.
DETERMINATION OF MALIGNANCY: Importance of Washout, Presence, Timing, and Intensity
A first step in the interpretation of CEUS of a liver mass is the determination of malignancy.25 This is best performed by demonstration of washout of a lesion after its AP enhancement, such that the mass appears less enhanced than the adjacent liver parenchyma.26 Washout is shown to have a high predictive value for the determination of malignancy.20,21,27
Differentiation of Malignancy: Hepatocellular From Nonhepatocellular
In the study of all malignant tumors with CEUS, it is found that the timing and the intensity of washout are critical components. Unlike CT and MR scan, where washout alone is monitored for its presence, on CEUS, careful precise timing and observation for intensity relative to the liver allows for differentiation of hepatocellular from nonhepatocellular malignancy. Hepatocellular carcinoma (HCC) is diagnosed by demonstration of a hypervascular nodule with late (>1 minute) and weak washout.25,28,29 By comparison, nonhepatocellular tumors, including metastases and cholangiocarcinoma (ICC), are characterized by variable AP enhancement and rapid and marked washout so that the tumor appears as a black punched out hole in the portal and the LP. This rapid washout may even occur so early as to be within the traditionally defined AP, before 30 seconds.
Detection of Malignancy
As these malignant tumors appear black within the enhanced parenchyma, their increased conspicuity makes sweeping of the entire liver in the PVP and LP the ideal technique and timing for improved detection of malignant liver masses on CEUS. Recognizing the significance of washout as an indicator of malignancy, it follows that sustained enhancement is highly associated with benign outcome.
Diagnosis of Benign Tumors: Suggestive AP Features and Sustained Enhancement
Benign tumors commonly encountered on CEUS examinations include hemangioma, focal nodular hyperplasia (FNH), and much less often, hepatic adenoma. It is recognized that CEUS has a unique capability in that all may demonstrate highly suggestive enhancement patterns in the AP, optimally shown by the real-time dynamic scanning afforded by CEUS. They show, additionally, sustained enhancement in the PVP and LP, such that the lesion will remain as enhanced as the adjacent liver to 4 or even 5 minutes after injection. Hemangiomas are characterized by peripheral nodular enhancement with centripetal progression of this enhancement over time. Focal nodular hyperplasia is a highly vascular tumor and is characterized by stellate vessel morphology with filling of the lesion from its center to the periphery.30
Hepatic adenoma, a fairly rare liver tumor, is an exception to these general rules and may show diffuse enhancement or a more specific filling from the periphery to the center of the lesion. Additionally, adenoma is shown to have the possibility for washout, occurring in up to 50% of cases.31
Diagnosis of Malignant Tumors: Suggestive AP Features and Washout
Evaluation of malignant lesions shows that the specific AP enhancement patterns characteristic of most benign tumors on CEUS are not found in most malignant lesions where the AP enhancement features are more variable and nonspecific.32 In metastases, the most common liver tumor are characterized by their rapid washout on CEUS, generally appearing before 1 minute after contrast injection.32 In the AP, metastases are variable and may show hyperenhancement, isoenhancement, or hypoenhancement. Rim AP enhancement is, however, highly associated with metastatic disease and other nonhepatocellular malignancies. Without clinical information, ICC and metastases appear virtually identical on CEUS.
Hepatocellular carcinoma generally shows globular APHE although necrosis may cause heterogeneity.
An Essential Exception
The MBCA for US are purely intravascular agents and they do not have any interstitial phase. This is unlike contrast agents for CT and MR scanning where there is a well-recognized interstitial phase, especially evident in malignant tumors with permeable vascular endothelium and a fibrous stroma where the contrast agent leaks into the interstitium, creating a type of pseudoenhancement in the LP. This produces a valuable discordance with MR scan of these tumors where washout is appropriately recognized in association with malignant tumors on CEUS only.5 This is most important for diagnosis of ICC in any liver, either cirrhotic or normal.
In summary, CEUS is invaluable for the characterization of both benign and malignant liver tumors. It is a recognized modality for resolution of indeterminate masses from CT and MR scan. Occasional discordance of CEUS with CT and MR scan may be associated with the behavior of the purely intravascular contrast agents for CEUS showing washout, whereas CT and MR interstitial agents may show pseudoenhancement instead.
Contrast-enhanced ultrasound shows comparable performance with CT and MR for liver mass characterization and for the prediction of malignancy.1–3 Further, although of secondary importance to characterization, CEUS is shown to have equivalent, and in some cases superior, performance to CECT and CEMR scan in the detection of metastatic disease.18,32–34
Table 7 details the fundamentals for the characterization of liver tumors on CEUS. Figure 2 is a graphic of the enhancement patterns for various FLLs. The intensity of the signals reflects the volume of the microbubbles in the ROI with changes over time. Figures 3-7 (Videos 1–5, http://links.lww.com/RUQ/A209, http://links.lww.com/RUQ/A210, http://links.lww.com/RUQ/A211, http://links.lww.com/RUQ/A212, http://links.lww.com/RUQ/A213) demonstrate the classic appearance of both benign and malignant liver lesions.
TABLE 7 -
Fundamentals for the Characterization of Liver Tumors on CEUS
|• Washout is the most sensitive indicator of malignancy on CEUS.
|• Benign liver tumors are characterized by easily recognized specific enhancement patterns in the AP.
|• Sustained enhancement in the PV and LP is highly associated with a benign outcome.
|• The hallmark feature of all metastases is their rapid washout by earlier than 1 min.
|• Timing and intensity of washout is highly valuable for differentiation of HCC from nonhepatocellular malignancy.
|• HCC is characterized by late (>1 min) and weak washout.
|• Nonhepatocellular malignancy is characterized by early (<1 min) and marked washout.
|• In non-HCC malignancy, intravascular MBCA will show washout, whereas interstitial contrast agents for CT and MR scan may show instead increasing pseudoenhancement, the recognition of which is highly suggestive of their correct diagnosis.
MBCA, microbubble contrast agent.
Hepatocellular carcinoma is an important and deadly cancer and is the only solid organ cancer with an increasing incidence in the United States. Today, it is the second cause of cancer death worldwide. As it occurs in an identifiable high-risk population with chronic liver disease, screening for its detection is possible, recommended as US at 6-month intervals. Identification of a focal nodule above a threshold size of 1 cm, on a screening US, should lead to a contrast-enhanced imaging study to provide an appropriate diagnosis. Cholangioacarcinoma comprises an additional malignant tumor with a predilection to occur within a cirrhotic liver, making correct differentiation of HCC from ICC a major challenge on all imaging, including CEUS.
Before the interpretation of imaging for HCC with CEUS, however, there is requisite knowledge to understand the variability of enhancement imaging of HCC that can be seen in this population. First, liver cancer does not arise de novo in the liver. Rather, it arises by a step wise process of hepatocarcinogenesis whereby a small regenerative nodule within a cirrhotic liver enlarges as it develops cellular atypia, followed by the identification of a small HCC within the original nodule that will grow to become a larger tumor ultimately taking over the entire nodule.35
During the process of hepatocarcinogenesis, there are parallel changes in the blood supply to the original regenerative nodule with progressive decrease in its normal hepatic arterial and PV blood supply, whereas neoangiogenesis is stimulated by the growing tumor to produce a new and abnormal blood supply feeding the tumor. Considering the complexity, therefore, of the development of a liver cancer, is it any wonder that the vascular changes shown on contrast-enhanced imaging are highly variable, making the interpretation of all a great challenge?
LI-RADS for Imaging of Patients at Risk for HCC
The CEUS LI-RADS, liver imaging reporting, and data systems, is recently developed under the direction of the American College of Radiology, ACR, to supplement the already developed and implemented LI-RADS for CT and MR scan.34
The Intent of LI-RADS is to
- ❖ Apply consistent terminology,
- ❖ Reduce imaging interpretation variability and errors,
- ❖ Enhance communication with referring clinicians,
- ❖ Facilitate quality assurance and research,
- ❖ Facilitate integration and correlation between imaging modalities,
- ❖ Facilitate communication with and understanding by patients,
The CEUS LI-RADS algorithm (https://www.acr.org/Clinical-Resources/Reporting-and-Data-Systems/LI-RADS/CEUS-LI-RADS-v2017)2 provides categories for all focal liver observations that may be encountered on a CEUS scan of an at-risk patient, ranging from benign tumors (eg, hepatic hemangioma) to malignant tumors (eg, metastases and ICC), and including also pseudomasses. Although LI-RADS for CEUS is developed along the same lines and principles and with the same objectives as used for CT and MR LI-RADS, there are noticeable differences between the techniques which have led to CEUS LIRADS having their own unique algorithm and interpretation.34
The algorithm for the interpretation of CEUS imaging of a liver nodule or observation in a high-risk patient for HCC includes an entire spectrum of imaging possibilities. Lesion size, the type and degree of AP enhancement, and presence, timing, and degree of washout are the major features used for categorization of all nodules visible in the at-risk liver.33
Nodules are categorized from LR-1, a definitely benign lesion such as a hemangioma, through to the most important category LR-5, a definite HCC, with a variety of observations in between representing a continuum of likelihood for the finding of HCC within any category. The diagnostic table, which is a component within the Algorithm, includes the categories which comprise the liver nodules during their evolution through hepatocarcinogenesis, from LR-3, with intermediate possibility of HCC; LR-4, a highly suspicious nodule, but not meeting the rigorous requirements for confident diagnosis of HCC; and the most important category of LR-5, a classic HCC.
The LR-4 criteria are more variable and include all of the marginal features of LR-5, either slightly smaller than 1 cm, or without the APHE or more commonly with APHE but without the washout. The LR-4 category is highly suspicious for malignancy and will include some patients with HCC. Therefore, the recommendation for biopsy will occur frequently within this category.
LR-3 CRITERIA are more variable and impart an intermediate possibility of HCC. They include variations of size, AP enhancement and also washout. Many traditional regenerative and dysplastic nodules are within this category as well as some HCC. Although less concerning than LR-4 and LR-M categories, short interval surveillance and even biopsy may be selected after multidisciplinary discussion.
The LR-2, likely benign, and LR-1, definitely benign, include virtually all of the other nodules that may be encountered while imaging this at-risk population, including hemangiomas and also focal fat and focal fat sparing.
