The development of ultrasound contrast agents has allowed for the evaluation of vascularity in digestive organs by contrast-enhanced endoscopic ultrasonography (EUS). Contrast-enhanced Doppler EUS and contrast-enhanced harmonic EUS (CH-EUS) have improved characterization of pancreatic tumors, lymph nodes, and gastrointestinal submucosal tumors and compliment EUS fine-needle aspiration (FNA) in identifying malignant tumors. Moreover, CH-EUS can be used to identify the target for EUS-guided FNA by clearly depicting the outline of the lesions.
Ultrasound contrast agents
Intra-arterial infusion of carbon dioxide (CO 2 ) gas was the first technology used for contrast-enhanced ultrasonography. In this method, CO 2 is infused into the regional artery through a catheter during angiography. Fundamental B-mode ultrasonography sufficiently depicts signals from CO 2 microbubbles in a real-time manner. Although intra-arterial CO 2 infusion combined with ultrasonography allows imaging with very high spatial and time resolutions, it has the limitation that ultrasonographic scanning must be performed during angiography.
Intravenous ultrasound contrast agents are more convenient for contrast-enhanced ultrasonography because their use requires only a bolus infusion of the agent from a peripheral vein. There are several ultrasound contrast agents commercially available. Most of them are microbubbles consisting of gas covered with a lipid or phospholipid membrane. A certain range of acoustic power induces microbubble oscillation or breakage. When microbubbles are oscillated or broken, signals are emitted that have different frequencies from the transmitted signals. These signals can then be depicted by contrast-enhanced ultrasonography.
The first-generation ultrasound contrast agents included Levovist (Schering AG, Berlin, Germany), which is composed of microbubbles of room air covered with a palmitic acid membrane. Levovist required high acoustic power to oscillate or break its microbubbles. To overcome this disadvantage, second-generation ultrasound contrast agents, including SonoVue (Bracco Imaging, Milan, Italy), Sonazoid (Daiichi-Sankyo, Tokyo, Japan; GE Health care Milwaukee, WI, USA), and Definity (Lantheus Medical Imaging, North Billerica MA, USA), were created. These agents are composed of gasses different from room air, and microbubbles of these agents can be oscillated or broken by lower acoustic powers. These second-generation agents are more suitable for endoscopic ultrasonography (EUS) because the small transducer of EUS produces limited acoustic power.
Vascular assessment by EUS
In the early days of EUS development, it was difficult to enhance vessels by mechanical radial EUS. The first reports about contrast-enhanced EUS used fundamental B-mode EUS with an intravenous ultrasound contrast agent composed of sonicated albumin. Although this method slightly enhanced the signals from lesions with rich vessels such as neuroendocrine tumors and cystic tumors in the pancreas, it did not enhance signals of other diseases and has a limitation in selective depiction of the contrast agent. Electronic EUS equipped with color and power Doppler modes first enabled the identification of large vessels with colored images. In particular, this method allowed the visualization of large vessels behind the gastrointestinal wall and improved the avoidance of intervening vessels during needle puncture. However, those modes only detect large vessels with fast flow because they depict the phase shift of signals from quickly moving substances.
Ultrasound contrast agents located in vessels emit phase shift (pseudo-Doppler) signals and enhance Doppler signals from vessels. Contrast-enhanced Doppler EUS (CD-EUS) is used to evaluate not only large vessels but also tumor vascularity, by enhancing the intratumoral vessels ( Fig. 1 ). However, even the use of ultrasound contrast agents cannot depict fine vessels with slow flow because Doppler ultrasonography has low sensitivity to low flow. Moreover, contrast-enhanced Doppler ultrasonography suffers from poor spatial resolution as well as motion and blooming artifacts, which can make it difficult to evaluate tumor vascularity. Motion artifacts refer to the low signal intensity of flowing blood compared with that of tissue movement. Blooming refers to the widened appearance of a blood vessel with power Doppler compared with the results with fundamental B-mode imaging (see Fig. 1 ).
Contrast-enhanced harmonic imaging was developed to allow for more specific imaging of ultrasound contrast agents. The main purpose of contrast-enhanced harmonic ultrasonography is the selective sensitive depiction of signals from microbubbles in situ by filtrating signals from the tissue. The most important advantage of contrast-enhanced harmonic ultrasonography over contrast-enhanced Doppler ultrasonography is that it can depict microbubbles even though they do not flow. By depicting microbubbles located in microvasculature, contrast-enhanced harmonic ultrasonography allowed imaging of parenchymal perfusion. In addition, it can depict vessels with very high resolution without Doppler-related artifacts.
Contrast-enhanced harmonic EUS (CH-EUS) was impossible with Levovist because the transducer of the echoendoscope was too small to oscillate and break the microbubbles, necessitating the use of CD-EUS. Because second-generation ultrasound contrast agents can be oscillated or broken by lower acoustic powers, CH-EUS can be used with these agents.
Vascular assessment by EUS
In the early days of EUS development, it was difficult to enhance vessels by mechanical radial EUS. The first reports about contrast-enhanced EUS used fundamental B-mode EUS with an intravenous ultrasound contrast agent composed of sonicated albumin. Although this method slightly enhanced the signals from lesions with rich vessels such as neuroendocrine tumors and cystic tumors in the pancreas, it did not enhance signals of other diseases and has a limitation in selective depiction of the contrast agent. Electronic EUS equipped with color and power Doppler modes first enabled the identification of large vessels with colored images. In particular, this method allowed the visualization of large vessels behind the gastrointestinal wall and improved the avoidance of intervening vessels during needle puncture. However, those modes only detect large vessels with fast flow because they depict the phase shift of signals from quickly moving substances.
