Ultrasonographic detection of focal liver lesions: increased sensitivity and specificity with microbubble contrast agents

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Abstract

Ultrasonography (US) is the first choice for screening patients with suspected liver lesions. However, due to a lack of contrast agents, US used to be less sensitive and specific compared with computed tomography (CT) and magnet resonance imaging (MRI). The advent of microbubble contrast agents increased both sensitivity and specificity dramatically. Rapid developments of the contrast agents as well as of special imaging techniques were made in recent years. Today numerous different US imaging methods exist which based either on Doppler or on harmonic imaging. They are using the particular behaviour of microbubbles in a sound field which varies depending on the energy of insonation (low/high mechanical index, MI) as well as on the properties of the agent themselves. Apart from just blood pool enhancement some agents have a hepatosplenic specific late phase. US imaging during this late phase using relatively high MI in phase inversion mode (harmonic imaging) or stimulated acoustic emission (SAE; Doppler method) markedly improves the detection of focal liver lesions and is also very helpful for lesion characterisation. With regards to detection, contrast enhanced US performs similarly to CT as shown by recent studies. Early results of studies using low MI imaging and the newer perfluor agents are also showing promising results for lesion detection. Low MI imaging with these agents has the advantage of real time imaging and is particularly helpful for characterisation of focal lesions based on their dynamic contrast behaviour. Apart from the techniques which based on the morphology of liver lesions there were some attempts for the detection of occult metastases or micrometastases by means of liver blood flow changes. Also in this field the use of US contrast agents appears to have advantages over formerly used non contrast-enhanced methods although no conclusive results are available yet.

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

References (43)

  • E. Leen et al.

    Potential role of Doppler perfusion index in selection of patients with colorectal cancer for adjuvant chemotherapy

    Lancet

    (2000)
  • T. Albrecht et al.

    Non-invasive diagnosis of hepatic cirrhosis by transit time analysis of an ultrasound contrast agent

    Lancet

    (1999)
  • P.J. Robinson

    Imaging liver metastases: current limitations and future prospects

    Br. J. Radiol.

    (2000)
  • D.O. Cosgrove

    Malignant liver disease

  • G. Larcos et al.

    Sonographic screening for hepatucellular carcinoma in patients with chronic hepatitis or cirrhosis: an evaluation

    Am. J. Roentgenol.

    (1998)
  • P.J. Karhunen

    Benign hepatic tumours and tumour like conditions in men

    J. Clin. Pathol.

    (1986)
  • H. Edmunson et al.

    Neoplasms of the liver

  • E.C. Jones et al.

    The frequency and significance of small (less than or equal to 15 mm) hepatic lesions detected by CT

    Am. J. Roentgenol.

    (1992)
  • B. Kreft et al.

    Häufigkeit und Bedeutung von kleinen fokalen Leberläsionen

    Rofo. Fortschr. Geb. Rontgenstr. Neuen. Bildgeb. Verfahr.

    (2001)
  • K. Wernecke et al.

    Detection of hepatic masses in patients with carcinoma: comparative sensitivities of sonography, CT, and MR imaging

    Am. J. Roentgenol.

    (1991)
  • M.P. Clarke et al.

    Prospective comparison of preoperative imaging and intraoperative ultrasonography in the detection of liver tumors

    Surgery

    (1989)
  • B. Ohlsson et al.

    Detection of hepatic metastases in colorectal cancer: a prospective study of laboratory and imaging methods

    Eur. J. Surg.

    (1993)
  • M.J. Blomley et al.

    Liver vascular transit time analyzed with dynamic hepatic venography with bolus injections of an US contrast agent: early experience in seven patients with metastases

    Radiology

    (1998)
  • A. Parkin et al.

    Liver perfusion scintigraphy-method, normal range and laparatomy correlation in 100 patients

    Nucl. Med. Commun.

    (1983)
  • S.H. Leveson et al.

    Deranged liver blood flow patterns in the detection of liver metastases

    Br. J. Surg.

    (1985)
  • L.E. Hann et al.

    Hepatic sonography: comparison of tissue harmonic and standard sonography techniques

    Am. J. Roentgenol.

    (1999)
  • R.S. Shapiro et al.

    Tissue harmonic imaging sonography: evaluation of image quality compared to conventional sonography

    Am. J. Roentgenol.

    (1998)
  • P.N. Burns et al.

    Pulse inversion imaging of liver blood flow: improved method for characterizing focal masses with microbubble contrast

    Invest. Radiol.

    (2000)
  • C.J. Harvey et al.

    Ultrasound of focal liver lesions

    Eur. Radiol.

    (2001)
  • K. Koito et al.

    Differential diagnosis of small hepatocellular carcinoma and adenomatous hyperplasia with power Doppler sonography

    Am. J. Roentgenol.

    (1998)
  • P. Soyer et al.

    Detection of liver metastases from colorectal cancer: comparison of intraoperative US and CT portography

    Radiology

    (1992)
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