An important additional category is LR-M a probable but not definite malignancy. This important category is designed to include malignancy of nonhepatocellular origin, metastases, and ICC. It may additionally include some HCC, not meeting the stringent criteria for LR-5. As the diagnosis of masses within LR-M remains unconfirmed, biopsy is generally recommended for nodules within this category. The LR-M comprises an effort to categorize malignant nonhepatocellular tumors without reducing specificity for HCC. It safeguards the patients with HCC that missed inclusion within the LR-5 designation and also detects the other malignancies, notably ICC and metastases.
LR-M CRITERIA (any 1 of 3 is adequate)
- ❖ APHE
- ❖ rapid washout, at less than 60 seconds
- ❖ marked washout, confirmed by less than 2 M
A category called LR-TIV, LIRADS tumor in vein describes a soft tissue nodule filling a portal or hepatic vein, showing additionally APHE and washout indicative of malignant tumor within the vein. This designation does not require the identification of a tumor nodule within the parenchyma if the evidence for enhancing tumor in the vein is sufficient.
Lastly, LI-RADS includes a category which removes poor quality scans on the basis of technical failure or poor quality, resulting in a noncategorizable nodule, LR-NC.
The overwhelming objective of the performance of LI-RADS is to obtain close to 100% specificity for the diagnosis of HCC within the category of LR-5. That is to say, there should be no false positive cases within LR-5. Therefore, the criteria for inclusion in LR-5 are rigorous and include 3 features, all of which must be present.
LR-5 CRITERIA (all 3 are requisite)
- ❖ APHE
- ❖ late and weak washout, at greater than 60 seconds
- ❖ size of 10 mm or greater
These rigorous criteria allow for confident diagnosis of HCC and allow for treatment of patients with LR-5 nodules without requirement for biopsy. This has an incredible positive impact on patient management and outcomes. Validation studies show high specificity for diagnosis with low false positives.36,37
Not all patients who harbor an HCC will show an LR-5 nodule on imaging because of the variable vascular changes, already described, and the rigorous inclusion features for designation as LR-5. Therefore, some of the HCC tumors will instead be categorized as LR-4, nodules which are highly suspicious for HCC; LR-M, a category of definitely or probably malignant tumors, which should include all nonhepatocellular tumors, especially ICC and also HCC; and even fewer HCC within LR-3.
Differences Between CEUS LI-RADS and LI-RADS for CT and MRI Scan
- ❖ Imaging techniques: CEUS is a real-time dynamic scan showing enhancement regardless of its timing or duration. It facilitates the identification of the rapidly changing enhancement patterns of benign tumors especially flash-filling hemangiomas and may show APHE missed on MR scan due to mistiming of the AP. The CT and MR scan take more of a snapshot in time, limiting their temporal resolution.
- ❖ Contrast agent properties: CEUS is performed with a purely intravascular contrast agent whereas CT and MR are performed with agents which diffuse into the interstitium of some malignant tumors, notably those with permeable membranes and a fibrous stroma, especially ICC. Therefore, these tumors generally show rapid and brisk washout on CEUS while showing sustained or increasing pseudoenhancement in the portal and LP on CT and MR scan.5 Discordance of enhancement in the PVP between CEUS and CT or MR scan is a valuable clue that the diagnosis is ICC.
- ❖ What are we looking at? CT and MR scan use the term observation throughout their algorithm as many things which are seen on CT and MR scan may be related to perfusion abnormalities or to arterioportal shunting (APS), neither of which shows any abnormality on a baseline image performed without the benefit of contrast agent. By comparison, virtually everything studied with CEUS is focused on a visible NODULE, making the importance of showing APHE on CEUS of considerably greater importance than on CT and MR scan where many observations of APHE may have no significance. A focus of APHE on US which is nodule based has a high likelihood of being a HCC regardless of its behavior in the PVP.25
- ❖ Washout has great significance as a predictor of malignancy. However, its presence or not is what is documented on CT and MRI scan. On CEUS, we document both the TIMING, rapid at less than 1 minute or late at greater than 1 minute, and its INTENSITY, mild, with retention of some bubbles throughout the lesion, or marked whereby the nodule begins to look black or punched out. These features differentiate the type of malignancy with HCC characterized by late and weak washout and nonhepatocellular malignancy characterized by rapid and marked washout.33
LI RADS Summary
Each of the categorizations within LI-RADS comprise a true identifiable nodule which is categorized based on its size, its enhancement in the AP, and its subsequent enhancement or washout in the PVP. Implementation should mean that patients with similar pathology in different geographic regions will be put in similar categories and will receive similar management. This is an improvement in patient care.
The kidney is easily accessible and provides an excellent organ for study with CEUS. Ultrasound contrast agents are true intravascular agents and are not excreted. The medullary pyramids have less blood flow that the renal cortex and are therefore, usually easily identified. The phases of renal enhancement are referred to as the early corticomedullary and the later nephrographic phase. Because the UCAs are not excreted by the kidney, there is no enhancement of the renal pelvis, calyces, and infundibula.
Indeterminate renal masses are a common clinical problem. There are many renal masses found incidentally during all imaging examinations, and it is estimated that more than half of patients older than 50 years have at least 1 renal mass. In the elderly population, renal compromise, limiting the use of contrast agents for CT and MR scan, is associated with the discovery of renal masses with inadequate characterization and the inability to use contrast agents to assist with the problem. Many renal masses are benign simple cysts and can be confidently diagnosed on routine gray scale imaging, CT or MRI. Complicated cystic lesions with enhancing soft tissue components and most solid contrast enhancing renal masses on CEUS are malignant. Benign enhancing renal masses include inflammatory masses, vascular abnormalities, pseudotumors, oncocytomas, and angiomyolipomas.
There are a wide range of complicated cysts between those that are obviously benign and obviously malignant. These complicated cystic lesions are categorized by using the Bosniak classification system, originally described for CT. The Bosniak classification for CT and MRI has been recently revised.38 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.
In this classification, there are 4 categories. Bosniak category 1 represents a simple cyst that does not require additional follow-up, with a malignancy rate of essentially zero. Bosniak category 2 lesions are minimally complex. A subset of Bosniak category 2 lesions, classified as Bosniak 2F, has an increased complexity. Most Bosniak category 2 lesions are reliably considered benign; however, there are rare lesions within this classification that are found to be potentially malignant or malignant at histologic evaluation.39–42 Although most Bosniak category 2 lesions do not require additional work-up; Bosniak category 2F renal lesions, which are slightly more complicated, have a malignancy rate of approximately 5% and do require additional follow-up.39–42 Bosniak category 3 lesions have increased complexity and cannot be diagnosed confidently as benign or malignant. The prevalence of malignancy among resected category 3 masses has ranged from 31% to 100%. Bosniak category 4 includes lesions with obvious solid enhancing components and is not generally problematic as they are all malignant.
Contrast-enhanced ultrasound 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 “snap-shot” images of CT and MRI. The CEUS 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.
The CEUS alone has been successfully used to evaluate renal abnormalities.3,43–54 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%.53 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.55 In that study, it was found that appropriately 2/3 of Bosniak 3 lesions, and a number of Bosniak 4 lesions could be classified as benign based on confirmed long term follow-up.
Recommended CEUS Use
- Characterization of indeterminate renal masses
- Evaluation of renal parenchyma in patient with suspected renal abscess
- Evaluation of renal transplants in patients with suspected renal vascular complications and renal infarcts
Renal CEUS Protocol
Perform continuous recording from first arrival of a bubble in the 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.
Contrast Agent Dosing
This depends on transducer and instrumentation and body habitus. In general, for the majority of adult patients, a dose of 1.5 to 2.4 mL Lumason; Definity, 0.2 to 0.4 mL; Optison, 1.0 to 1.5 mL.
CEUS Image Interpretation
Table 8 shows the enhancement patterns for various renal masses. Figures 8–14 (Videos 6–8, http://links.lww.com/RUQ/A214, http://links.lww.com/RUQ/A220, http://links.lww.com/RUQ/A215) demonstrate the enhancement patterns of benign and malignant renal lesions.
TABLE 8 -
Enhancement Patterns for Characterization of Renal Masses on CEUS
|No flow within lesion
|Occasional bubble in septations
|Constant flow of bubbles with a fine septation without nodularity
|Enhancement equal to normal cortex on all enhancement phases
And present of a central pyramid
|Echogenic mass with enhancement less than renal cortex often
With a peripheral distribution; CT or MRI advised to confirm macroscopic fat in lesion
|Echogenic mass with enhancement = or > normal renal cortex
|Any other mass with blood flow (cystic or solid)
Note: may be pyelonephritis/abscess in the appropriate clinical setting
- 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 on CEUS. Occasional individual bubbles, identified traversing a septation, or constant flow, within a septation without nodularity, are benign findings.53
- Pseudotumors, commonly called column of Bertin, demonstrate an enhancement pattern equal to that of normal renal cortex in all enhancement phases with the presence of a central pyramid.
- Angiomyolipomas usually have enhancement less than the renal cortex often in a peripheral distribution. The CT or MRI imaging is advised to confirm macroscopic fat in the lesion.53 This contrasts to echogenic renal cell carcinomas (RCCs) which show uniform enhancement (unless there is central necrosis) that is equal to or greater than normal renal cortex and washout. Any other mass cystic or solid, with blood flow, is considered malignant and includes Bosniak category 4.
- Pyelonephritis usually has decreased flow to normal renal cortex. If an abscess is present, it would be avascular.
- 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 (less than 1%). The classification of RCC into subtypes is important because of their different prognoses.56,57 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.58–60 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.61,62
In the case of echogenic renal masses, there is often shine through in the later phases which can have the appearance of enhancement. If there is actual identification of movement of the bubbles, considering nonlinear (shine through) as real enhancement should always show true movement of the bubbles within the enhancement zone.63
Contrast-enhanced ultrasound of the kidney is indisputably an incredibly successful technique, improving historic renal mass characterization utilizing the Bosniak criteria for complex renal cystic masses and reducing the necessity for frequent follow-up examinations to resolve the nature of renal lesions. Because the Bosniak classification can only be applied to contrast-enhanced studies, CEUS is the preferred examination for characterization of an indeterminate renal mass if CT or MRI contrast cannot be administered.
The overwhelmingly most successful use of CEUS in the bowel is in the patient with inflammatory bowel disease (IBD). The addition of CEUS for assessment of bowel pathology has significantly improved our ability to detect, evaluate and objectively quantify the presence of bowel inflammation and its complications. Bowel wall blood flow, viewed as a reflection of inflammatory activity, is historically assessed with color Doppler imaging (CDI), but now, more effectively assessed with CEUS.64–66 As compared with subjective evaluations on CDI and CEUS, quantification analyses diminish operator dependency and allow for more reliable intrapatient and interpatient correlation. The nonionizing nature of this technique makes US a desirable alternative in the frequently young patient with IBD who has a high demand for imaging throughout the chronic course of their disease.
