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Contrast enhanced ultrasound: A review of radiology applications
Clinical Imaging 60 (2020) 209–215
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Clinical Imaging journal homepage: www.elsevier.com/locate/clinimag
Body Imaging
Contrast enhanced ultrasound: A review of radiology applications a,⁎
b
a
David B. Erlichman , Amanda Weiss , Mordecai Koenigsberg , Marjorie W. Stein a b
T
a
Department of Radiology, Montefiore Medical Center, Albert Einstein College of Medicine, United States of America Northwell Health System, Zucker School of Medicine at Hofstra/Northwell, United States of America
A R T I C LE I N FO
A B S T R A C T
Keywords: Contrast enhanced ultrasound Renal Liver Ultrasound contrast agent
Ultrasound contrast agents have been used for decades in Europe and Asia for cardiac and abdominal imaging and are now being more commonly utilized in the United States for radiology applications. Our article reviews the basics of contrast-enhanced ultrasound including how the contrast agent works, advantages and disadvantages, as well as pearls and pitfalls to help the radiologist efficiently integrate this technology into day-today clinical practice. We also discuss the diagnosis of focal hepatic lesions as well as off-label applications such as evaluation of renal masses.
1. Introduction Ultrasound contrast agents (UCA) are gas-filled microspheres which reflect sound waves and enhance the ultrasound image. First introduced in 1996, they have been used for decades in > 40 countries, primarily in Europe and Asia, for cardiac and abdominal imaging [1]. The various UCA differ in their gas and microsphere composition. Definity (Lantheus Medical Imaging) and Optison (GE Healthcare) have been used in the United States (US) for cardiac imaging, and UCA were used off-label in the US for other indications. It was not until 2015 that the FDA approved Lumason (sulfur hexafluoride lipid-type A microsphere, Bracco Diagnostics, Monroe Township, NJ), for characterization of liver lesions and evaluation of vesicoureteral reflux in children. Thus, there has been a recent increase in interest and use of contrast-enhanced ultrasound (CEUS) in the US for abdominal imaging [2,3]. Our review article explains the basics of CEUS including how the microbubbles work, advantages and disadvantages, as well as pearls and pitfalls to help the radiologist efficiently integrate this technology into day-to-day clinical practice. We will discuss the diagnosis of focal hepatic lesions as well as off-label applications such as evaluation of renal masses. UCA gas-filled microbubbles, stabilized within a lipoprotein shell, are smaller than red blood cells. They travel throughout the capillaries, but are large enough to remain within the vascular system and not cross into the interstitium, unlike CT and MRI contrast agents. Most of the UCA is eliminated via the lungs within 20 min of administration. Contrast specific software using low mechanical index (MI) is required to perform CEUS. The microbubbles have a non-linear response when used with a low MI compared to other tissue types which have a
linear response. An insonation pulse is followed by another pulse 180 degrees out of phase which results in canceling of tissue echoes which have a linear response. Specific computer software with CEUS augments the non-linear response from the bubbles, creating a vascular only image. After one injection sequence is recorded, a high MI may be used to burst residual bubbles before a second injection [3]. There are numerous advantages of UCA compared with agents used in contrast-enhanced CT (CECT) and MRI (CEMRI). The lack of radiation is a huge benefit compared to CT. UCA are not nephrotoxic nor hepatotoxic and renal or hepatic function tests are not needed before a patient undergoes CEUS, as opposed to CECT and CEMRI. Patients in renal failure and even dialysis can safely undergo CEUS. UCA have very few side effects and those that occur are extremely mild, including headache and nausea. The rate of serious adverse reactions in two large studies with over 100,000 patients was 1 in 10,000 patients with no deaths reported [4]. The International Contrast Ultrasound Society in 2018 reported the rate of life threatening reaction to low osmolar iodinated contrast was 1/5000 compared with UCA, where the rate of anaphylactoid reaction and severe fatal allergic reaction was 1/15,000 and 1/500,000, respectively. Most serious reactions occur within 30 min after injection. UCA can be used in patients with iodine allergies. The only contraindication to the use of Lumason is sulfur hexafluoride allergy, which is extremely rare. Allergy to sulfa medication is not a contraindication. However, although extremely safe, it is prudent to have resuscitation personnel and equipment readily available. With CECT and CEMRI, images are obtained at one point in time. Arterial phase images are obtained at about 35 s post injection and
⁎ Corresponding author at: Department of Radiology, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th Street Bronx, New York 10467, United States of America. E-mail address: derlichm@montefiore.org (D.B. Erlichman).
https://doi.org/10.1016/j.clinimag.2019.12.013 Received 31 October 2019; Received in revised form 8 December 2019; Accepted 16 December 2019 0899-7071/ © 2019 Elsevier Inc. All rights reserved.
