Contrast-Enhanced Endoscopic Ultrasonography: History
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Contributor:
Kensuke Yokoyama
,
Atsushi Kanno
,
Tetsurou Miwata
,
Hiroki Nagai
,
Eriko Ikeda
,
Kozue Ando
,
Yuki Kawasaki
,
Kiichi Tamada
,
Alan Kawarai Lefor
,
Hironori Yamamoto

Endoscopic ultrasound can be useful for obtaining detailed diagnostic images for pancreatic disease. Contrast-enhanced harmonic endoscopic ultrasound has allowed to demonstrate not only microvasculature but also real perfusion imaging using second-generation contrast agents. Furthermore, endoscopic ultrasound fine-needle aspiration cytology and histology have become more ubiquitous.

  • endoscopic ultrasound
  • contrast-enhanced endoscopic ultrasound

1. Introduction

Ultrasonography (US) can be useful for patients with hepatic, biliary, and pancreatic diseases. This modality allows for noninvasive diagnostic imaging, with the Doppler mode being useful for assessing tumor blood flow. However, although blood flow in large blood vessels can be evaluated, evaluating blood flow in capillaries and obtaining perfusion images remain challenging. Studies have shown that contrast-enhanced ultrasonography using an ultrasound contrast agent enables the acquisition of perfusion images of parenchymatous organs [1][2][3] and is expected to contribute to the improvement of diagnostic accuracy. Despite the several reports on the use of contrast-enhanced ultrasonography for the diagnosis of pancreatic tumors [4][5][6][7][8], this approach has not gained popularity considering that the ultrasound contrast agent is not covered by Japanese public health insurance.
Endoscopic ultrasonography (EUS) has enabled detailed sonography of the pancreas, which can be diagnosed via ultrasonic observation from within the digestive tract [9][10]. Previously, EUS was performed by mechanical radial scanning; thus, blood flow data could not be obtained using the Doppler mode. However, with the advent of electronic radial EUS and advancements in ultrasound contrast agents, observation using the Doppler mode and contrast-enhanced EUS has become possible.

2. Contrast-Enhanced EUS

2.1. Contrast Agents

The contrast agent is composed of gas-filled microbubbles of 2–5 μm and the lipids or phospholipids that cover them. CE-EUS had first been by Kato in 1995 as a method of injecting CO2 bubbles from a celiac artery or superior mesenteric artery to evaluate the characteristic of pancreatic mass [11]. The development of the intravenous ultrasonic contrast agent Levovist® (Bayer Schering Parma, Berlin, Germany), which consists of microbubbles with a diameter of about 3 μm, made possible the visualization of small blood vessels through contrast-enhanced harmonic imaging, and the qualitative diagnostic ability improved in the transabdominal US [12]. Levovist® is a first-generation ultrasound contrast agent with which air microbubbles are coated with galactose and palmitic acid. This contrast agent delineates nonlinear signals generated by the collapse of air bubbles by applying ultrasonic waves with high sound pressure [2][13].
While this agent allows for Kupffer imaging and liver tumor identification, only intermittent contrasting of sound waves can be obtained, and only images of blood vessels can be depicted, such as by frame-by-frame playback. Furthermore, given that perfusion images of the pancreatic parenchyma cannot be obtained, this contrast agent may be unsuitable for obtaining contrast-enhanced ultrasound images of the pancreas. On the other hand, several second-generation ultrasound contrast agents, such as SonoVue (Bracco SpA, Milan, Italy), Sonazoid (Daiichi-Sankyo, Tokyo, Japan; GE Healthcare, Milwaukee, WI, USA), and Definity (Lantheus Medical Imaging, Billerica, MA, USA), have been developed. Sonazoid® is a second-generation ultrasound contrast agent containing perflubutane of approximately 3 μm in size covered by a phospholipid film [14][15]. Similar to Levovist®, Sonazoid® identifies liver tumors by utilizing its ability to be taken up by Kupffer cells. By delineating nonlinear signals obtained by applying ultrasonic waves with low sound pressure to resonate with the contrast agent, it is possible to obtain contrast enhancement of peripheral blood vessels and perfusion images of parenchymatous organs, which could not be obtained with Levovist®. Therefore, future applications of Sonazoid® in contrast-enhanced ultrasonography of abdominal parenchymatous organs, such as the pancreas, has been highly anticipated. In recent years, reports have suggested the usefulness of contrast-enhanced ultrasonography from the body surface in the differential diagnosis of pancreatic diseases [4][5][6][7][8][9][10]. Notably, Kitano et al. reported on the effectiveness of contrast-enhanced ultrasonography in clearly depicting pancreatic tumors and classifying the contrast enhancement pattern for the differential diagnosis of pancreatic tumors [16]. Faccioli et al. reported that performing contrast-enhanced ultrasonography more clearly delineates the margin of pancreatic tumors and that it was useful for determining surgical indications [5]. Moreover, other reports have shown that contrast-enhanced ultrasonography can determine the viability of the pancreas prior to transplantation. However, even now, several years after Sonazoid® has been made commercially available, this contrast agent is still not covered by Japanese public health insurance except in the diagnosis of liver tumors. Moreover, contrast-enhanced ultrasonography of the pancreas must be performed in clinical trials (Table 1).
Table 1. List of contrast agents for ultrasonography.
Contrast Agent Composition
First generation  
 Albunex 5% sonicated serum albumin with stabilized microbubbles
 Echovist (SHU 454) Standardized microbubbles with galactose shell
 Levosist (SHU 508) Stabilized, standardized microbubbles with galactose, 0.1% palmitic acid shell
 Myomap Albumin shell
 Qantison Albumin shell
 Sonavist Cyanoacrylate shell
Second generation  
 Definity/luminity C3F8 with lipid stabilizer shell
 Sonazoid C4F10 with lipid stabilizer shell
 Imagent-imavist C6F14 with lipid stabilizer shell
 Optison C3F8 with denatured human albumin shell
 Bisphere/cardiosphere Polylactide-coglycolide shell with albumin overcoat
 Sono Vue SF6 gas with lipid stabilizer shell
 AI700/imagify C4F10 gas core stabilized with polymer shell