Recommended CEUS Use
- To detect, evaluate, and objectively quantify the presence of bowel inflammation and its complications in patients with IBD;
- To differentiate the nature of inflammatory masses found in patients with IBD;
- To differentiate strictures in IBD;
- To monitor response to IBD therapy.
Imaging is performed with the patient is a supine position. The transducer is placed at the ROI selected on the initial gray scale assessment. The abnormal bowel segment is evaluated in a sagittal orientation to minimize out-of-plane effects of respiratory motion and to facilitate generation of quality TIC allowing for quantification analysis. After contrast is injected through the patient's IV, a continuous acquisition is initiated, even before the arrival of the first bubble in the FOV and lasting for 2 minutes with no motion of the transducer. Most US equipment will allow for initial evaluation of the quantification curves at the bedside to assess technical quality of the TIC and to obtain preliminary results. If CEUS fails, or is technically inadequate, a second contrast injection may be performed, after a several minute delay.
Contrast Agent Dosing
Dependence on transducer and instrumentation, body habitus. In general, twice the dose used for liver imaging is perfect for evaluation of the bowel. For the majority of adult patients, a dose of 3.0 to 4.8 mL Lumason; Definity, 0.4 mL; Optison, inadequate literature.
CEUS Image Interpretation
Subjective evaluation may show the transmural enhancement of the bowel wall and also a comb sign to reflect the vessels in the mesentery which increase in response to inflammation. Perfusion may be visualized and may be quantified by the placement of ROI within the bowel wall and quantifying the change with software designed for quantification purposes.
Generation of TIC, allows for measurements of the fractional blood volume including the peak intensity (PI) or peak enhancement (PE), and the area under the curve (AUC).67–69 Measurements of blood flow include the rise time (RT), and transit time, as the mean transit time. These measurements provide objective evidence reflecting the degree of inflammation involving the bowel wall, for assessment of inflammatory activity at diagnosis,70 comparison between examinations in the same patient,71 for determination of response to therapy,72 and in the assessment of strictures.73,74
Although initial analysis of data may be performed directly on many US machines, there is a requirement for dedicated independent software for detailed analysis of quantification data. A TIC calculates the change in mean ROI intensity over time. Use of raw linearized data is optimal. Most analytical software programs offer 2 types of graph for viewing a TIC, a linear, and a log representation. The linear display shows the most realistic presentation of raw data, and consequently provides the most reliable method for performing most of the possible measurements. However, dynamic viewing of the generation of TIC allows in log format is more compelling as the range of decibel values for the PI shown with log data roughly equates with the visual capability of the human eye making estimations of activity possible at the time of performance of the scans.
Vast differences in the output of quantification data from various US manufacturers make the implementation of quantification techniques difficult at this time. Internationally, there are considerable differences in quantification methods and results between centers. In Europe, CEUS quantification analysis is often expressed as a percentage change of PE and of the AUC before and after treatment.72 Further, these studies use a ROI placed in the adjacent mesentery as a reference and they only compare examinations between the same patient. We prefer, instead, that this robust technique allows for integration of CEUS parameters with other subjective and objective measures of disease activity to allow for categorization of disease between large numbers of patients and for more easily applied determinations of disease activity.75
Contrast-enhanced ultrasound is not only valuable to differentiate the nature of inflammatory masses found often in association with IBD but also with other pathology. Abscesses are avascular in keeping with their cystic nature and phlegmonous masses are vascular.76 Contrast-enhanced ultrasound may not only be used in the characterization of bowel wall masses especially hypervascular neuroendocrine and gastrointestinal stromal tumors but also adenocarcinoma (Fig. 15, Video 9, http://links.lww.com/RUQ/A216). A summary of interpretation for IBD is presented in Table 9.
TABLE 9 -
USGA Showing Disease Activity Scores on Gray Scale US and CDI
|Gray scale ultrasound features of activity
|Wall thickness (mm)
• Perienteric region resembles normal mesenteric fat
• Slightly echogenic
• Of less area than the bowel on axial view
• More echogenic
• Equal area to the bowel on axial view
• Significantly echogenic
• Of greater than the bowel on axial view
Mural blood flow
||• Small regions of color without the vessel
||• Medium length segments of color vessels in the bowel wall
||• Circumferential or continuous depiction of vessels in the bowel wall with or without mesenteric vessels
||• No signs of active disease
||• Mild wall thickness
• Minimal inflammatory fat
• Present but not minimal signal on CDI
• Wall layer preservation
|• Moderate wall thickness
• Moderate inflammatory fat
• Moderate signal on CDI
• +/− wall layer preservation*
|• Moderate to severely thickened bowel wall
• Abundant inflammatory fat
• Long continuous mural blood vessels on CDI
• +/− wall layer preservation*
Spiculation of serosal border*
* If present, suggest more disease severity.
USGA, Ultrasound Global Assessment.
Pick the most abnormal loop of bowel for analysis, as far as possible from the diaphragm to limit respiratory motion. Use long axis of bowel. Bolus technique is preferred. Limit motion. Gluagon can be used in select patients to help limit bowel peristalsis. If the bowel in low in the pelvis, an endocavity probe can be used.
The addition of CEUS for assessment of bowel pathology has significantly improved our ability to detect, evaluate and objectively quantify the presence of bowel inflammation and its complications.
Splenic lesions are uncommon and usually clinically silent. B-mode US has a limited ability to characterize focal splenic lesions. The addition of CEUS can significantly improve the accuracy of detection and characterization of focal splenic lesions.
Recommended CEUS Use
- Detection and characterization of indeterminate spleen lesions,
- To confirm the presence of splenic infarction.
Imaging and timer begin with the start of the saline flush. Continuous recording from first arrival of bubble in the FOV until the lesion is characterized which is usually less than 3 minutes. Still images can then be saved from the cine clips at the end of the study. Scanning of the entire lesion is required, particularly for indeterminate masses.
Contrast Agent Dosing
This depends on transducer and instrumentation and body habitus. In the majority of adult patients, a dose of 1.5 to 2.4 mL Lumason; Definity, 0.2 to 0.3 mL; or Optison, 1.0 to 1.5 mL is adequate.
CEUS Image Interpretation
- Benign lesions: The absence of enhancement or persistent late-phase enhancement, especially when accompanied by APHE, is a feature associated with benign lesions. Contrast-enhanced ultrasound can also confirm the nature of accessory splenic tissue and the presence of splenic infarction. As noted in the Trauma section, CEUS can be used in select patients for diagnosis and follow-up of splenic injury.77
- Malignant lesions: Similar to the liver, AP enhancement followed by washout in the LP of enhancement is a feature of malignancy although it can also be seen in atypical benign lesions.
The unique vascular architecture of the spleen must be taken into account when assessing lesions with CEUS. Early enhancement may result in a transient, inhomogeneous “zebra” pattern. Approximately 60 seconds after contrast injection, the splenic parenchyma will appear homogeneous, with enhancement persisting throughout the venous and delayed phases, frequently lasting more than 5 minutes. Evaluation of the splenic parenchyma is, therefore, most reliably performed in the PV and delayed phases of enhancement.
Contrast-enhanced ultrasound is a useful diagnostic tool for splenic imaging. Contrast-enhanced ultrasound increases the conspicuity of the majority of incidentally identified splenic lesions and can be used to characterize cysts, hemangiomas, infarctions, and abscesses, as well as to facilitate the differentiation between benign and malignant lesions.
Several single site studies of CEUS to characterize pancreatic masses have been published. These demonstrate that CEUS improves the characterization of pancreatic masses, is accurate in the characterization of ductal adenocarcinoma, and may be performed immediately after US detection of a pancreatic mass.78,79 CEUS may be helpful in the characterization of both inflammatory and neoplastic masses. The former includes acute pancreatitis, which may show a focal or diffuse enlargement with hypovascularity on CEUS. Pseudocysts are highly variable in appearance but show complete avascularity in comparison to cystic neoplasms where the vascularity of both the wall, septa, and nodules may be striking. Masses associated with chronic pancreatitis and autoimmune pancreatitis may additionally present with a focal or diffuse enlargement of the pancreas that is often strikingly hypoechoic on gray scale. Their enhancement characteristics on CEUS are more difficult but may overlap with the hypoenhancement pattern typical of ductal adenocarcinoma or may show considerable enhancement in which case, their inflammatory nature maybe suspected.
Imaging and timer begin with the start of the saline flush. Continuous recording from first arrival of a bubble in the FOV until the lesion is characterized. Usually less than 3 minutes. From the cine clip, still images can then be saved at the end of the study. Scanning the entire lesion particularly in indeterminate masses is required.
CONTRAST AGENT DOSING
This depends on transducer and instrumentation, and body habitus. In general, in the majority of adult patients a dose of 1.5 to 2.4 mL Lumason; Definity, 0.2 to 0.3 mL; Optison, 1.0 to 1.5 mL.
Recommended CEUS Use
- Characterization of focal pancreatic masses.
CEUS Image Interpretation
Pancreatic tumors include solid tumors, ductal adenocarcinoma, neuroendocrine tumors, and metastases, as well as cystic tumors, which are subdivided into serous and mucinous varieties.
Ductal adenocarcinoma typically shows hypovascularity relative to the enhancing parenchyma on CEUS. This reliable observation is highly contributory to management. Neuroendocrine neoplasia shows hypervascularity, often with regions of necrosis and avascularity, aiding in both characterization and detection of intraparenchymal lesions which may be multiple or large aggressive lesions. Washout is invariably shown. Contrast-enhanced ultrasound improves detection and characterization of neuroendocrine tumors. Metastatic involvement of the pancreas is virtually always associated with primary tumor in the kidney, which may be remote in terms of its timing of occurrence. Because these tumors are hypervascular, their CEUS appearance will overlap with neuroendocrine neoplasia. History is obviously important for this distinction of metastatic RCC from neouroendocrine neoplasia as these 2 tumors also have a tendency for multiplicity.
Cystic neoplasms include benign serous cystadenoma and malignant mucinous tumors. Serous cystadenoma is a well-defined microcystic tumor with thin septa and small size of cysts. A honeycomb appearance of enhancing septa on CEUS and a central scar are features. Women in the 6th decade are most often affected. If confidently predicted on US/CEUS, these lesions are generally followed with conservative management.
