Ultrasonographic detection of focal liver lesions: increased sensitivity and specificity with microbubble contrast agents
Introduction
The liver has several features that make it a favourite site for metastases of malignancies of other organs. These are the dual blood supply via the portal vein and the hepatic artery, the high volume of blood flow (about a quarter of the cardiac output), the microscopic anatomy with different possibilities for tumor cells to get trapped and the major role of the liver in biochemical activities that provides an ideal environment for rapid growth [1]. Therefore, in patients with a known carcinoma in 25–50% liver metastases are found at autopsy with decreasing frequency in colon, gastric, pancreatic, breast and lung cancer [2]. Accurate detection of metastases is very important because of the far-reaching therapeutic and prognostic implications. This should be done as early as possible and, therefore, it is necessary to detect very small lesions, ideally at a stage where they appear as micrometastases.
Apart from metastases there are of course a number of other types of focal liver lesions which have to be able to differentiate from metastases and from each other. Firstly, there is a world-wide increase of primary malignant liver lesions, namely hepatocellular carcinomas (HCC), about 80% of them are associated with cirrhosis and/or chronic viral hepatitis [3]. Other primary malignant liver lesions are exceedingly rare and the vast majority of other focal liver lesions are benign. Benign liver lesions are very common: their prevalence is over 20% in autopsy series [4], [5] and in patients with malignancy about 50% of lesions under 2 cm in size are benign [6], [7]. The most common benign liver lesions are simple cysts, haemangiomas, focal nodular hyperplasia (FNH) and focal fatty change/sparing. Adenomas are much rarer and occur almost exclusively in patients on sex hormone medication. Other rare benign lesions are due to focal hepatic infections (pyogenic, parasitic or fungal absesses).
Conventional imaging methods such as computed tomography (CT), magnetic resonance imaging (MRI) and greyscale ultrasonography (US) are based on assessment of lesion morphology. The availability of contrast agents allows to increase both sensitivity and specificity of lesion detection and provides additional information about the dynamic contrast behaviour for lesion characterisation. In contrast to CT and MRI US is inexpensive and widely available with no radiation exposure and good patient acceptance. Therefore, US is the first choice for screening patients with suspected liver lesions. However, mainly due to a lack of contrast agents, US used to be less sensitive and specific compared with CT and MRI [8], [9], [10]. The advent of US contrast agents and new contrast-specific imaging techniques such as harmonic imaging overcomes this limitations and in some cases gives contrast-enhanced sonography the edge over the other imaging modalities.
Apart from conventional imaging methods it also appears possible to detect haemodynamic changes produced by micrometastases using US contrast agents as tracers for functional imaging. This approach is currently subject to investigation and parallels radionuclide methods [11], [12], [13].
Section snippets
Greyscale and Doppler US
Basic techniques for liver imaging are standard greyscale as well as colour Doppler US. Detection of focal liver lesion then depends primarily on echogenicity, size and location. Isoechoic lesions are easily missed but if they are large enough, secondary signs like deviation of intrahepatic vessels can be helpful for its detection.
In greyscale imaging-without Doppler or contrast-enhanced information—recent developments have improved lesion detection. Most important is the tissue harmonic
Intraoperative US
The most sensitive imaging method for detecting small liver lesions is intraoperative US (IOUS). It detects 10–15% more lesions than CT arterial portography [19] and has an influence on the surgical management in a high number of patients. One prospective study showed a rate of about 50% in which the therapeutic decision was affected by IOUS [9]. In another more recent study laparascopic ultrasound revealed additional information of therapeutic relevance in 15% of patients with gastrointestinal
Techniques for detection of micrometastases
Beyond the various US techniques for detecting the metastases as lesions in a surrounding normal tissue, which requires a high contrast and spatial resolution as well as a certain size of the lesion (≥5 mm), there are attempts for detecting haemodynamic changes caused by very small ‘occult’ metastases. All these attempts exploit the ‘arterialisation’ of liver blood flow after metastatic seeding. The first technique used was dynamic radionuclide scintigraphy in the mid 1980s [12], [13] which
Contrast enhanced US
The most important developments for liver US are in the field of contrast agents, including both imaging techniques and the different kinds of contrast agents with their various properties. The advent of the first US contrast agents was in the mid 1990s which was relatively late compared with CT and MRI.
Clinical use of US contrast agents for liver imaging
As with other imaging modalities, contrast-enhanced US imaging is performed at different times after contrast agent injection, namely in the arterial, the portal venous and the delayed vascular phase. Additionally some agents (i.e. Levovist, Sonazoid, BR14 and Sonavist) have a liver-specific (post vascular) late phase during which the bubbles accumulate in normal liver parenchyma after blood pool clearance. Depending on the agent this late phase occurs as early as about 3 min post injection and
Results of clinical studies on detection of liver metastases with contrast-enhanced US
The most extensive experience in the field of detection of metastases with contrast-enhanced US has been made with PIM in the late liver-specific phase of Levovist, which was the first commercially available contrast agent for US liver imaging. However, studies using other agents have recently been presented.
Two pilot studies which used PIM in the late phase of Levovist showed promising early results. Harvey et al. found additional metastases in all of the 11 examined patients on
Conclusion
There are different imaging modalities for the detection and also the characterisation of liver lesions. Until recently US was the preferred screening method for focal liver lesions disease because of the inherent advantages but it suffered relatively poor sensitivity and specificity compared with other imaging techniques like CT and MRI and further imaging was often required for a definitive diagnosis.
Since the advent of US contrast agents and new contrast-specific US techniques liver US has
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