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portal venous images at 70 s. But with CEUS, blood flow can be observed dynamically, allowing real-time examination which can aid in lesion characterization. Also with CEUS, the background tissue can be eliminated, providing a truly vascular image, with superior visualization of small structures such as septa and mural nodules. Another advantage is the short half-life of UCA of about 5 min that allows for a second injection at the same session. Disadvantages of CEUS include the necessity of equipping the ultrasound machine with specific computer hardware. The large amount of data accrued with CEUS may pose a storage issue for the PACs system. As with CECT and CEMRI, an IV must be placed, but two personnel are needed, one to scan and the other to inject. Another disadvantage is that only one or two specific lesions can be evaluated per session, and thus CEUS is not a useful screening tool. For CEUS, a 20 gauge or larger IV line is placed, as a smaller gauge IV will destroy the bubbles. Using a three-way stopcock, the contrast is injected in line with the IV and a saline flush to push the contrast out of the tubing is placed perpendicular to the IV. In this way, the fragile microbubbles will have a straight course into the patient. The contrast must not be injected too quickly to avoid bursting the bubbles. An initial non-contrast ultrasound exam is performed. The sonographer must identify the best imaging plane to keep the lesion in the field of view during inspiration and expiration. If the lesion is very deep, visualization will be limited so the patient must be positioned to bring the lesion closer to the transducer. Once the lesion is optimally visualized, Lumason is activated. Saline is injected into the Lumason vial and thoroughly shaken until the white liquid suspension is homogeneous. The contrast followed by saline flush is injected with the patient's arm straightened, to avoid bursting the fragile bubbles if the arm is bent. For adults, a maximum of two injections can be performed, using 2.4 ml per injection, but not > 4.8 ml. A dual screen image will be presented, with a B-mode display next to a contrast only image. Once contrast has been injected, start the timer and video continuously until the time of peak arterial enhancement. After this time, images may be acquired intermittently in order not to overwhelm the PACs system. Another reason is to avoid the cumulative slow destruction of the bubbles that may occur even at low MI when scanning continuously. The focal zone should be kept below the lesion as more bubbles will be destroyed at the focal zone. Because some hepatomas may take 5 min to washout, liver contrast imaging should be performed for at least 5 min. Renal imaging is quicker, usually 3 min or less, as we are merely looking to see if the lesion enhances or not and not evaluating washout. Certain technical pearls will be of practical use when CEUS technology is used. Lumason does not need to be refrigerated and can be stored at room temperature. If after Lumason is activated there is a delay in injecting, vigorously roll the contrast between your hands immediately before injection. Also, due to the 4–5 min half-life of Lumason, there may be residual contrast in the circulation from the first injection if a second injection is performed. To destroy the pre-existing bubbles, turn on color or Power Doppler which has high MI, and increase the field of view to include the aorta or heart. If UCA is given and no or minimal contrast is visualized, certain potential problems must be excluded. Check that the IV line did not infiltrate, the extension tubing is unclamped, and there is no filter within the line. Also, familiarize yourself with the 3-way stopcock beforehand, keeping in mind the stopcock points to the closed port. First inject the well-mixed, proper dose of UCA, and then the saline. The contrast mode must be turned on the ultrasound machine. To initiate a successful CEUS program at your institution, buy-in is necessary from referring physicians. You must spread the word to other departments such as hepatology, gastroenterology, transplant service, nephrology and urology. Meet with these clinicians and educate them about the benefits of CEUS and the appropriate indications for referral. Inform them that CEUS can result in cost savings to the health care
system because it is often diagnostic, avoiding higher cost CT and MRI [5]. 2. Liver CEUS is used to evaluate focal liver lesions detectable on gray-scale ultrasound. These lesions may be seen incidentally on routine US or identified during the work-up of a patient with known malignancy or hepatic parenchymal disease, especially, if there is a contraindication to CT or MRI or if pathology is inconclusive [6,7]. Although MRI has been considered the gold standard for characterization of liver lesions in the US, with recent FDA approval of CEUS for liver lesions, CEUS may be beneficial or at least equally efficacious and cost-effective [8,9]. In non-cirrhotic patients, the goal is to differentiate between malignant and benign lesions. This can be determined accurately by the pattern of late phase enhancement, with malignant lesions of all types demonstrating a hypovascular appearance due to washout, and benign lesions demonstrating an isovascular or hypervascular appearance. The vascular phases in CEUS are arterial (10–45 s), portal venous (45–120 s) and late/delayed (> 120 s), with slight overlap between phases due to hemodynamic factors [10]. Common benign focal lesions include hemangiomas, focal nodular hyperplasia (FNH), adenomas and cysts. The hallmark of a cyst on CEUS is lack of contrast uptake within the lesion in all phases. CEUS can be especially helpful in evaluating cases of complex cysts. While the Bmode appearance may mimic a hypoechoic solid mass, lack of enhancement can confirm it is a cyst [10] (Fig. 