Macrocystic mucinous lesions are comprised of larger cysts and may be unilocular or multilocular. They are generally considered to have a malignant potential and their management, therefore, is surgical. Features raising suspicion of this diagnosis include dense content within a cystic mass with an irregular, enhancing, and thick wall with similar septa. They are also most often seen in women in the fifth decade and their size may be considerable, greater than 8 cm. Their detection on CEUS should motivate careful evaluation of the peritoneal cavity as many malignant mucinous tumors will show peritoneal dissemination at the time of diagnosis.
Intraductal papillary mucinous neoplasm is the cystic lesions of the pancreas lined by intraductal dysplastic epithelium, which secretes excessive mucin, causing cystic dilation of the PD. Their involvement may be of the main pancreatic duct or dilated side branches. Ductal juxtaposition and ductal dilatation are features of this tumor. Contrast-enhanced ultrasound is invaluable to assess for enhancing nodules within cystic components as evidence of malignant transformation. Large cyst size, greater than 3 cm, dilatation of the pancreatic duct, and enhancing papillary excrescences are concerning features for malignancy. Intraductal papillary mucinous neoplasm occurs most often in elderly males.
Solid pseudopapillary tumor is a rare low-grade malignancy of the exocrine pancreas, typically presenting as a large well-defined round mass, without communication with the main pancreatic duct, in a young female in the third and fourth decades of life. On conventional US, it shows as a complex, solid/cystic mass, usually in the pancreatic body, often complicated by hemorrhage, necrosis, or cystic degeneration. Contrast-enhanced ultrasound typically shows inhomogeneous enhancement of the thickened peripheral capsule and solid components surrounding cystic and necrotic avascular regions.
Fasting is beneficial to pancreatic imaging and positional and breathing mechanisms to improve pancreatic visibility are essential for pancreatic CEUS.
Increasing solid components within complex cystic neoplasms and solid enhancing tumors have an increased incidence in malignant ovarian lesions. Although gray scale US alone, may, therefore, identify the most suspicious of lesions, motivation for early tumor detection and differentiation of indeterminate baseline lesions motivates the performance of CEUS. Contrast-enhanced ultrasound is obviously more sensitive to the detection of blood flow within solid and septal elements of ovarian masses. Further, TIC parameter analyses suggest that washout times and areas under the curves were significantly greater in ovarian malignancies than in other benign tumors (P < 0.001), leading to sensitivity estimates between 96% and 100% and specificity estimates between 83 and 98%.80
Several series have reported improved accuracy of CEUS for determining whether or not a mass is benign or malignant81–84 A recent meta-analysis including over 8000 patients showed enhanced specificity and sensitivity.85
The recent understanding that some ovarian cancers (type 2) arise from the tubal epithelium challenges the potential of labeled microbubbles for the early detection of these types of ovarian cancers. Preliminary work shows significant potential for labeled microbubbles.
Another potential application of CEUS of the ovary is the diagnosis of adnexal torsion. Contrast-enhanced ultrasound can potentially improve the depiction of the vascular pedicle as well as the perfusion of ovarian tumors.
Thus, future challenges for this technique include more extensive use of CEUS in programs designed to screen/early detect ovarian cancer, improved use of labeled microbubbles for type 2 ovarian cancers and more extensive use of CEUS for the diagnosis of adnexal torsion. Figure 16 demonstrates the appearance of a malignant ovarian lesion.
RECOMMENDED CEUS USE
- Characterization of indeterminate adnexal masses.
- Diagnosis of ovarian torsion.
Imaging and timer begin with the start of the saline flush. Continuous recording from first arrival of bubbles in the FOV until lesion is characterized. Usually less than 3 minutes. From the cine clips, still images can then be saved at the end of the study. Scanning the entire lesion particularly in indeterminate masses is required.
Contrast Agent Dosing
Depends on transducer and instrumentation, and body habitus. In general, for the majority of adult patient a dose of 1.5 to 2.4 mL Lumason; Definity, 0.2–0.4 mL; Optison, 1.0–1.5 mL. Depending on the size of the ovarian lesion under study, scans may be performed with endovaginal or transabdominal techniques.
CEUS Image Interpretation
For adnexal mass characterization, US imaging may be performed with either an endovaginal or a supra pubic technique depending on the size and location of the mass in question. In broad general terms, the determination of the enhancement of a mass is associated with consideration of malignancy with increased likelihood of surgical intervention. Malignancy is associated with increasing complexity of a mass as shown on a gray scale US examination. If in addition, there is high-intensity vascularity, with washout on CEUS, likelihood of malignancy is increased. Enhancement in conjunction with identified thick septa and septal and mural nodules are especially important and vascularity within a highly complex mass shown on gray scale is significant. Assessment of measured parameters on TIC may also be associated with malignancy including a higher PE and a shorter TTP.80,86 Unfortunately, original optimism for the value of US to screen for early ovarian malignancy and for CEUs to provide characterization has not been supported by clinical trials. Today, the American Medical Association feels that there is no good surveillance examination for ovarian cancer.
The addition of endovaginal technology with CEUS capability is invaluable. Although early publications evaluated Doppler techniques with different parameters suggesting malignancy and benignancy, today, the identification of vascularity alone, as on MR scan, is the major determent of neoplasia. Both malignant and benign ovarian tumors may show enhancement on CEUS.
Ultrasonography (US) is currently the imaging modality of choice for scrotal evaluation. However, there are a number of well-known limitations of the technique. Differentiation between hypovascular and avascular lesions is frequently difficult with conventional US which can confound the distinction between benign (usually avascular) and malignant lesions. In the setting of traumatic scrotal injury, the degree of testicular injury is frequently underestimated with conventional US. Diagnosis of testicular torsion can also be challenging, particularly in young children where blood flow to the normal testis may be low, especially in comparison to adult patients. Contrast-enhanced ultrasound can increase diagnostic confidence due to its greater sensitivity in depicting blood flow to focal lesions and to the testicular parenchyma. To date, however, there have been very few publications addressing the application of CEUS to disorders of the scrotum in either adults or children. Although scrotal CEUS is a theoretically appealing technique for use in children due to their small testes and relatively low flow, to date, there have been no dedicated clinical investigations of this application. Scrotal evaluation is performed off-label, with no standardized dosing scheme. Required doses will vary depending on testicular size and transducer frequency.
Recommended CEUS Use
- Discrimination of focal testicular lesions (identification of potentially malignant lesions),
- Detection of nonviable tissue after testicular trauma,
- Detection of segmental infarction,
- Discrimination of abscess formation in severe epididymo-orchitis3
Following conventional gray scale and color Doppler US evaluation, CEUS imaging of the scrotum is performed with particular attention paid to the AP of testicular enhancement. Arterial enhancement is followed within several seconds by parenchymal enhancement. Because there is no contrast accumulation within the testicular parenchyma, enhancement will progressively decrease with minimal residual enhancement by about 3 minutes.
Contrast Agent Dosing
This depends on transducer and instrumentation, and body habitus. In most adult patients, a double dose of contrast is required: 2.4 to 4.8 mL Lumason; Definity, 0.4 to 0.8 mL; Optison, 2.0 to 3.0 mL. There are currently no recommended pediatric doses for scrotal imaging.
Malignant testicular tumors are hypervascular by CEUS, except for regions of necrosis and cystic components. Contrast-enhanced ultrasound is useful in confirming the absence of blood flow in benign lesions such as infarct, hematoma or epidermoid cyst. The rapidity of contrast washin and washout are the parameters that best differentiate malignant from benign tumors, with a typically prolonged washout observed in Leydig cell tumors compared with seminomas.87–89 Several articles have discussed the performance of CEUS in conjunction with conventional gray scale and color Doppler US and elastography to enhance the diagnostic capability of US in differentiating benign from malignant testicular lesions, so-called multiparametric US.90–93
Segmental testicular infarction has a variable appearance on gray scale and color Doppler US. The presence of a wedge-shaped lesion with markedly decreased or absent flow with color Doppler usually establishes the diagnosis. Difficulty in diagnosis may arise, however, when the lesion has a rounded shape and may be confused with a poorly vascularized tumor. Contrast-enhanced ultrasound improves the characterization of segmental infarction by depicting ischemic parenchymal lobules separated by normal testicular vessels. Subacute segmental infarction typically demonstrates a perilesional rim of enhancement that decreases over time and eventually resolves along with decreased size of the lesion and change in shape.94
There are very few studies on the use of CEUS in the diagnosis of testicular torsion. A few examples have been reported in the literature where the absence of testicular enhancement has permitted a rapid and definitive diagnosis.95,96 In the setting of partial torsion, there will be a reduction of enhancement of the affected testis in comparison to the contralateral testis. Most of the publications to date have been experimental.97
Contrast-enhanced ultrasound has been shown to be useful in the setting of blunt scrotal trauma in identifying severely traumatized testes that show minimal, inhomogeneous, or patchy parenchymal enhancement. Patients with minor trauma demonstrate significant enhancement abnormality. Hematomas are depicted as nonenhancing lesions, whereas fractures are clearly depicted as nonperfused bands extending through the parenchyma with interruption of the tunica albuginea.98 Contrast-enhanced ultrasound can also be helpful in clarifying the nature of testicular lesions in patients with acute scrotal pain or trauma that are indeterminate by conventional gray scale and CDI.95,96
The CEUS aids in distinguishing abscesses from other inflammatory lesions and tumors by establishing the absence of internal vascularity. However, the gray scale appearance of extratesticular lesions is still essential for lesion characterization.99
Imaging of the testicles is usually best performed using a linear array transducer. To optimize the CEUS examination, a double dose of contrast is generally required.
Contrast-enhanced ultrasound is useful in improving the distinction between hypovascular and avascular lesions, with an avascular lesion presumed to represent benign disease. This differentiation between benign and malignant lesions permits more rapid institution of appropriate clinical management.
The AP at CEUS is the most important critical portion of the examination. The testis and epididymis will enhance rapidly although the contrast arrival time will vary between individuals. The arteries enhance initially, followed within seconds by complete parenchymal enhancement. The scrotal wall tends to enhance to a lesser degree than the scrotal contents. There is no accumulation of microbubbles in the testicular parenchyma and progressive loss of enhancement ensues with minimal residual contrast by 3 minutes.
