Evaluation of the Efficacy of Contrast Enhanced Ultrasound Compared to MRI for Differentiation of Hepatic Lesions
Phase: PHASE4
Conditions: Hepatic Disease
Sponsor: Indiana University

Protocol Version: August 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation of the efficacy of contrast enhanced ultrasound compared to MRI 
for differentiation of hepatic lesions 
 
 
 
NCT03652636 
 
 
 
August 20, 2019 
 

Protocol Version: August 2019 
Evaluation of the efficacy of contrast enhanced ultrasound compared to MRI 
for differentiation of hepatic lesions 
 
Principal investigator:  Jordan K. Swensson, M.D.  
Radiology 
 
Aim 
 
In patients with hepatic lesions, to evaluate the efficacy of contrast enhanced ultrasound (CEUS) 
compared to MRI in differentiating focal nodular hyperplasia (FNH) and hepatic adenoma. 
Studies from Europe (Dietrich et al, Roche et al) have described different patterns of 
enhancement between FNH and hepatic adenoma. MRI is the current imaging modality of choice 
for making this determination, but has limitations. This pilot study aims to test the hypothesis 
that CEUS has similar ability to differentiate FNH and adenoma, using MRI as the gold standard. 
 
Rationale 
 
Hepatic imaging plays an important role in identifying and differentiating both benign and 
malignant neoplasms of the liver. One of the clinical and radiologic dilemmas facing hepatic 
medicine is the accurate differentiation of focal nodular hyperplasia (FNH) and hepatic adenoma 
(HA). This is a question of some import, as there are significant prognosis and treatment 
differences between these entities, as well as overlap in the patient populations in whom they 
occur. 
 
FNH is the second most common benign neoplasm of the liver, with a strong female 
predilection. These lesions are usually asymptomatic and incidentally discovered, and carry only 
a small risk of complication such as bleeding. There is no malignant potential. Hepatic adenomas 
(HAs) are more rare benign neoplasms that also have a female predilection. However, these 
lesions are more likely to be symptomatic, and carry a higher bleeding risk especially as they 
grow over 4 cm. In addition, they harbor a small risk of malignant transformation to 
hepatocellular carcinoma (HCC). Of note, patients may present with both types of lesion 
concurrently. 
 
Currently, MRI with hepatobiliary contrast agents is the standard for differentiation of these 
lesions. These agents (such as gadoxetate disodium, or Eovist) are actively transported into 
hepatocytes, which are present in FNH and only in very rare cases with HA. Previous research 
(such as from Grazioli et al.) has shown that hepatobiliary agents can differentiate these lesions 
with excellent accuracy. However, there is still overlap between these lesions on imaging, and 
for certain patients MRI may be difficult or impossible. 
 
FDA approval of contrast enhanced ultrasound (CEUS) agents in 2016 has opened a new avenue 
for abdominal imaging. CEUS utilizes gas containing lipid microbubbles to provide pure 
intravascular contrast, allowing for evaluation of vascular and solid organ perfusion. It has an 
excellent safety profile and is not excreted by the kidneys, allowing for use in patients with acute 
and chronic renal disease. It has been used for some time outside of the US for liver lesion 
evaluation, and the enhancement patterns of both FNH and HA have been described in the 
literature as having different appearances. CEUS can be especially useful for focal liver lesion 

Protocol Version: August 2019 
imaging for patients who cannot or will not undergo MRI, and it has the advantages of 
flexibility, increased temporal resolution, and decreased cost. This study aims to compare the 
utility of CEUS for differentiating FNH and HA with the current standard of hepatobiliary 
contrast MRI. 
 
Performance site 
 
University Hospital 
Methodist Hospital 
 
Patient selection 
 
Inclusion criteria 
 
1.  Males and females  
2. Age 18 years or greater 
3. Recently have undergone (within 365 days) or are scheduled to undergo abdominal MRI with 
contrast at a performance site for evaluation of a hepatic lesion(s). 
 
Exclusion criteria 
 
1.  History of acute cardiac ischemia 
2.  History of hypersensitivity reaction to Lumason 
3.  Pregnancy 
 
Methods 
 
Potential subjects will be identified by three methods. 
 
1)  From the MRI schedule at the performance site, a radiology investigator will 
prospectively identify patients who are to undergo abdominal MRI with hepatobiliary 
contrast and who otherwise meet entry criteria.  Exclusion criteria will be evaluated by 
consulting the medical record.  At the time of MRI scanning, a radiology investigator will 
meet with the potential subject, confirm that exclusion criteria are not met, explain the 
study, answer any questions, and seek written informed consent.  If consent is granted, 
CEUS of the liver will be scheduled. 
2) From the surgery/hepatology clinic schedule, a surgery or hepatology investigator will 
identify patients who meet entry criteria.  The investigator will explain the study to the 
patient; if he/she expresses interest, the investigator will give a copy of the informed 
consent to the potential subject, and contact radiology and have the patient scheduled for 
CEUS of the liver.  At the time of CEUS, a radiology investigator will meet with the 
potential subject, confirm that exclusion criteria are not met, explain the study, answer 
any questions, and seek written informed consent.   
3) The principle investigator will retroactively review the radiology database, DORIS, for 
patients who have had a recent MRI with hepatobiliary contrast and who otherwise meet 
entry criteria that may have been missed by the previous methods mentioned.  A study 

Protocol Version: August 2019 
radiology investigator will reach out to the patient’s hepatologist about enrolling them in 
the trial and obtain best contact information.  A study coordinator will contact the patient 
by email or phone, with IRB approved script, to seek consent to contact for recruitment 
purposes. 
 