2.2. Contrast-Enhanced Doppler Endoscopic Ultrasound

EUS has been digitized in recent years, which has enabled the delineation of Doppler images. Ultrasound contrast agents have intensified the signals of Doppler images and allowed for more clearer images of blood flow. Doppler signals have blooming artifacts, which can hinder observations; however, the eFLOW mode of the Aloka α10 (Aloka) and the H-FLOW mode of the ME2 (Olympus) can control for blooming, enabling clear delineation of blood flow images and suggesting their suitability for contrast-enhanced Doppler EUS. Some studies have utilized contrast-enhanced Doppler EUS methods for pancreatic tumor diagnosis. Accordingly, Dietrich et al., who performed contrast-enhanced EUS using the Doppler method on 93 patients with pancreatic tumors, were able to delineate hypovascular pancreatic cancer with excellent diagnosability [17]. Moreover, Hocke et al. reported a case of autoimmune pancreatitis (AIP) diagnosed using contrast-enhanced EUS with the Doppler method [18]. This enhancement in the Doppler signal by the ultrasound contrast agent is critical for determining the presence or absence of blood flow.

2.3. Contrast-Enhanced Harmonic Endoscopic Ultrasound

Irradiation of the ultrasound contrast agent within blood vessels using low sound pressure ultrasonic waves causes the air bubble diameter to change in accordance with the ultrasound wave cycle, generating enhanced harmonics. Contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) selectively visualizes second harmonics generated from the ultrasound contrast agent, thereby enabling perfusion images of capillaries and parenchyma. CEH-EUS allows for not only clear blood vessel imaging but also delineation of the time–intensity curve (TIC) and graphing of the changes in brightness over time through contrast.

2.4. CEH-EUS for Pancreatic Diseases

EUS eliminates the impact of gastrointestinal gas by performing ultrasonography from within the digestive tract. Moreover, small tumors that are difficult to identify on computed tomography (CT) scan and magnetic resonance imaging (MRI) can be delineated on EUS. This has made EUS an indispensable modality in the imaging diagnosis of pancreatic diseases. Furthermore, using second-generation ultrasound contrast agents together with the phase inversion harmonic method allows the observation of blood flow in real time, which has enabled the application of CEH-EUS in EUS. Though it is difficult to perform CEH-EUS in all patients for whom pancreatic lesions were not found using EUS, CEH-EUS is useful to diagnose pancreatic disease. Napoleon et al. performed CEH-EUS and EUS-fine needle aspiration (FNA) on 36 patients with pancreatic tumors and compared the two techniques [19]. Although CEH-EUS had inferior specificity, it had better sensitivity compared to FNA. They also showed that CEH-EUS was useful for the differential diagnosis of pancreatic tumors. Moreover, Kitano et al., who conducted CEH-EUS for pancreatic tumors, reported that it might be useful for differential diagnosis [16].
However, the aforementioned studies only evaluated the presence or absence of blood flow and patterns of contrasting but did not quantitatively evaluate the intensity of contrast enhancement. Notably, Kersting et al. who quantitatively analyzed contrast-enhanced ultrasound waves from the body surface, reported the usefulness of the same in the differential diagnosis of pancreatic cancer and mass-forming pancreatitis [10]. Moreover, Imazu et al. utilized CEH-EUS for distinguishing pancreatic cancer and AIP using the TIC [20]. Although several reports had conducted quantitative analysis, consensus regarding the methods have yet to be established [8][20]. Another study also reported of a method through which the ratio of brightness at the start of contrast enhancement divided by peak brightness is calculated and compared [21]. As such, further studies are needed to quantitatively analyze contrast-enhanced EUS.
Recently, EUS-FNA has been performed to diagnose pancreatic tumors histologically. It is difficult to differentiate between viable and necrotic tissue using only CT scan or MRI images to obtain the correct histological diagnosis of pancreatic tumors. CEH-EUS will help differentiate between viable and necrotic tissue correctly because CEH-EUS can provide sequential blood flow images in pancreatic tumors. The endosonographer will be aided by CEH-EUS images to acquire viable tissue for histological diagnosis using EUS-FNA.

This entry is adapted from the peer-reviewed paper 10.3390/diagnostics12061311

References

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