Due to lack of sensitivity and specificity, breast CEUS is currently not recommended for routine clinical use. The studies which investigated the qualitative and quantitative CEUS features of benign versus malignant breast masses show that the exact parameters used for diagnostic purposes remain controversial. However, there is a recent research study which shows that CEUS may be a helpful tool when used in conjunction with mammography and conventional US to evaluate which indeterminate breast masses can avoid biopsy. This study showed that using CEUS may potentially reduce the number of false-positive biopsies by up to 31%.100 However, there appears to be promising results in recent research techniques including temporal accumulation (microvascular imaging) methods and labeled microbubbles.3,101,102 Typical enhancement pattern of a malignant breast lesion is presented in Figure 17.
This depends on transducer and instrumentation, and body habitus. In general, the majority of adult patients require a double dose of contrast. Dose of 2.4 to 4.8 mL Lumason; Definity, 0.42 to 0.8 mL; Optison, 2.0 to 3.0 mL.
Imaging and timer begins with the start of the saline flush. Continuous recording from first arrival of the first bubble in the FOV until the lesion is characterized. Usually less than 3 minutes. From the cine clip, still images can then be saved at the end of the study. Scanning the entire lesion particularly in indeterminate masses is required.
Contrast-enhanced ultrasound has been used to identify foci of prostate cancer (PCa). It should improve sensitivity; however, it is not sufficient to eliminate the standard systematic biopsies.103,104
A prostate CEUS examination is performed using the transrectal transducer using low MI below 0.2 with dedicated contrast imaging sequences. Prostate cancer exhibits earlier and increased enhancement compared with surrounding benign parenchyma.
Furthermore, newer CEUS techniques allow visualization of microvascular anatomy; vessels that supply areas of tumor are more numerous and irregular in configuration as compared with the normal radially oriented vessels that extend into the prostate parenchyma from the neurovascular bundles and periurethral vascular plexus.
The PCa enhancement is transient during the AP and can be distinguished from the surrounding parenchyma for less than 20 seconds after UCA bolus injection. A more important limitation is the development of benign prostatic hypertrophy which increases the size and vascularity of the transition zone and may overshadow the flow associated with malignancy. As prostate adenocarcinoma does not exhibit reliable washout, the short washin phase is more useful. Furthermore, in many published studies, prostate CEUS starts with identification of the most suspicious area, whatever the technique (B-mode, color or micro-Doppler imaging, elastography, or even MRI with cognitive or software-assisted registration). The transducer is maintained at this level and CEUS performed usually using a double dose of UCA. Prostate CEUS using UCA infusion may allow PCa detection by evaluation of the microvascular anatomy with a continuous imaging sweep through the prostate during the steady-state intravascular phase. The steady-state intravascular phase of UCAs can be used to evaluate vascular density and microvessel morphology.105
Contrast-enhanced ultrasound demonstrates improved diagnostic accuracy for PCa diagnosis compared with precontrast imaging, particularly for high grade cancer (Gleason score ≥ 7) with more than 50% biopsy core involvement, compared with precontrast imaging (P = 0.001) in a large prospective study of 272 patients (ROC AUC, 0.90).106 In a large prospective study enrolling 1024 patients, CEUS targeted biopsies detected 67/326 (20.5%) additional cases of clinically significant PCa, including 51 patients (15.6%) missed by systematic biopsy.107 A meta-analysis of prostate CEUS performance included 16 articles and 2624 patients concluded that CEUS appears as a promising tool for PCa detection with pooled sensitivity, pooled specificity and odds ratio of 70%, 74%, and 9.09, respectively. Nonetheless, CEUS is not adequately sensitive to avoid systematic biopsy.108 In addition to PCa detection, CEUS can provide assessment of hypoperfusion and necrosis after focal therapy with high-intensity focused US, or prostate artery embolization.109,110
Perfusion quantification has been used to evaluate prostate masses. Significant PCa exhibits higher PE, shorter RT and shorter time to peak than normal prostate tissue.111 To improve the detection of abnormal enhancement, it is possible to compute a TIC over the entire image and automatically estimate the heterogeneity of the enhancement based on the dispersion on the histogram of the washin rate.112,113 The software can automatically draw areas with abnormal enhancement. Parametric dispersion CEUS had better performance (with 91% sensitivity, 56% specificity, 57% PPV, and 90% NPV) than CEUS alone (with 73% sensitivity, 58% specificity, 50% PPV, and 79% NPV).114 These areas can be further targeted with biopsy.
This depends on transducer and instrumentation, and body habitus. In general, the majority of adult patients require a double dose of contrast. Dose of 2.4 to 4.8 mL Lumason; Definity, 0.42 to 0.8 mL; Optison, 2.0–3.0 mL.
Imaging and timer begin with the start of the saline flush. Continuous recording from first arrival of bubbles in the FOV until the lesion is characterized. Usually less than 3 minutes. From the cine clip, still images can then be saved at the end of the study. Scanning the entire lesion particularly in indeterminate masses is required.
There are limited studies utilizing CEUS for evaluation of thyroid and parathyroid lesions. The studies suggest that CEUS can improve the characterization of thyroid lesions with sensitivities and specificities of 80% to 85%.115,116
As with all small parts the use of a double dose of contrast may be required for adequate enhancement.
Imaging and timer begins with the start of the saline flush. Continuous recording from first arrive of bubble in the FOV to lesion characterization. Usually less than 3 minutes. From the cine clip, still images can then be saved at the end of the study. Scanning the entire lesion particularly in indeterminate masses is required.
Contrast-enhanced ultrasound has been used to evaluate the tendinopathy and postsurgical evaluation of patients with rotator cuff tears.117–120 The literature on the use of CEUS in musculoskeletal imaging is limited, and no recommendations can be made.
Trauma is a leading cause of death worldwide, and rapid identification of organ injury is essential for successful treatment. In the hemodynamically unstable patient, prompt surgical intervention may be lifesaving.
In cases of high-energy polytrauma, CECT is the imaging modality of choice for the rapid detection and grading of thoracoabdominal, skeletal, and neurological injuries. However, there is a wide range in the degree of severity of traumatic injuries, and lower energy trauma is associated with a decreased rate of abnormalities detected by CT. Drawbacks of CT include the associated ionizing radiation and injection of iodinated contrast media with the potential for contrast reactions and renal toxicity.
Ultrasound can be used in traumatized patients to identify intraperitoneal fluid. The so-called focused assessment with sonography for trauma scan is a technique that was developed for the detection of hemoperitoneum, especially in patients with hemodynamic instability. However, conventional US is not sufficiently sensitive to reliably identify parenchymal injury.
Contrast-enhanced US is an appealing alternative to CECT in the evaluation of adults and children with blunt abdominal trauma, particularly with respect to the potential reduction of population-level exposure to ionizing radiation. This is particularly important in the pediatric population which is more vulnerable to the hazards of ionizing radiation than adults. Several published series have shown that CEUS permits a confident exclusion of major abdominal injuries. Patients with minor trauma can therefore be managed without the need for CT examination.
Two contrast doses are administered, with imaging of the right kidney, right adrenal gland, liver, and pancreas after the first injection, and imaging of the left kidney, left adrenal gland, and spleen after the second injection. Injuries are depicted as nonenhancing defects that are clearly delineated from the homogeneously enhancing normal parenchyma, especially during the venous phase. On follow-up CEUS, targeted imaging of the injured organs identified on the initial study can be performed, and often only a single-contrast dose will be necessary.
Contrast-enhanced ultrasound can detect abnormalities that are not apparent by conventional US, including infarcts, pseudoaneurysms, and contrast extravasation. The latter appears as a pool or jet of contrast lying outside the blood vessels. Leakage of contrast-enhanced blood into the organ parenchyma, peritoneal cavity, or retroperitoneum is important to detect as it indicates on-going bleeding and the need for surgery. Indeterminate findings and artifacts present on CECT can also potentially be evaluated on CEUS.
Contrast-enhanced ultrasound is not useful in evaluation of injuries to the gastrointestinal tract. Because UCAs are not excreted by the kidney, trauma to the renal collecting system and urinoma cannot be directly diagnosed, a disadvantage when this technique is compared with CECT.
In summary, CEUS can be used as an alternative to CECT in stable patients with isolated blunt, low- to moderate-energy abdominal trauma to rule out solid organ injuries, especially in children; to further evaluate uncertain CT findings; and in the follow-up of conservatively managed traumatic injuries.121,122
Dosing should be the same as evaluation of a mass within the organ of interest.
Scanning should evaluate the entire organ looking for extravasation of contrast from the organ or areas of hypoperfusion.
Endovascular repair of AAA was first described by Dr. Juan Parodi in 1991.123 Now, endovascular aortic repair (EVAR) accounts for over 56% of all AAA repairs in the United States.124 This approach significantly reduces perioperative morbidity and mortality in the appropriately selected patient population.125 However, up to 20% to 50% of patients treated with EVAR will develop endoleaks.126
Endoleak is defined as continued pressurization of the aneurysm sac or aneurysm sac expansion despite being treated with covered endograft.126 Endoleaks are classified by 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.126
- Type II endoleaks occur due to retrograde filling of excluded aneurysm sac from collateral flow in the vessels, such as lumbar of inferior mesenteric artery.126
- Type III endoleaks occur through gaps between components of the graft or, much less commonly, tears in the graft material.126
- Type IV endoleaks occur due to porosity of graft wall material.126
- Type V endoleaks are diagnosed in patients for whom the aneurysm sac expansion occurs but no definite perfusion source is identified. These may be due to a phenomenon called “endotension” in which increased sac pressure is experienced despite no identifiable inflow or, most likely, due to slow-flow type II or III endoleaks, not identified by routine imaging.126
Because the endoleaks are often asymptomatic, early recognition is critical for appropriate patient management. The Society of Vascular Surgery (SVS) recommends lifelong surveillance of patients treated with EVAR.127 According to the SVS recommendations, the criterion standard for imaging is computed tomography angiography (CTA) with 3-dimensional (3D) reconstruction at 1 month after stent placement and then annually.127 If an abnormality is noted on the initial posttreatment CTA, a second scan is performed at 6 months to document stability.127 The SVS concede that there are concerns with cost, nephrotoxicity, and radiation exposure with lifelong CT imaging. It suggested that color Doppler US might be performed instead of CTA if no abnormalities are detected in the first year after treatment or in patients with contraindications to CTA.127
Color Doppler ultrasonography, however, is less sensitive than CTA in detecting EVAR complications, failing to detect as many as 31% of endoleaks.127–129 Shadowing from metal parts of the stent graft or calcifications in the graft wall of from preexisting aortoiliac disease usually complicate US imaging.130 In addition, interposed bowel gas and in some cases patient's body habitus limit US examination of the abdominal aorta.130 Finally, there are technical limitations of color and power Doppler US that make it less sensitive to slow flow endoleaks, which might not be detectable on US examination.129–131
The 2009 SVS practice guidelines noted a need for clinical research on evaluating the role of CEUS in postoperative surveillance of EVAR patients.127
Systematic reviews and meta-analyses have been published demonstrating a comparable diagnostic accuracy of CEUS and CTA in the diagnosis and classification of endoleaks.132–135 As a result, the 2011 European Federation of Societies for Ultrasound in Medicine and Biology practice guidelines suggested that CEUS may actually be more suited for characterization of endoleaks than CTA.3
Contrast-enhanced ultrasound holds several potential advantages over CTA in patients treated by EVAR. There is no concern for nephrotoxicity or radiation exposure with lifelong surveillance.136 In addition, CTA might be technically limited in characterizing endoleaks obscured by metallic streak artifact (from the endograft) and particularly endoleaks with slow flow.131,137 Additionally, ultrasonography is more cost effective than CTA.132
On the other hand, the CEUS requires appropriate equipment, personnel training and expertise.132 In addition, interposed bowel gas can make obtaining an adequate acoustic window without appropriate patient preparation difficult.132 When examining post-EVAR patients, the initial CEUS examination should be focused on early assessment of the aneurysmal sac and the graft itself. Synchronous enhancement suggests an antegrade leak (type I or type III), whereas delayed enhancement suggests a retrograde leak (type II). No sac enhancement suggests no endoleak. The CEUS examination should be continued for at least 10 minutes to allow detection of delayed and low flow endoleaks. When endoleak is detected, repeat contrast injections may be performed to identify the anatomic source of endoleak.