1a, b). Hemangiomas have a typical B-mode appearance of homogeneously hyperechogenic, round lesions with slight posterior acoustic enhancement and no flow on color Doppler. CEUS can achieve accurate diagnosis in up to 95% of cases [7]. The enhancement pattern parallels the CT and MRI appearance of nodular peripheral enhancement with progressive centripetal fill-in [11] (Fig. 2a, b, c). This is diagnostic of hemangiomas regardless of B-mode appearance. The lesion should remain hyperechoic or isoechoic on delayed phase imaging without evidence of wash-out, typical of benign lesions. However, in larger lesions areas of decreased enhancement may be seen due to focal fibrosis/thrombosis [12]. FNH demonstrates a non-specific B-mode appearance with a central scar occasionally identified. CEUS can be utilized to increase the conspicuity of the central scar [13]. On CEUS, FNHs are typically homogenously hypervascular and remain slightly hyperechoic or more often become isoechoic on delayed phase with a central hypoechoic scar [14]. Adenomas demonstrate a variable B-mode appearance. On CEUS, adenomas show arterial enhancement with rapid filling in that becomes isoechoic or slightly hyperechoic on delayed phase, usually earlier than an FNH. However, differentiating this lesion from FNH is primarily based on lack of a central scar [15]. Other benign entities include focal fatty sparing or deposition that on CEUS demonstrate isoenhancement to surrounding liver on all phases (Fig. 3a, b) [10]. Malignant lesions include HCC and cholangiocarcinoma, which are more often seen in the setting of cirrhosis, and metastatic disease. HCC on CEUS demonstrates arterial enhancement with delayed washout (Fig. 4a, b, c). Washout typically occurs > 90 s after injection whereas metastases or cholangiocarcinoma typically show more rapid washout of < 60 s [16]. Any homogeneously hypervascular lesion in a cirrhotic patient, even without washout and without enhancement typical of a hemangioma, is highly suspicious for HCC [17]. LIRADS categorization has been developed for evaluating lesions on CEUS in cirrhotic patients, allowing for grading of observations based on enhancement pattern and size [18]. Cholangiocarcinoma has variable arterial phase enhancement, including irregular rim-like enhancement, heterogeneous hyperenhancement, or homogenous hyperenhancement that becomes hypovascular 210
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Fig. 1. a. Complex liver cyst- Ultrasound B-mode image demonstrates a hypoechoic lesion with associated hyperechoic foci, likely representing calcification (black arrow). b. Complex liver cyst- CEUS image demonstrates an anechoic appearance compatible with a cyst (black arrow).
on delayed phase. Unlike CT or MRI, CEUS does not demonstrate delayed enhancement within the lesion. Metastasis is commonly hypovascular with usually slight enhancement on the early arterial phase that rapidly washes out [19]. Hypervascular metastasis demonstrates enhancement on early hepatic arterial phase with washout on delayed phase [20]. Limitations of CEUS in the liver include the inability to evaluate lesions smaller than 5 mm or those close to the diaphragm or heart that can be difficult to keep in the field of view due to respiratory motion. Deep lesions in the setting of a fatty liver can be difficult to evaluate due to limited acoustic penetration [10]. 3. Renal CEUS is especially useful in the setting of known or presumed renal disease. Unlike CT or MRI contrast, CEUS microbubble agents do not adversely affect renal function. Microbubbles allow for qualitative perfusion analysis of microcirculation, diagnosis of vascular problems, and assessment of tumor vascularity [21]. Evaluation is based on the presence or absence of contrast uptake. The renal cortical phase of
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Fig. 2. a. Hemangioma- Ultrasound B-mode image demonstrates a hyperechoic lesion in the left hepatic lobe (black arrow). b. Hemangioma- CEUS early hepatic arterial phase image demonstrates peripheral nodular enhancement (black arrow). c. Hemangioma- CEUS portal venous phase image demonstrates centripetal filling in (black arrow).
Fig. 3. a. Focal fat- Ultrasound B-mode image demonstrates a slightly hyperechoic region in the liver (black arrow). b. Focal fat- Ultrasound B-mode image (Left) and CEUS image (Right) demonstrates isoehancement of the region in comparison to the adjacent parenchyma (black arrows).
enhancement begins 10–15 s post contrast administration and lasts 20–40 s. The medullary phase follows, lasting 45–120 s [21]. After some time, the contrast is eliminated and the image becomes hypoechoic. The collecting system is unaffected, as UCA is not renally excreted. Renal applications of CEUS include evaluating for renal infarct, differentiating between solid and cystic lesions, characterizing complex cystic lesions, and distinguishing between tumor and pseudotumor. A renal infarct on CECT appears as a wedge shaped area of nonperfusion. When iodinated contrast administration is not feasible, CEUS is a viable alternative. CEUS also depicts renal infarcts as wedge-shaped areas of non-perfusion and is more accurate than B mode or Doppler US alone. CEUS can also distinguish between renal infarct and cortical
Fig. 4. a. Hepatocellular carcinoma- Ultrasound B-mode image demonstrates a heterogeneous lesion (black arrow). b. Hepatocellular carcinoma- CEUS early hepatic arterial phase image demonstrates enhancement in the lesion (black arrow). c. Hepatocellular carcinoma- CEUS portal venous phase image demonstrates washout in the lesion (black arrow). 212
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Fig. 6. Dromedary hump- Ultrasound B-mode image (Left) shows a prominent round/bulging region in the mid left kidney (black arrow) and CEUS ultrasound image (right) demonstrates the region enhancing similar to the adjacent parenchyma (white arrow).