Ultrasound contrast agents located in vessels emit phase shift (pseudo-Doppler) signals and enhance Doppler signals from vessels. Contrast-enhanced Doppler EUS (CD-EUS) is used to evaluate not only large vessels but also tumor vascularity, by enhancing the intratumoral vessels ( Fig. 1 ). However, even the use of ultrasound contrast agents cannot depict fine vessels with slow flow because Doppler ultrasonography has low sensitivity to low flow. Moreover, contrast-enhanced Doppler ultrasonography suffers from poor spatial resolution as well as motion and blooming artifacts, which can make it difficult to evaluate tumor vascularity. Motion artifacts refer to the low signal intensity of flowing blood compared with that of tissue movement. Blooming refers to the widened appearance of a blood vessel with power Doppler compared with the results with fundamental B-mode imaging (see Fig. 1 ).
Contrast-enhanced harmonic imaging was developed to allow for more specific imaging of ultrasound contrast agents. The main purpose of contrast-enhanced harmonic ultrasonography is the selective sensitive depiction of signals from microbubbles in situ by filtrating signals from the tissue. The most important advantage of contrast-enhanced harmonic ultrasonography over contrast-enhanced Doppler ultrasonography is that it can depict microbubbles even though they do not flow. By depicting microbubbles located in microvasculature, contrast-enhanced harmonic ultrasonography allowed imaging of parenchymal perfusion. In addition, it can depict vessels with very high resolution without Doppler-related artifacts.
Contrast-enhanced harmonic EUS (CH-EUS) was impossible with Levovist because the transducer of the echoendoscope was too small to oscillate and break the microbubbles, necessitating the use of CD-EUS. Because second-generation ultrasound contrast agents can be oscillated or broken by lower acoustic powers, CH-EUS can be used with these agents.
Contrast-enhanced Doppler EUS
Intravenous ultrasound contrast agents improve the Doppler detection of flow in vessels. CD-EUS is significantly more sensitive and accurate than power Doppler EUS in detecting the relatively hypovascular ductal adenocarcinomas of the pancreas. Hypovascularity as a sign of ductal carcinomas in CD-EUS obtained a sensitivity of 85% to 94% and a specificity of 71% to 100%. EUS is also a highly sensitive method for detection of pancreatic ductal carcinomas, particularly small ones. In a study comparing the abilities of CD-EUS and contrast-enhanced multidetector-row computed tomography (MDCT) to diagnose small pancreatic tumors, the sensitivities for detecting pancreatic carcinomas sized 2 cm or less by EUS and MDCT were 94% and 50%, respectively, and CD-EUS diagnosed small pancreatic carcinomas sized 2 cm or less as tumors with hypoenhancement significantly better than MDCT. EUS is also useful to detect small neuroendocrine tumors. Detection rate of EUS for neuroendocrine tumors (92%–95%) is significantly higher than that of MDCT (63%–81%). Ishikawa and colleagues reported on the usefulness of EUS combined with contrast enhancement in the preoperative localization of pancreatic endocrine tumors. In their report, CD-EUS indicated that hyperenhancement was observed in 98% of neuroendocrine tumors. In those previous reports about CD-EUS, ductal carcinomas and neuroendocrine tumors are characterized by CD-EUS as solid lesions with hypoenhancement and hyperenhancement, respectively. Taking into consideration the superiority of EUS in the detection rates, CD-EUS is a promising tool to characterize small pancreatic tumors that cannot be detected by other imaging methods.
In discrimination between benign and malignant mediastinal and abdominal lymph nodes, 2 groups reported the usefulness of CD-EUS. Kanamori and colleagues found that all malignant lymph nodes showed a defect of enhancement (sensitivity 100%), whereas diffuse enhancement was observed in 86% of benign lymph nodes (specificity 86%). Hocke and colleagues used the following criteria for malignant lymph nodes: irregular appearance of the vessels and only arterial vessels visible. Using these criteria, the sensitivity and specificity in differentiating malignant from benign lymph nodes were 60% and 91%, respectively. If malignant lymphoma were excluded, the sensitivity of the CD-EUS for malignant lymph nodes increased to 73%. Even though those reports differ in criteria and diagnostic accuracy for malignancy, CD-EUS is useful for characterization of enlarged lymph nodes.
Principle of contrast harmonic imaging
When exposed to a certain range of ultrasonic beams, the microbubbles of ultrasound contrast agents are disrupted or resonated, which releases a large amount of harmonic signals ( Fig. 2 ). When the tissues and microbubbles receive transmitted ultrasound waves, both produce harmonic components that are integer multiples of the fundamental frequency; however, the harmonic content from the microbubbles is higher than that from the tissues (see Fig. 2 ). Selective depiction of the second harmonic component visualizes the signals from the microbubbles more strongly than those from the tissues.
Related posts:
Endoscopic Ultrasonography/Fine-Needle Aspiration and Endobronchial Ultrasonography/Fine-Needle Aspiration for Lung Cancer Staging
Endoscopic Ultrasonography-Guided Biliary Drainage: Rendezvous Technique
Endoscopic Ultrasound-Guided Fiducial Markers and Brachytherapy
Endoscopic Ultrasound Image Enhancement Elastography
Endoscopic Ultrasonography-Guided Tumor Ablation
Endoscopic Ultrasonography-Guided Pancreatic Drainage
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