Early experiences with CEUS in patients after EVAR suggested diagnostic performance in endoleak detection similar to CTA.132–135 In one of the earliest meta-analyses evaluating CEUS in endoleak detection compared with CTA, Mirza et al132 pooled 7 (of 21 total) studies evaluating CEUS. Using CTA as the criterion standard, the authors reported a pooled CEUS sensitivity of 98% and pooled specificity of 88%.132 Of the 288 scan pairs, in only 2 patients the endoleaks were detected on CTA but not CEUS.132 On the other hands, 24 endoleaks were diagnosed on CEUS and missed on CTA.132 The authors comment that “high false-positive rate” of CEUS may suggest its increased sensitivity to slow-flow endoleaks compared with CTA (the criterion standard).132
In 2012, Karthikesalingam et al133 included 3 additional studies comparing CEUS with CTA and in their analysis and reported a pooled sensitivity of 96% and pooled specificity of 85%. They performed a secondary analysis using CEUS as the “criterion standard” and reported a CTA pooled sensitivity of 70% and pooled specificity of 98%, indicating that the true sensitivity of CEUS may actually exceed that of the sensitivity of CTA.133
In 2016, Guo et al135 pooled 19 studies comparing endoleak detection on CEUS and CTA with a total of 1694 paired scans. The authors noted that CEUS detected 138 endoleaks that were missed by CTA, whereas CTA only detected 51 endoleaks not seen on CEUS.135 However, in examination limited only to type I and type III endoleaks, just 5 endoleaks were detectable on CEUS alone, compared with 3 endoleaks on CTA alone.135 These findings suggest that majority of the endoleaks detected by CEUS alone and missed by CTA represent type II endoleaks.
More recently, in 2017, Sun et al134 performed meta-analysis of 14 studies and noted a pooled sensitivity of 88.9% and pooled specificity of 86.2% using CTA as the “criterion standard.” Similar to prior reports, they noted that in 11 of their 14 pooled studies, CEUS had a higher rate of endoleak detection compared with CTA.134
However, these recent meta-analyses share several common limitations. Substantial variability exists in CEUS technique, CT protocols, and surveillance protocols between the institutions.132,135 Additionally, if many of the unrecognized endoleaks are actually low-flow type II endoleaks for which close imaging surveillance is advocated, the benefits of in increased endoleak detection sensitivity for overall patient management may be limited.135
The ability to differentiate antegrade endoleaks (types I and III) from retrograde endoleaks (type II) is critical to patient management.126 Antegrade endoleaks result from a true mechanical failure of aneurismal sac exclusion by the graft.126 Contrastingly, retrograde endoleaks pressurize the sac by backward flow from feeding collateral vessels (usually lumbar arteries of inferior mesenteric artery).126 Although type II endoleaks, especially with slow- or low-pressure flow, are usually observed, most type I and III endoleaks result in sac expansion and require intervention.126
Contrast-enhanced ultrasound may be uniquely positioned for early detection and characterization of endoleaks, especially in patients with slow flow endoleaks.135 It is also particularly useful in differentiation between antegrade verse retrograde endoleaks, especially those misclassified or unclassified by CTA.138–141 Investigation into the role of CEUS in type IV (fabric porosity) and type V (endotension) endoleaks is much more limited. Detection of type IV endoleaks by CEUS have been reported.130 However, others have suggested that a type V endoleak may actually be a previously undetectable low-flow endoleak (type I or type II) that could be easily now appreciable on CEUS.137,141,142 Newer technological advances with 4-dimensional CEUS (CEUS with 3D reconstruction and real-time interrogation) and CEUS-CT fusion techniques are extremely promising and may provide a tool for even more early detection and characterization endoleaks in patients after EVAR.143,144 An example of an endoleak is presented in Figure 18 (Videos 10–11, http://links.lww.com/RUQ/A217, http://links.lww.com/RUQ/A218).
There is an overwhelming amount of literature from large single center studies to meta-analyses illustrating the diagnostic efficacy of CEUS in diagnosing and characterizing endoleaks with rates comparable to (or better than) CTA.
Bolus injection of 2.4 mL Lumason/0.2 mL Definity, Optison 1 mL or continuous infusion of Optison using a 3-mL vial of Optison and 57 mL normal saline combined in a sterile 60-mL syringe. When given as an infusion, the solution is delivered by a syringe pump at 4 mL/min, typically delivered via an upper-extremity peripheral vein.
The first part of the examination consists of a complete B-mode study of the abdominal aorta from the diaphragm to the iliac arteries, including color and power Doppler evaluation of the vessel and most importantly of the aneurysm sac. Blood flow velocities are measured with spectral Doppler and the widest portion of the aneurysmal sac is measured in longitudinal and transverse dimensions.
After UCA administration, the entire abdominal aorta is examined to the level of the common iliac arteries for 5 to 10 minutes, and the presence of enhancement within the aneurysm sac is evaluated, by monitoring the time of appearance (if synchronous or delayed with respect to prosthesis enhancement) and persistence in inflow and outflow vessels.
CEUS IN INTERVENTIONAL ONCOLOGY
Procedural Image Guidance
Percutaneous tumor sampling and ablation are critical for appropriate cancer patient management and US continues to play an important role in procedural image guidance. Percutaneous tissue sampling with routine US is limited by several factors, including tumor size, composition, and location. It is well known that the accuracy and adequacy of percutaneous sampling is lower in large tumors due to their heterogeneity of tumor composition and presence of tumor necrosis.145 Unfortunately, necrotic tissue is not clearly identified on B-mode US, especially before liquefaction has occurred, leading to decreased diagnostic yield of US-guided tissue sampling of large necrotic tumors.146 Small or deep lesions might also be difficult to biopsy due to limited visualization on routine B-mode US.147 As a result, despite all the advantages offered by US guidance, the overall sensitivity of percutaneous tissue sampling in the diagnosis of solid organ tumors has remained around 70% to 90%.147–149
Contrast-enhanced ultrasound has shown the ability to improve sensitivity of US-guided tissue sampling in a variety of solid organs to 96% to 100%. Additionally, CEUS has been used to guide biopsies of solid organ lesions identified on other imaging modalities and not visible on routine gray scale US.150 In sampling of peripheral lung lesions with US guidance, the addition of CEUS substantially increased adequacy and diagnostic yield of biopsies, predominantly by allowing the interventionalist to avoid necrotic areas of the tumor and to differentiate tumor from surrounding atelectasis.151–153 Similarly, interventional radiologist can use CEUS to improve image guidance during percutaneous ablation treatments by improving tumor boundary visualization.3,154
Contrast-enhanced ultrasound is gaining popularity in image-guided prostate biopsies.106 Transrectal gray scale US and Power Doppler US are shown to be poor predictors for malignancy, with sensitivity around 11% to 35% and the PPV between 17% and 57%.155 As a result, the current standard of care is performance of systematic multicore biopsies of all prostate regions.3,156 Nodular tumor hyperenhancement seen on CEUS may serve as a valuable guidance tool for needle placement in the more suspicious areas.3 As a result, several authors demonstrate increased adequacy of prostate tumor sampling with CEUS.106,157–161
When performing CEUS guidance for biopsies, several injections of US contrast might be required. The first bolus injection is used to identify the target lesion and plan the procedural approach. In addition, the first contrast injection can be used to locate the surrounding intrahepatic anatomical landmarks, plan a safe needle trajectory, adjust patient positioning, and go over breathing instructions. For liver tumors, careful scanning in the both arterial and delayed phases of CEUS imaging is very beneficial to identify target lesions which most often demonstrate APHE and washout on delayed phases of CEUS imaging.
The second bolus (or in some cases continuous contrast infusion) is used to guide biopsy needle placement. The biopsy needles usually are clearly visible on both CEUS and reference B-mode images due to tissue motion in the vicinity of the needle tip generating harmonic signals and the presence of air in the side notch of core biopsy needles which shows as bright echogenic reflectors.162 When the target lesion begins to clearly appear after the second contrast agent injection (or infusion), the biopsy needle is advanced into the target and tissue sampling is performed. Timing of needle placement will depend on type of the tumor being sampled. In large/partially necrotic tumors, sampling should be performed based on APHE of actively perfused viable tumor components. In smaller lesions, poorly identifiable on routine B-mode US, the biopsy is performed in the LP of CEUS imaging, targeting areas of tumor washout surrounded by actively perfused normal liver parenchyma.
Intraprocedural CEUS guidance could be improved by utilizing fusion imaging techniques when real-time CEUS imaging may be crosslinked with preprocedural CT, MRI, or PET imaging to target lesions detected on prior imaging and not visible on CEUS.163
Finally, CEUS is a powerful tool that can alleviate need for interventional procedures in select patients, when the clearly benign nature of suspected malignancy can be definitely shown in CEUS, such as hemorrhagic or proteinaceous cyst in the kidney or classic liver hemangioma in patients with suspected liver metastasis.