gold standard imaging studies to diagnose renal transplant vascular complications, with Doppler the initial study [24–26]. A limitation of Doppler ultrasound is that it only provides information up to the level of the interlobar and arcuate arteries and cannot reliably assess more distal vascularity at the subcapsular level. CEUS can assess more distal vessels, increasing its sensitivity for vascular complications. When compared to normal kidneys, transplant kidneys with acute vascular complications demonstrate delayed contrast enhancement and decreased peak intensity [25]. At least one study has shown a comparable sensitivity of CEUS for vascular complications compared to the gold standards [24]. Though CECT is the gold standard [27] for renal mass determination, at least one study has shown CEUS to be more sensitive than CECT [28]. Additionally, unlike liver masses where some solid masses are characteristically benign, any solid renal mass is deemed a renal cell carcinoma (RCC) until proven otherwise. When employed to assess an indeterminate renal lesion, the presence of microbubbles proving intralesional vascularity is sufficient to characterize a lesion as a solid mass highly suspicious for malignancy (Fig. 5a, b) [29]. At least one study assessed CEUS pattern of contrast uptake to differentiate between the two most common subtypes of RCC: clear cell RCC (ccRCC), which accounts for 70% of all RCCs, and papillary RCC (pRCC), which accounts for 10–15% [29]. It has long been established that pRCC enhances less avidly than ccRCC on CECT [30]. The CEUS correlate is a pattern of generally slower wash-in, faster wash-out, overall hypoenhancement and presence of a pseudocapsule with pRCC when compared to ccRCC [31]. The authors found all 25 cases of pRCC demonstrated some degree of enhancement on CEUS, while 5 of the 25 cases were equivocal or lacked enhancement on CECT, suggesting improved sensitivity of CEUS compared to CECT. Other studies have also demonstrated improved sensitivity of CEUS for intralesional blood flow compared to cross-sectional imaging [32]. Anatomic variants that may mimic renal masses on imaging (pseudotumors) include fetal lobulation, hypertrophied column of Bertin, and a dromedary hump. If a pseudotumor is suspected, but not diagnosable on grayscale US, a patient would likely be referred to CECT or CEMRI for further evaluation. CEUS, however, can show that the pseudotumor exhibits the same perfusion characteristics as the surrounding parenchyma during all imaging phases (Fig. 6) obviating the need for cross sectional imaging [33,34]. CEUS is particularly helpful for differentiating solid renal masses from cysts when equivocal on grayscale US, for characterizing complex
Fig. 5. a. Renal cell carcinoma- Ultrasound B-mode image demonstrates a hypoechoic lesion (black arrow) and an anechoic lesion (white arrow) in the right kidney. b. Renal cell carcinoma- CEUS image demonstrates a hypoenhancing lesion in the right kidney (black arrow) compatible with malignancy and an anechoic lesion compatible with a cyst (white arrow).
necrosis; in the setting of cortical necrosis, renal hilar vascularity is maintained, while the cortex lacks perfusion [22]. Since CEUS can image renal blood flow in real time with high temporal and spatial resolution, CEUS has been shown to be helpful in evaluating early diabetic nephropathy by measuring renal hemodynamic and microvascular perfusion changes in early and late stage diabetes. Patients with diabetic nephropathy will demonstrate overall decreased perfusion with delayed time to peak enhancement [23]. The safety profile of microbubble agents makes CEUS particularly useful for evaluating renal transplants when early vascular complications are suspected. Early vascular complications include arterial or venous thrombus, arterial stenosis, vascular leak or pseudoaneurysm and cortical necrosis. Other complications include urologic or surgical complications, infection and nephrologic causes, such as acute rejection, acute tubular necrosis and anticalcineurin toxicity. In the early post-operative period, visualization of renal vascularity is key, as early diagnosis and intervention for a vascular complication may save the allograft from failure. Doppler US, CT, digital subtraction angiography (DSA) and nuclear medicine radioisotope renography are the current
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[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18] [19]
Fig. 7. a. Complex renal cyst- Ultrasound B-mode image demonstrates 2 hypoechoic lesions in the left kidney (black arrows). b. Complex renal cyst- CEUS image demonstrates an anechoic appearance compatible with cysts (black arrows).
[20]
[21]
cystic masses and for interval follow-up of non-surgical lesions (Fig. 7a, b) [35]. Multiple studies have demonstrated that CEUS is more sensitive than CECT in detecting vascularity in hypovascular lesions and demonstrating wall, septal and solid component enhancement in complex cysts [29,32,35,36]. CEUS is a major addition to the imaging armamentarium in the characterization of hepatic and renal lesions, without the use of nephrotoxic agents or radiation. CEUS improves the detection and characterization of tumor vascularity in hepatic and renal masses, can differentiate solid masses from cysts, and improves visualization of blood flow within septa and walls of complex cystic masses [36].
