The detection of focal liver lesions with contrast-enhanced ultrasound

Medical imaging techniques have played an evolving role in the diagnosis of
focal
liver lesions. Non-enhanced ultrasound is usually the first-line investigation,
due to its low cost, non-invasiveness, repeatibility and easy access. MRI is
nowadays mostly used to establish the definitive diagnosis, however, there are
important limitations (expensive, nephrogenic systemic sclerosis,
claustrophoby). Another method - CT - has also its limitations (allergy,
irradiation, renal insufficiency). New ultrasound contrast agents with tissue
harmonic imaging gained appropriate diagnostic accuracy. Microbubbles can be
detected wherever they lie and regardless of whether they are moving or
stationary. This means that they can be detected also in the microcirculation.
The diagnostic pattern is based on the vascular pattern and consists of
enhancement in the arterial, portal and late phases. When patterns of contrast
enhancement on sonography are compared with those on CT or MRI, a high level of
agreement in type and pattern of enhancement is seen. The use of
contrast-enhanced ultrasonography (CEUS) as a reliable alternative for
characterisation of liver tumors (as hepatocellular carcinoma) has recently
been endorsed by the American and European associations of liver disease.
In everyday clinical practice, doctors face cases in which the focal liver
lesions have not been fully characterized, although it has been determined to
be benign or malignant, which is often what the referring physician and the
patient really need to know. For this purpose, CEUS has a diagnostic accuracy
around 90% for all focal liver lesions.
In both situations (characterization and benign/malignant differentiation), the
clinical question could be answered, partially or completely, without requiring
the patient to undergo other imaging studies. Therefore, CEUS can - in unknown
percentage of patients - replace CT, MRI, or biopsy, providing a definitive
answer for the patient.

Our primary objective is the development of an algorithm for liver tumour
diagnosis using CEUS. This provides us with a more flexible, readily available
and cheaper method without compromising specificity and sensitivity. We will
compare diagnostic efficacy and costs of both methods (MRI). The diagnostic
outcome criterion is the ability to diagnose benign versus malignant lesions.
The innovative step would be, that CEUS could be routinely used as the first
step in the diagnostic algorithm for the characterization of focal liver
lesions detected on baseline ultrasound and being performed during the same
examination. Further studies are necessary to evaluate the cost-effectiveness
of this approach.

Patients referred to the Erasmus MC specialized liver-tumor outpatient clinic
will be enrolled. This is a specialized service for patients with focal liver
lesion (-s). The idea is to minimize the diagnostic work-up to 4 days. CEUS is
the only additional examination implemented by the study and serves as a second
imaging method.
Single center, blinded study. Ultrasound blinded to MRI results and vice versa.
Ultrasound blinded also to blood tests results.
CEUS agent used will be SonoVue (Bracco SpA), administered IV as 5-mL boluses
through the antecubital vein in 2-3 seconds. Hitachi sonography system will be
used. The vascularity and pattern of SonoVue enhancement of the lesion compared
with the adjacent liver parenchyma and vessels during the hepatic arterial,
portal venous, and late phases will be evaluated. Two trained physicians will
review stored US pictures and videos.
Results of MRI, lab results or - if needed - results of biopsy will be used for
diagnosis. Lesions diagnosed as benign will be further followed by a serial
examinations for at least 6 months.
Biopsy will not serve as the reference standard in all of the cases.
Intraoperative ultrasound will not be used in all patients. CT will be used
only as a third imaging method where MRI is not conclusive and biopsy/FNAB is
not possible to obtain.

CEUS agents are very safe and the examination does not need radiation exposure.
They could be used in patients allergic to MRI/CT agents, with renal
insufficiency and in pediatric population. They are not recommended in patients
with acute cardiac diseases, as non-stabile angina pectoris among others.
There has been a thorough search for adverse events in 2nd generation of
contrast ultrasound agents. Post marketing surveillance has covered more than 2
million injections and the disputable death of 4 registered cardiac patients
after application of Definity would have meant a risk 1:500 000. A 2006 study
of more than 23,000 injections of Sonovue showed no deaths and 2 serious
adverse events, giving a measured serious adverse event rate of less than
1:10,000 . These number reflect the general safety of US contrast agents.
The inconveniences to the patient will be 1) intravenous cannule placing (which
would be placed at liver tumor clinic for blood examination anyway) and 2)
painless abdominal ultrasound examination (20 minutes with an immediate
result).