EARLY ASSESSMENT OF TUMOR RESPONSE AFTER LOCOREGIONAL TREATMENT
Contrast-enhanced CT and MRI are the traditional methods to assess tumor response after locoregional treatment of solid organ tumors. However, imaging is frequently delayed from between 4 weeks to several months after therapy because of inability to differentiate posttreatment inflammatory/desmoplastic response from the residual tumor, often producing false-positive results in the early posttreatment period.164,165 This limits the potential for early repeat interventions in patients with residual viable malignancy.
Contrast-enhanced ultrasound has found value in early posttreatment assessment after cryoablation, hyperthermal ablation, and intraarterial chemotherapy/radiation therapy. Cryoablation mediates cellular destruction by repeated freeze-thaw-refreeze cycles induced by a needle-sized cryoprobe.166 When utilized for RCC, CECT is typically obtained 2 to 3 months after treatment to reduce false positives from postablation inflammation.136 Early experience with CEUS in cryoablation suggests excellent concordance with cross-sectional imaging without the need for nephrotoxic contrast agents or repeated radiation exposure.167,168 Additionally, CEUS may show early tumor perfusion (an indicator of residual tumor viability) several weeks to months before it is detectable on CT imaging.169 In some studies, CEUS has shown the ability to detect residual disease within 20 to 30 minutes after treatment while the patient is still in the interventional suite—with a reduction in up to 31% of patients requiring a second treatment.170,171
Hyperthermal ablative therapies (radiofrequency and microwave) utilize heat produced by resistive tissue friction to cause cellular destruction (and protein denaturation or cellular vaporization).166 CEUS plays a vital role in the planning of ablative therapies, in the guidance of their performance and in the immediate postprocedural assessment. Additionally, CEUS will expedite treatment when secondary surveillance scans performed with CT or MR scan are indeterminate.172
Contrast-enhanced ultrasound has been used for immediate assessment of treatment effect to reduce the rates of incomplete radiofrequency ablation for HCC to as low as 6% after initial treatment.1,173 Although early delayed CEUS (24 hours posttreatment) has shown lower diagnostic accuracy, CEUS obtained at 1 month has proven to have excellent concordance with CECT.174 In 2018, the current LI-RADS working group will address use of CEUS for secondary surveillance of patients after local ablative therapy.
Finally, transarterial chemoembolization and transarterial radioembolization have found a particular role in locally advanced HCC.166 As in thermal ablative therapies, cross-sectional imaging is obtained at least 4 weeks after therapy to minimize inflammatory findings and decrease amount of artifact from intraparenchymal lipiodol.164,165 Findings suggest that CEUS can detect residual tumor viability and enhancement within 2 weeks of treatment with strong concordance to CT and MRI obtained weeks to months after treatment.165,175–178
Contrast-enhanced ultrasound in interventional oncology is gaining significant momentum, its value already expanded from simply identifying targets for tissue sampling to guiding interventional procedures and monitoring tumor treatment response. Additionally, retreatment of recurrent and residual tumors is also greatly facilitated by direct CEUS guidance at the time of the procedure due to the complex gray scale appearances, which may include both avascular treatment sites and arterial enhancing tumor.
The off-label use of UCAs in children went on for almost 20 years outside the United States before the breakthrough approval in 2016 of Lumason by the FDA, IV for liver and intravesical imaging179).180 Only after these approvals did the European Medicines Agency approve in 2017 the same UCA (SonoVue) for intravesical use in Europe. The pediatric IV use of UCAs in Europe and remains off-label to this date.
The most common indications for IV use of UCAs in children are FLLs (48%) followed by blunt abdominal trauma (37%) as described in the largest series from King's College London, encompassing 305 pediatric patients with a mean age of 11.7 years and range 0.1 to 18 years.181 In another retrospective study from the Karolinska Institute in Stockholm, the indications were similar to the above in a series of 287 CEUS examinations in children.182 The safety profile of the UCA approved for IV use for liver examination in children, Lumason, is similar to that in adults with very few (0.7%) minor and transient adverse events like tachycardia and hypertension.181,182 However, very rarely anaphylactic reaction can occur, and thus it is important to have a code cart near the US suite.183 Yusuf et al181 demonstrated the significant diagnostic impact of CEUS for pediatric liver lesions; in 49.7% of patients CEUS examination resulted in conclusive results eliminating the need for further CT or MRI study. The focal lesions commonly diagnosed include hemangiomas, FNH, focal fatty sparing, adenoma, and malignant tumors.184,185 These have similar CEUS characteristics as in adults. The use of IV UCA is expanding beyond the liver in children, in a similar manner as in adults, including the evaluation of kidneys, spleen, pancreas, adrenal glands, bowel, ovaries, testes, lungs, brain, and the liver and kidney specifically for posttransplant complications.186,187
The approved dose for Lumason is 0.03 mL/kg with a maximum dose of 2.4 mL per injection. The dose is administered in 1 or multiple boluses, each time followed by a normal saline flush. In practice, a clear dose dependency is noted based on the US scanner or transducer used. The sensitivity to depict microbubbles, that is, their conspicuity, is variable across different US scanners. The higher the frequency of the transducer the higher the dose of the US contrast administered. Furthermore, conspicuity of the lesion or lesions to be depicted and the depth of the area to be scanned require adjustment of the US contrast dose. Once a lesion in 1 organ is adequately characterized, there may not be the need to administer additional doses. The evaluation of additional lesions in an organ or the assessment of additional organs as in trauma may entail additional US contrast boluses.
This is similar to that employed in adults. Basically, there are 2 scanning techniques. The sweep through an organ is a screening method to detect 1 or more lesions in any part of the organ, particularly after complete enhancement. This is important in the evaluation of the abdominal organs in suspected case of blunt abdominal trauma. In the dynamic scan mode, US examination of a specific lesion is carried out visualizing the early (arterial/portal-venous) and delayed (venous) phases. Usually, a clip is done for the first minute followed by static images or short clips intermittently until about 5 minutes. This is important to detect early washout of the lesion compared with the surrounding parenchyma.
The IV administration is best carried out utilizing a peripheral line. A 24 G line would be best. However, it is possible to use a central line. A connector device attached to the line through which the injection is done may increase the destruction of microbubbles. The syringe with the UCA needs to be attached straight to the line and not at 90 degrees. The perpendicular port on a 3-way stopcock is reserved for the normal saline flush.188
The intravesical administration of UCA is best known as contrast-enhanced voiding urosonography or ceVUS. It is the most widespread pediatric application. There is an abundance of studies demonstrating the safety of intravesical use of UCAs. A composite of the safety data from multiple publications and different UCAs encompassing 7082 pediatric patients found the rate of adverse events to be only 0.8%. These comprise primarily of dysuria, transient macrohematuria and abdominal discomfort/pain.14 A study by Zerin and Shulkin189 showed that such findings are likely due to the transurethral catheter placement into the bladder rather than the filling of the bladder. A prospective safety analysis specifically of the UCA Lumason in 1010 children carried out only as ceVUS, without the addition of voiding cystourethrogram (VCUG) for comparison, had similar results pointing to catheterization as the cause of the transient adverse events rather than the UCA.190
Comparative studies of ceVUS with VCUG or direct radionuclide cystography have again and again demonstrated the higher sensitivity of ceVUS in the detection of vesicoureteral reflux.180,191 More than 2300 children are included in the comparative studies with VCUG alone demonstrating for ceVUS higher vesicoureteral reflux detection rate of 9% and more. There are 4 ceVUS studies with the same methodology and US contrast dosing of 1 mL of Lumason per bladder filling.192–194 These include a total of 508 patients with an age range of 2 days to 13 years. The comparison with VCUG yielded a pooled sensitivity of 89% and specificity of 81%. The comparison of the vesicoureteral reflux grading between ceVUS and VCUG has shown that in 74%, the grades are concordant, and in 20%, the grade in ceVUS is higher than that in VCUG.180 The latter is primarily due to the fact that 65% of grade 1 vesicoureteral refluxes are grade 2 or higher on ceVUS. The indications for ceVUS include suspected vesicoureteral reflux and/or urinary tract dilation. The ceVUS is focused on the detection of vesicoureteral reflux in the ureters or pelvicalyces. This can be combined with sonourethrography during voiding for the evaluation of the urethra.
In the Lumason official prescribing information, it is recommended to administer via direct injection into the bladder 1 mL of the reconstituted solution. In practice, similar to the IV administration, the dose of the UCA depends on the type of the US scanner or transducer used. With a higher frequency transducer, one may use higher dose of UCA than when scanning with a low frequency transducer. When using an US scanner with high sensitivity in depicting the microbubbles, it may suffice to inject only 0.2 mL of the Lumason. If one uses an infusion method instead of the direct injection for administering the UCA, again the dose when using a sensitive US scanner may be only 0.2% of Lumason- 0.9% normal saline suspension.
A bladder catheter is placed with standard sterile technique and the bladder emptied.179 Then, 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 3-way stopcock. In the direct injection method, the syringe with the UCA is attached to the 180-degree port. Initially, the bladder is slightly filled with normal saline followed by direct injection of the UCA. The syringe is removed and replaced with the tube connected to a normal saline bag. The normal saline infusion is continued. To facilitate homogenous distribution of the UCA in the bladder, a normal saline flush is carried out from the 90-degree port. In the case of the infusion method, a 0.2% of Lumason-0.9% normal saline solution is prepared, for example, by administering 0.5 mL of the Lumason in a 250-mL normal saline bag.195 This method is started with the infusion. A normal saline flush is done from the 90-degree port if the UCA is not homogenous. The infusions are continued until the maximum bladder capacity as calculated by the Koff's formula, (age + 2) × 30 in mL, is reached or the patient voids, whichever comes first. The bladder filling is under sonographic monitoring. It is important to have a homogenous filling of the bladder with depiction of the retrovesical space. The latter is important for the evaluation of vesicoureteral reflux into the terminal ureters. The scan of the kidneys can be carried out with the patient supine, prone or in the decubitus position. Alternatively, it is possible to have the child sit on a potty or the boy standing up and peeing in a urinal while being scanned from the back. The right and left kidneys are scanned alternatingly while intermittently monitoring the bladder filling. This is carried out during the bladder filling and when the patient is voiding. In addition, during voiding the urethra can be scanned from the suprapubic region or transperineal.195,196 All kinds of pathologies particularly of the male urethra have been described.197 Reflux is diagnosed when microbubbles are detected in a ureter and/or pelvicalyceal system. The grading of reflux in ceVUS is similar to that of VCUG into 5 grades as described by Darge et al.198 Images of a normal and abnormal ceVUS are presented in Figure 19 (Video 12, http://links.lww.com/RUQ/A219).