[22]
[23]
[24]
[25]
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Clinical Imaging journal homepage: www.elsevier.com/locate/clinimag
Body Imaging
Contrast enhanced ultrasound: A review of radiology applications a,⁎
b
a
David B. Erlichman , Amanda Weiss , Mordecai Koenigsberg , Marjorie W. Stein a b
T
a
Department of Radiology, Montefiore Medical Center, Albert Einstein College of Medicine, United States of America Northwell Health System, Zucker School of Medicine at Hofstra/Northwell, United States of America
A R T I C LE I N FO
A B S T R A C T
Keywords: Contrast enhanced ultrasound Renal Liver Ultrasound contrast agent
Ultrasound contrast agents have been used for decades in Europe and Asia for cardiac and abdominal imaging and are now being more commonly utilized in the United States for radiology applications. Our article reviews the basics of contrast-enhanced ultrasound including how the contrast agent works, advantages and disadvantages, as well as pearls and pitfalls to help the radiologist efficiently integrate this technology into day-today clinical practice. We also discuss the diagnosis of focal hepatic lesions as well as off-label applications such as evaluation of renal masses.
1. Introduction Ultrasound contrast agents (UCA) are gas-filled microspheres which reflect sound waves and enhance the ultrasound image. First introduced in 1996, they have been used for decades in > 40 countries, primarily in Europe and Asia, for cardiac and abdominal imaging [1]. The various UCA differ in their gas and microsphere composition. Definity (Lantheus Medical Imaging) and Optison (GE Healthcare) have been used in the United States (US) for cardiac imaging, and UCA were used off-label in the US for other indications. It was not until 2015 that the FDA approved Lumason (sulfur hexafluoride lipid-type A microsphere, Bracco Diagnostics, Monroe Township, NJ), for characterization of liver lesions and evaluation of vesicoureteral reflux in children. Thus, there has been a recent increase in interest and use of contrast-enhanced ultrasound (CEUS) in the US for abdominal imaging [2,3]. Our review article explains the basics of CEUS including how the microbubbles work, advantages and disadvantages, as well as pearls and pitfalls to help the radiologist efficiently integrate this technology into day-to-day clinical practice. We will discuss the diagnosis of focal hepatic lesions as well as off-label applications such as evaluation of renal masses. UCA gas-filled microbubbles, stabilized within a lipoprotein shell, are smaller than red blood cells. They travel throughout the capillaries, but are large enough to remain within the vascular system and not cross into the interstitium, unlike CT and MRI contrast agents. Most of the UCA is eliminated via the lungs within 20 min of administration. Contrast specific software using low mechanical index (MI) is required to perform CEUS. The microbubbles have a non-linear response when used with a low MI compared to other tissue types which have a
linear response. An insonation pulse is followed by another pulse 180 degrees out of phase which results in canceling of tissue echoes which have a linear response. Specific computer software with CEUS augments the non-linear response from the bubbles, creating a vascular only image. After one injection sequence is recorded, a high MI may be used to burst residual bubbles before a second injection [3]. There are numerous advantages of UCA compared with agents used in contrast-enhanced CT (CECT) and MRI (CEMRI). The lack of radiation is a huge benefit compared to CT. UCA are not nephrotoxic nor hepatotoxic and renal or hepatic function tests are not needed before a patient undergoes CEUS, as opposed to CECT and CEMRI. Patients in renal failure and even dialysis can safely undergo CEUS. UCA have very few side effects and those that occur are extremely mild, including headache and nausea. The rate of serious adverse reactions in two large studies with over 100,000 patients was 1 in 10,000 patients with no deaths reported [4]. The International Contrast Ultrasound Society in 2018 reported the rate of life threatening reaction to low osmolar iodinated contrast was 1/5000 compared with UCA, where the rate of anaphylactoid reaction and severe fatal allergic reaction was 1/15,000 and 1/500,000, respectively. Most serious reactions occur within 30 min after injection. UCA can be used in patients with iodine allergies. The only contraindication to the use of Lumason is sulfur hexafluoride allergy, which is extremely rare. Allergy to sulfa medication is not a contraindication. However, although extremely safe, it is prudent to have resuscitation personnel and equipment readily available. With CECT and CEMRI, images are obtained at one point in time. Arterial phase images are obtained at about 35 s post injection and
⁎ Corresponding author at: Department of Radiology, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th Street Bronx, New York 10467, United States of America. E-mail address: derlichm@montefiore.org (D.B. Erlichman).
https://doi.org/10.1016/j.clinimag.2019.12.013 Received 31 October 2019; Received in revised form 8 December 2019; Accepted 16 December 2019 0899-7071/ © 2019 Elsevier Inc. All rights reserved.