The subjects will be scanned in the University or Methodist Hospital ultrasound department by 
technicians trained in use of CEUS, under supervision of one of the study's key personnel. The 
contrast agent used will be Lumason (sulfur hexafluoride lipid-type A microspheres) distributed 
by Bracco Diagnostics Inc. Previous MRI images will be reviewed, and up to two of the largest 
lesions will be evaluated. Each lesion will be interrogated with a single intravenous dose of 
contrast (2.5 mL). If there is a single lesion, a second 2.5 mL injection may be used as needed to 
improve lesion visualization. If there are two lesions, each will be evaluated with one injection. 
Since the intention to treat includes all lesions chosen from MRI, if the injection(s) do not 
provide adequate images, the lesion in question will not be excluded from the study. 
 
Once the study is closed to enrollment and all subjects have completed the research CEUS scan.  
The obtained CEUS images will then be reviewed in consensus by two radiologist investigators, 
blinded to clinical information and MRI findings.  Each lesion assessed will be given a presumed 
diagnosis of FNH, HA, or indeterminate. At the completion of the study, the CEUS data will be 
compared to the official reports from the MRIs dictated by IUH radiologists to assess 
concurrence between the two imaging modalities.   
 
The PI and another investigator will quarterly review data quality, subject recruitment, accrual, 
outcome and adverse event data; assess scientific reports or therapeutic development, results of 
related studies that may impact subject safety, and procedures designed to protect the privacy of 
subjects. 
 
We will compile descriptive statistics comparing the sensitivity, specificity, and accuracy of 
CEUS for differentiating FNH and hepatic adenoma, compared with MRI results as the gold 
standard. 
 
Enrollment 
 
As this study explores a new method of diagnosing hepatic lesions and there is little published 
data on the subject, we do not have sufficient knowledge to do power and sample size 
calculations to demonstrate the number of patients needed to show equivalence between the two 
imaging methods.  The proposed enrollment of 40 patients reflects the availability of both 
Lumason and the approximate number of qualifying patients who would undergo MRI for 
evaluation of these lesions in one year. 
 
Resources/Budget 
 
At the performance site, patients with suspected FNH or HA typically undergo MRI of the liver 
as part of standard of care, and the patient or insurer will be billed for the examination and 
radiologic interpretation.  CEUS is not routinely performed in this population.  The cost 

Protocol Version: August 2019 
associated with CEUS and the time of the investigators will be the responsibility of the 
Department of Radiology and Imaging Sciences. 
 
Subjects will be compensated for their time and effort with a $50.00 gift card upon completion of 
research imaging. 
 
References 
 
Bieze M, van den Esschert JW, Nio CY, et al.  Diagnostic accuracy of MRI in differentiating 
hepatocellular adenoma from focal nodular hyperplasia: prospective study of the additional value 
of gadoxetate disodium.  AJR Am J Roentgenol 2012; 199:26-34. 
 
Dietrich CF, Schuessler G, Trojan J, Fellbaum C, Ignee A.  Differentiation of focal nodular 
hyperplasia and hepatocellular adenoma by contrast-enhanced ultrasound.  Br J Radiol 2005; 
78:704-707. 
 
Grazioli L, Morani G, Kirchin GA, Schneider G.  Accurate differentiation of focal nodular 
hyperplasia from hepatic adenoma at gadobenate dimeglumine–enhanced MR imaging: 
prospective study.  Radiology 2005; 236:166-177. 
 
Kim TK, Jang HJ, Burns PN, Murphy-Lavallee J, Wilson SR.  Focal nodular hyperplasia and 
hepatic adenoma: differentiation with low-mechanical-index contrast-enhanced sonography.  
AJR Am J Roentgenol 2008; 190:58-66. 
 
Kong WT, Wang WP, Huang BJ, et al.  Contrast-enhanced ultrasound in combination with color 
Doppler ultrasound can improve the diagnostic performance of focal nodular hyperplasia and 
hepatocellular adenoma.  Ultrasound Med Biol 2015; 41:944-951. 
 
Purysko AS, Remer EM, Coppa CP, et al.  Characteristics and distinguishing features of 
hepatocellular adenoma and focal nodular hyperplasia on gadoxetate disodium-enhanced MRI.  
AJR Am J Roentgenol 2012; 198:115-123. 
 
Quaia E, Calliada F, Bertolotto M, et al.  Characterization of focal liver lesions with contrast-
specific US modes and a sulfur hexafluoride-filled microbubble contrast agent: diagnostic 
performance and confidence. Radiology 2004; 232:420-430. 
 
Roche V, Pigneur F, Tselikas L, et al.  Differentiation of focal nodular hyperplasia from 
hepatocellular adenomas with low-mechanical-index contrast-enhanced sonography (CEUS): 
effect of size on diagnostic confidence.  Eur Radiol 2015; 25:186-95.  
 
Roux M, Pigneur F, Calderaro J, et al.  Differentiation of focal nodular hyperplasia from 
hepatocellular adenoma: Role of the quantitative analysis of gadobenate dimeglumine-enhanced 
hepatobiliary phase MRI.  J Magn Reson Imaging 2015; 42:1249-1258.  
 

Protocol Version: August 2019 
Taimr P, Bröker MEE, Dwarkasing RS, et al.  A Model-Based Prediction of the Probability 
of Hepatocellular Adenoma and Focal Nodular Hyperplasia Based on Characteristics on 
Contrast-Enhanced Ultrasound.  Ultrasound Med Biol 2017; 43:2144-2150.