It is best to use normal saline solution from plastic containers as glass containers may be sealed under vacuum and lead to rapid diffusion of the gas contained in the microbubbles into the solution.199 The presence of X-ray, CT or MR contrast in the bladder will prevent homogenous mixing of the UCAs.200 Thus, a ceVUS examination needs to be carried out before the above ones with contrast. When using the contrast-specific modality, it is important to ensure that there is no excessive “subtraction” of the background but sufficient delineation of the borders of the kidneys. On the other hand, it is important to not to have much shine through of the renal sinus fat and thus potential confusion with reflux in the renal pelvis. It is best to do baseline images of the kidneys in the contrast-specific dual mode for possible comparison later on if reflux is suspected.
The intracavitary use of UCAs for diagnostic or therapeutic purposes outside the intravesical method is an emerging modality. There are not many publications on this topic, and currently, only few pediatric radiology units are using UCAs in the intracavitary route. One such application is contrast-enhanced gentiography for evaluation of patients with ambiguous genitalia in place of fluoroscopic genitography.180 Intracavitary contrast US is also used for identification of the location of a chest catheter as well as demonstrating its patency.201 Intracavitary administration into the pleural cavity can reveal the presence of loculations which may require the intrapleural injection of fibrinolytics.201 Further intracavitary applications include delineation of abscess cavities and evaluation of enteric tube position.
Potential Future Applications
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 assessing tumor blood flow and measuring bowel wall vascularity in IBD. 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, quantitation of tissue vascularity with these contrast agents requires complex, multicompartmental pharmacokinetic modeling. Also, these modalities either expose the patient to the harmful effects of radiation or can require sedation. Alternatively, CEUS has unique attributes that make it more appealing for measuring blood flow than other imaging modalities. Compared with dynamic CECT and MR, CEUS is relatively easy and quick to perform. Ultrasound contrast agents are gas-filled microspheres that approximate the size of red blood cells, remain in the vascular space and, therefore, have simpler pharmacodynamics. Because UCAs are highly reflective on US imaging, they can be given in very small doses and are detectable at the capillary level. Furthermore, CEUS is less expensive than CECT and MRI, can be performed at the bedside, does not require sedation and, most importantly (especially in the pediatric population), does not expose the patient to the harmful effects of ionizing radiation.
Quantitative CEUS studies are performed by first identifying an anatomic site of interest using gray scale and Doppler US. During the CEUS examination, the US transducer is held in a single plane over the area of interest during and after the bolus, IV administration of a UCA. Using the contrast-specific mode on the US machine, the dynamic CEUS study is recorded beginning immediately after the injection and continued for an appropriate length of time as determined by the examiner. Once the cine clip has been stored, it can be reviewed either in the US vendor's on-line quantitation software program or exported and opened offline using commercially available quantitative CEUS software. The investigator then manually draws an ROI within the tissue of interest, and the software program measures the brightness (which increases with contrast enhancement) within the ROI on each frame of the cine clip. From these data, TICs are generated and specific, quantitative CEUS parameters are derived. Parameters that have shown value include the PE intensity, the time-to-PE (or RT) and the AUC.9
There are a variety of potential applications of quantitative CEUS in the management of adult and pediatric patients. Several investigators have reported the value of quantitative CEUS in assessing disease activity in Crohn disease. Although results have been somewhat conflicting, quantitative CEUS shows promise as a method of distinguishing fibrotic from inflammatory disease and may be helpful in identifying responders to medical therapy.202 Some of the variability in results stems from differences in scanning technique and postprocessing methods. Also, there is no consensus on which parameters are most robust in assessing this disease process.203
Perhaps, the most active area of quantitative CEUS research is in the area of oncology. There is a growing body of literature regarding the value of quantitative CEUS to distinguish benign from malignant masses in solid organs and soft tissue, to monitor response to therapy in pediatric and adult malignancies, and to assess liver tumors treated with transarterial chemoembolization and radiofrequency ablation. Because UCAs are strictly intravascular, they can be used as surrogate markers of blood flow and are uniquely suited for assessing tumor response to antiangiogenic therapy.204 Unlike conventional chemotherapies, which are cytotoxic, antiangiogenic agents are cytostatic. That is, they halt tumor growth but may not cause cell death. As such, these agents may be effective with causing tumors to shrink. Therefore, the conventional method of assessing tumor response to chemotherapy, the Response Evaluation Criteria in Solid Tumors (RECIST), which relies on a change in tumor size, may not accurately reflect the activity of these agents. In contrast, quantitative CEUS can measure changes in tumor blood flow and can show a response to therapy earlier than the RECIST criteria.205 More recent studies show that quantitative CEUS is also valuable in assessing tumor response to conventional chemotherapy. Clearly, there is substantial interest in the development of CEUS to diagnose and assess treatment response in the oncology population. Limitations to the widespread use of quantitative CEUS in oncology are the need for validation in large clinical trials, standardization of the scanning technique and postprocessing, the need for volumetric tumor data/US transducers, standardization of the terminology used to describe CEUS parameters and identification of the most robust and reproducible CEUS parameters to assess response to therapy.73,206
In addition to diagnostic purposes, US and microbubbles (MB) can be used for therapeutic applications. Through a process called sonoporation, US and MB (USMB)-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 (REF). Cavitation is defined as the growing and shrinking response of MB subjected to the alternating low and high-pressure portions of the US wave.207 There are 2 types of cavitation, stable and inertial cavitation. Stable cavitation occurs at low acoustic pressure when MB stably oscillate without collapsing in an acoustic field. When MB violently grow and eventually collapse using higher acoustic pressures, this is called inertial cavitation. Dynamic MB motion along with fluid motion can exert mechanical forces on blood vessels. Also, energetic MB collapse results in secondary mechanical phenomena including liquid jetting and shockwaves (REF). These cavitation-induced mechanical effects can lead to both short-term responses (eg, cell morphology change) and extended bio-effects (eg, temporal cell permeability changes, cell lysis, etc.), enhancing the transmembrane transport and cellular uptake of therapeutic agents. Moreover, USMB-mediated drug delivery can potentially overcome disadvantages such as irreversible thermal damages to tissues (in particular of surrounding normal tissue) commonly associated with hyperthermia-mediated drug delivery.208
Multiple preclinical studies have demonstrated that USMB-mediated drug delivery has great potential for treating cancer, showing improved tumoricidal effects and reversal of drug resistance to mention a few. Also, because therapeutic agents can be highly localized into target tissues by delivery through real-time imaging guidance, USMB-mediated drug delivery can also reduce systemic toxicity of treatments.209–212 For more details, readers are referred to a recent review articles.213 Recently, 2 first-in-human clinical trials showed feasibility and safety of USMB-mediated sonoporation in patients.214,215 In a pilot study of 10 patients with pancreatic ductal adenocarcinoma, gemcitabine was infused intravenously over 30 minutes and a clinically used UCA (SonoVue/Lumason) was administered and sonicated using a routine clinical US scanner and transducer (GE LOGIQ 9; 4C curvilinear probe) operated at low mechanic index (MI = 0.2), likely inducing stable cavitation only. Compared with historical controls of patients treated with gemcitabine only, there was no increased toxicity in patients treated with a USMB-mediated drug delivery protocol. In addition, all 10 treated patients tolerated an increased number of gemcitabine cycles compared with historical controls and in 5 of these 10 patients, the maximum diameter of the primary pancreatic ductal adenocarcinoma decreased during the course of the treatment. Most strikingly, the median survival of all 10 patients increased from 8.9 months to 17.6 months, again compared with historical controls.216 Although this study is limited by a small number of patients and the fact that the treatment protocol did not optimize acoustic parameters or MB dosage for optimal drug delivery, it is an important first step toward clinical development of this promising application of MB and hopefully encourages subsequent clinical trials. Recently, the first-in-human trial using US and MB was performed for opening the blood-brain barrier following promising results in animal models.217,218
Similar to measuring temperature with MRI during HIFU ablations, a critical prerequisite for clinical translation of USMB-mediated drug delivery is a real-time feedback on drug delivery outcomes in the treated tissues to ensure homogenous and high enough therapeutic delivery of drugs. A promising feature of USMB-mediated drug delivery is that the drug delivery outcomes could be correlated with MB cavitation as a potential biomarker of successful drug delivery. Upon application of US, MB not only reflect incident US (echo) but they also produce cavitation signals (harmonic and broadband emissions), which are different from the US frequency.219 This cavitation dose (calculated from the cavitation signals) could potentially be used as an universal unit of successful drug delivery because the delivered cavitation dose is directly proportional to the amount of delivered drug in the target tissue.220
In conclusion, USMB-mediated drug delivery is a promising therapeutic approach that further broadens the clinical applications of CEUS. Multiple preclinical studies have confirmed improved efficiency of this drug delivery strategy to treat a wide variety of disease processes and first-in-human clinical trials have shown feasibility and safety of this approach in the clinical realm. Standardization of treatment protocols including acoustic parameters, MB types and doses, and technical developments to allow homogenous 3D treatment of varying sizes of diseases are warranted to support further clinical development of this technique.
Limitations of CEUS
Contrast-enhanced ultrasound suffers from the same problems as noncontrast US; artifacts due to overlying bowel gas, poor acoustical windows, and limited FOV compared with CT and MRI. 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 1 lesion (or adjacent lesions) can be assessed with 1 injection.
This article nicely describes a broad range of clinical applications for CEUS. Although the variability and specific requirements differ, all demand the same excellent performance of the US systems for their successful performance. Precisely, bubble resolution, near-field resolution, reduction of bubble destruction, and the ability to scan in the far field of the transducer are ongoing demands. The incredible performance improvements over the past 2 decades heralds a bright future for CEUS for body imaging which will then benefit from the many standard US advantages of safety, low-cost high availability, and patient acceptance.
Questions for Future Development/Research
Prospective confirmation of LIRADS for lesions in patients at risk for HCC.
Studies to determine the detection rate of metastatic lesions in the liver compared with CT and MRI.
Determination if TICs can differentiate different types of malignancies in any solid organ.
Continued use of CEUS for interventional procedures.
Confirmation of CEUS as a first-line modality for resolution of nodules found on surveillance US in those at risk for HCC.
Prospective studies to validate CEUS as an essential modality for the imaging of the kidney and the liver.
Establishment of CEUS as a procedure of choice for ablative therapies performed in the liver and the kidney.
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