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portal venous images at 70 s. But with CEUS, blood flow can be observed dynamically, allowing real-time examination which can aid in lesion characterization. Also with CEUS, the background tissue can be eliminated, providing a truly vascular image, with superior visualization of small structures such as septa and mural nodules. Another advantage is the short half-life of UCA of about 5 min that allows for a second injection at the same session. Disadvantages of CEUS include the necessity of equipping the ultrasound machine with specific computer hardware. The large amount of data accrued with CEUS may pose a storage issue for the PACs system. As with CECT and CEMRI, an IV must be placed, but two personnel are needed, one to scan and the other to inject. Another disadvantage is that only one or two specific lesions can be evaluated per session, and thus CEUS is not a useful screening tool. For CEUS, a 20 gauge or larger IV line is placed, as a smaller gauge IV will destroy the bubbles. Using a three-way stopcock, the contrast is injected in line with the IV and a saline flush to push the contrast out of the tubing is placed perpendicular to the IV. In this way, the fragile microbubbles will have a straight course into the patient. The contrast must not be injected too quickly to avoid bursting the bubbles. An initial non-contrast ultrasound exam is performed. The sonographer must identify the best imaging plane to keep the lesion in the field of view during inspiration and expiration. If the lesion is very deep, visualization will be limited so the patient must be positioned to bring the lesion closer to the transducer. Once the lesion is optimally visualized, Lumason is activated. Saline is injected into the Lumason vial and thoroughly shaken until the white liquid suspension is homogeneous. The contrast followed by saline flush is injected with the patient's arm straightened, to avoid bursting the fragile bubbles if the arm is bent. For adults, a maximum of two injections can be performed, using 2.4 ml per injection, but not > 4.8 ml. A dual screen image will be presented, with a B-mode display next to a contrast only image. Once contrast has been injected, start the timer and video continuously until the time of peak arterial enhancement. After this time, images may be acquired intermittently in order not to overwhelm the PACs system. Another reason is to avoid the cumulative slow destruction of the bubbles that may occur even at low MI when scanning continuously. The focal zone should be kept below the lesion as more bubbles will be destroyed at the focal zone. Because some hepatomas may take 5 min to washout, liver contrast imaging should be performed for at least 5 min. Renal imaging is quicker, usually 3 min or less, as we are merely looking to see if the lesion enhances or not and not evaluating washout. Certain technical pearls will be of practical use when CEUS technology is used. Lumason does not need to be refrigerated and can be stored at room temperature. If after Lumason is activated there is a delay in injecting, vigorously roll the contrast between your hands immediately before injection. Also, due to the 4–5 min half-life of Lumason, there may be residual contrast in the circulation from the first injection if a second injection is performed. To destroy the pre-existing bubbles, turn on color or Power Doppler which has high MI, and increase the field of view to include the aorta or heart. If UCA is given and no or minimal contrast is visualized, certain potential problems must be excluded. Check that the IV line did not infiltrate, the extension tubing is unclamped, and there is no filter within the line. Also, familiarize yourself with the 3-way stopcock beforehand, keeping in mind the stopcock points to the closed port. First inject the well-mixed, proper dose of UCA, and then the saline. The contrast mode must be turned on the ultrasound machine. To initiate a successful CEUS program at your institution, buy-in is necessary from referring physicians. You must spread the word to other departments such as hepatology, gastroenterology, transplant service, nephrology and urology. Meet with these clinicians and educate them about the benefits of CEUS and the appropriate indications for referral. Inform them that CEUS can result in cost savings to the health care
system because it is often diagnostic, avoiding higher cost CT and MRI [5]. 2. Liver CEUS is used to evaluate focal liver lesions detectable on gray-scale ultrasound. These lesions may be seen incidentally on routine US or identified during the work-up of a patient with known malignancy or hepatic parenchymal disease, especially, if there is a contraindication to CT or MRI or if pathology is inconclusive [6,7]. Although MRI has been considered the gold standard for characterization of liver lesions in the US, with recent FDA approval of CEUS for liver lesions, CEUS may be beneficial or at least equally efficacious and cost-effective [8,9]. In non-cirrhotic patients, the goal is to differentiate between malignant and benign lesions. This can be determined accurately by the pattern of late phase enhancement, with malignant lesions of all types demonstrating a hypovascular appearance due to washout, and benign lesions demonstrating an isovascular or hypervascular appearance. The vascular phases in CEUS are arterial (10–45 s), portal venous (45–120 s) and late/delayed (> 120 s), with slight overlap between phases due to hemodynamic factors [10]. Common benign focal lesions include hemangiomas, focal nodular hyperplasia (FNH), adenomas and cysts. The hallmark of a cyst on CEUS is lack of contrast uptake within the lesion in all phases. CEUS can be especially helpful in evaluating cases of complex cysts. While the Bmode appearance may mimic a hypoechoic solid mass, lack of enhancement can confirm it is a cyst [10] (Fig. 1a, b). Hemangiomas have a typical B-mode appearance of homogeneously hyperechogenic, round lesions with slight posterior acoustic enhancement and no flow on color Doppler. CEUS can achieve accurate diagnosis in up to 95% of cases [7]. The enhancement pattern parallels the CT and MRI appearance of nodular peripheral enhancement with progressive centripetal fill-in [11] (Fig. 2a, b, c). This is diagnostic of hemangiomas regardless of B-mode appearance. The lesion should remain hyperechoic or isoechoic on delayed phase imaging without evidence of wash-out, typical of benign lesions. However, in larger lesions areas of decreased enhancement may be seen due to focal fibrosis/thrombosis [12]. FNH demonstrates a non-specific B-mode appearance with a central scar occasionally identified. CEUS can be utilized to increase the conspicuity of the central scar [13]. On CEUS, FNHs are typically homogenously hypervascular and remain slightly hyperechoic or more often become isoechoic on delayed phase with a central hypoechoic scar [14]. Adenomas demonstrate a variable B-mode appearance. On CEUS, adenomas show arterial enhancement with rapid filling in that becomes isoechoic or slightly hyperechoic on delayed phase, usually earlier than an FNH. However, differentiating this lesion from FNH is primarily based on lack of a central scar [15]. Other benign entities include focal fatty sparing or deposition that on CEUS demonstrate isoenhancement to surrounding liver on all phases (Fig. 3a, b) [10]. Malignant lesions include HCC and cholangiocarcinoma, which are more often seen in the setting of cirrhosis, and metastatic disease. HCC on CEUS demonstrates arterial enhancement with delayed washout (Fig. 4a, b, c). Washout typically occurs > 90 s after injection whereas metastases or cholangiocarcinoma typically show more rapid washout of < 60 s [16]. Any homogeneously hypervascular lesion in a cirrhotic patient, even without washout and without enhancement typical of a hemangioma, is highly suspicious for HCC [17]. LIRADS categorization has been developed for evaluating lesions on CEUS in cirrhotic patients, allowing for grading of observations based on enhancement pattern and size [18]. Cholangiocarcinoma has variable arterial phase enhancement, including irregular rim-like enhancement, heterogeneous hyperenhancement, or homogenous hyperenhancement that becomes hypovascular 210
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Fig. 1. a. Complex liver cyst- Ultrasound B-mode image demonstrates a hypoechoic lesion with associated hyperechoic foci, likely representing calcification (black arrow). b. Complex liver cyst- CEUS image demonstrates an anechoic appearance compatible with a cyst (black arrow).
on delayed phase. Unlike CT or MRI, CEUS does not demonstrate delayed enhancement within the lesion. Metastasis is commonly hypovascular with usually slight enhancement on the early arterial phase that rapidly washes out [19]. Hypervascular metastasis demonstrates enhancement on early hepatic arterial phase with washout on delayed phase [20]. Limitations of CEUS in the liver include the inability to evaluate lesions smaller than 5 mm or those close to the diaphragm or heart that can be difficult to keep in the field of view due to respiratory motion. Deep lesions in the setting of a fatty liver can be difficult to evaluate due to limited acoustic penetration [10]. 3. Renal CEUS is especially useful in the setting of known or presumed renal disease. Unlike CT or MRI contrast, CEUS microbubble agents do not adversely affect renal function. Microbubbles allow for qualitative perfusion analysis of microcirculation, diagnosis of vascular problems, and assessment of tumor vascularity [21]. Evaluation is based on the presence or absence of contrast uptake. The renal cortical phase of
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Fig. 2. a. Hemangioma- Ultrasound B-mode image demonstrates a hyperechoic lesion in the left hepatic lobe (black arrow). b. Hemangioma- CEUS early hepatic arterial phase image demonstrates peripheral nodular enhancement (black arrow). c. Hemangioma- CEUS portal venous phase image demonstrates centripetal filling in (black arrow).
Fig. 3. a. Focal fat- Ultrasound B-mode image demonstrates a slightly hyperechoic region in the liver (black arrow). b. Focal fat- Ultrasound B-mode image (Left) and CEUS image (Right) demonstrates isoehancement of the region in comparison to the adjacent parenchyma (black arrows).
enhancement begins 10–15 s post contrast administration and lasts 20–40 s. The medullary phase follows, lasting 45–120 s [21]. After some time, the contrast is eliminated and the image becomes hypoechoic. The collecting system is unaffected, as UCA is not renally excreted. Renal applications of CEUS include evaluating for renal infarct, differentiating between solid and cystic lesions, characterizing complex cystic lesions, and distinguishing between tumor and pseudotumor. A renal infarct on CECT appears as a wedge shaped area of nonperfusion. When iodinated contrast administration is not feasible, CEUS is a viable alternative. CEUS also depicts renal infarcts as wedge-shaped areas of non-perfusion and is more accurate than B mode or Doppler US alone. CEUS can also distinguish between renal infarct and cortical
Fig. 4. a. Hepatocellular carcinoma- Ultrasound B-mode image demonstrates a heterogeneous lesion (black arrow). b. Hepatocellular carcinoma- CEUS early hepatic arterial phase image demonstrates enhancement in the lesion (black arrow). c. Hepatocellular carcinoma- CEUS portal venous phase image demonstrates washout in the lesion (black arrow). 212
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Fig. 6. Dromedary hump- Ultrasound B-mode image (Left) shows a prominent round/bulging region in the mid left kidney (black arrow) and CEUS ultrasound image (right) demonstrates the region enhancing similar to the adjacent parenchyma (white arrow).
gold standard imaging studies to diagnose renal transplant vascular complications, with Doppler the initial study [24–26]. A limitation of Doppler ultrasound is that it only provides information up to the level of the interlobar and arcuate arteries and cannot reliably assess more distal vascularity at the subcapsular level. CEUS can assess more distal vessels, increasing its sensitivity for vascular complications. When compared to normal kidneys, transplant kidneys with acute vascular complications demonstrate delayed contrast enhancement and decreased peak intensity [25]. At least one study has shown a comparable sensitivity of CEUS for vascular complications compared to the gold standards [24]. Though CECT is the gold standard [27] for renal mass determination, at least one study has shown CEUS to be more sensitive than CECT [28]. Additionally, unlike liver masses where some solid masses are characteristically benign, any solid renal mass is deemed a renal cell carcinoma (RCC) until proven otherwise. When employed to assess an indeterminate renal lesion, the presence of microbubbles proving intralesional vascularity is sufficient to characterize a lesion as a solid mass highly suspicious for malignancy (Fig. 5a, b) [29]. At least one study assessed CEUS pattern of contrast uptake to differentiate between the two most common subtypes of RCC: clear cell RCC (ccRCC), which accounts for 70% of all RCCs, and papillary RCC (pRCC), which accounts for 10–15% [29]. It has long been established that pRCC enhances less avidly than ccRCC on CECT [30]. The CEUS correlate is a pattern of generally slower wash-in, faster wash-out, overall hypoenhancement and presence of a pseudocapsule with pRCC when compared to ccRCC [31]. The authors found all 25 cases of pRCC demonstrated some degree of enhancement on CEUS, while 5 of the 25 cases were equivocal or lacked enhancement on CECT, suggesting improved sensitivity of CEUS compared to CECT. Other studies have also demonstrated improved sensitivity of CEUS for intralesional blood flow compared to cross-sectional imaging [32]. Anatomic variants that may mimic renal masses on imaging (pseudotumors) include fetal lobulation, hypertrophied column of Bertin, and a dromedary hump. If a pseudotumor is suspected, but not diagnosable on grayscale US, a patient would likely be referred to CECT or CEMRI for further evaluation. CEUS, however, can show that the pseudotumor exhibits the same perfusion characteristics as the surrounding parenchyma during all imaging phases (Fig. 6) obviating the need for cross sectional imaging [33,34]. CEUS is particularly helpful for differentiating solid renal masses from cysts when equivocal on grayscale US, for characterizing complex
Fig. 5. a. Renal cell carcinoma- Ultrasound B-mode image demonstrates a hypoechoic lesion (black arrow) and an anechoic lesion (white arrow) in the right kidney. b. Renal cell carcinoma- CEUS image demonstrates a hypoenhancing lesion in the right kidney (black arrow) compatible with malignancy and an anechoic lesion compatible with a cyst (white arrow).
necrosis; in the setting of cortical necrosis, renal hilar vascularity is maintained, while the cortex lacks perfusion [22]. Since CEUS can image renal blood flow in real time with high temporal and spatial resolution, CEUS has been shown to be helpful in evaluating early diabetic nephropathy by measuring renal hemodynamic and microvascular perfusion changes in early and late stage diabetes. Patients with diabetic nephropathy will demonstrate overall decreased perfusion with delayed time to peak enhancement [23]. The safety profile of microbubble agents makes CEUS particularly useful for evaluating renal transplants when early vascular complications are suspected. Early vascular complications include arterial or venous thrombus, arterial stenosis, vascular leak or pseudoaneurysm and cortical necrosis. Other complications include urologic or surgical complications, infection and nephrologic causes, such as acute rejection, acute tubular necrosis and anticalcineurin toxicity. In the early post-operative period, visualization of renal vascularity is key, as early diagnosis and intervention for a vascular complication may save the allograft from failure. Doppler US, CT, digital subtraction angiography (DSA) and nuclear medicine radioisotope renography are the current
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[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18] [19]
Fig. 7. a. Complex renal cyst- Ultrasound B-mode image demonstrates 2 hypoechoic lesions in the left kidney (black arrows). b. Complex renal cyst- CEUS image demonstrates an anechoic appearance compatible with cysts (black arrows).
[20]
[21]
cystic masses and for interval follow-up of non-surgical lesions (Fig. 7a, b) [35]. Multiple studies have demonstrated that CEUS is more sensitive than CECT in detecting vascularity in hypovascular lesions and demonstrating wall, septal and solid component enhancement in complex cysts [29,32,35,36]. CEUS is a major addition to the imaging armamentarium in the characterization of hepatic and renal lesions, without the use of nephrotoxic agents or radiation. CEUS improves the detection and characterization of tumor vascularity in hepatic and renal masses, can differentiate solid masses from cysts, and improves visualization of blood flow within septa and walls of complex cystic masses [36].
[22]
[23]
[24]
[25]
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