Development of radial scanning endoscopic ultrasound

Although transabdominal ultrasound has been widely used as a noninvasive imaging method, it has limitations when used for observation of the pancreas and biliary system because of the interference of alimentary gas and the attenuation of echo signals by visceral fat. To overcome these limitations, endoscopic ultrasound (EUS), which involves a gastrointestinal endoscope equipped with an ultrasound transducer at its tip, was developed as a device for intraluminal ultrasonography. In 1980, Hisanaga et al.1 succeeded in observing major abdominal structures including the pancreas, left kidney and abdominal aorta, using a mechanical radial scanning transducer inserted in the gastric lumen. However, this device was not equipped with gastrointestinal endoscope. In the 1980s Olympus (Tokyo, Japan) developed the first EUS system with a mechanical radial scanning transducer (Figs 1,2). Yasuda et al.2 first demonstrated that, among several imaging methods including endoscopic retrograde cholangiopancreatography (ERCP), computed tomography (CT), angiography and transabdominal ultrasonography, EUS was the most useful method for detecting small pancreatic cancer <20 mm in size.

History of technologies for endoscopic ultrasound (EUS) diagnosis. All EUS technologies employ either of two primary scanning methods; mechanical radial or electronic scanning. Electronic scanning includes curved linear and radial arrays. EUS-FNA, EUS-guided fine-needle aspiration; EUS-FNB, EUS-guided fine-needle biopsy.

Prototype echoendoscope produced by Olympus. The ultrasonic images were viewed by a small monitor (arrow). The picture was provided by Olympus.

In the 2000s, tissue harmonic EUS was developed to improve the resolution of EUS images (Fig. 1). Technology of electronic scanning allowed depiction of harmonic components within the insonated tissue as a consequence of nonlinear sound propagation. Using an electronic radial scanning echoendoscope, Ishikawa et al.3 compared the quality of EUS images with tissue harmonic imaging and fundamental B-mode imaging in the diagnosis of pancreatic diseases. They found that tissue harmonic images were significantly clearer than fundamental B-mode images for visualizing the boundary, septum and nodules of cystic lesions, and the boundary and internal structures of solid lesions.3 Since these EUS technologies were developed, EUS has played an important role in diagnosis of digestive diseases, particularly in the early diagnosis of pancreatic cancer.

Development of intraductal ultrasound during ERCP

Before the development of EUS, ERCP was the sole endoscopic imaging method. Although ERCP is a sensitive method for examining ductal structure with contrast opacification, it is difficult to make observations in and adjacent to the pancreatobiliary ducts. In the 1990s, the technology of mechanical radial scanning was applied to intraductal ultrasound by reducing the size of the transducer (Fig. 1). In 1993, Furukawa et al.4 first performed in vitro and in vivo preclinical studies to observe pancreatobiliary system with intraductal ultrasonography (IDUS) during ERCP. In four patients, they demonstrated that the pancreatic and bile ducts could be scanned by inserting an IDUS catheter via the major papilla without requiring endoscopic sphincterotomy.4 Five years later, Kanemaki et al.5 first reported the utility three-dimensional IDUS, demonstrating the courses of vessels surrounding the bile duct and accurately assessing tumor extension and the relationship with surrounding organs. Since its development, IDUS has been employed for diagnosis of small lesions in and adjacent to pancreatic and bile ducts including stones, neoplasms and stenosis during ERCP.

Development of the curved linear array EUS and EUS-guided fine-needle aspiration

In 1991, Harada et al. first proposed the concept of EUS-guided fine-needle aspiration (EUS-FNA) using electronic scanning with a linear array transducer (Fig. 1). Using a prototype echoendoscope with a linear transducer for EUS-FNA, they succeeded in making transesophageal punctures of mediastinal lymph nodes and longus colli muscles in preclinical studies using a phantom model and dogs, respectively.6 Since this report, EUS-FNA has played an important role for tissue acquisition of tumors in and adjacent to the gastrointestinal tract.

Development of the techniques, needles and pathological processing of samples improved diagnostic accuracy of EUS-FNA. To standardize technique for EUS-FNA, Yamao et al.7 proposed standard imaging techniques for EUS-FNA using a curved linear array echoendoscope, techniques that are currently used as a gold standard. Because the sample sizes are small, several sessions are needed during EUS-FNA. To decrease the number of sessions of EUS-FNA, rapid onsite cytologic evaluation (ROSE) in which rapid feedback on the adequacy of each session is provided by the onsite cytopathologist during EUS-FNA. However, ROSE requires attendance of onsite cytopathologist, which is unavailable in many centers. Iwashita et al.8 proposed macroscopic onsite evaluation (MOSE) to estimate the adequacy of a core specimen for histologic diagnosis during EUS-FNA using 19-gauge needles for solid lesions, and indicated that EUS-FNA can be terminated once a macroscopic visible core of 4 mm or higher was obtained on MOSE.

In the 2010s, needles of EUS-guided fine-needle biopsy (EUS-FNB) with a tip of specific structure to core biopsy have been developed (Fig. 1). Kamata et al.9 performed randomized control study comparing 25-gauge needles of EUS-FNA and EUS-FNB in their ability to obtain histological samples from solid pancreatic masses and showed that EUS-FNB needles provided histologic samples of better quality than EUS-FNA needles. Improvement of these techniques for tissue acquisition has recently facilitated gene analysis of malignant pancreatobiliary tumor for selecting drugs of chemotherapy.

Development of vascular imaging with EUS for characterization of tumors

In depicting small lesions in and adjacent to the gastrointestinal tract, EUS is superior to any other imaging method. However, it has limitations in terms of the characterization of tumors with vascularity. Development of electronic scanning allowed color or power Doppler imaging which detects large vessels for identifying the image location and the puncture line during EUS-FNA (Fig. 1). However, Doppler imaging has limitations in depiction of slow flow in fine vessels.

Kato et al.10 first performed contrast-enhanced EUS of pancreatic lesions during arterial angiography. They infused carbon dioxide microbubbles through a catheter following conventional angiography, and visualized vessels in the pancreas. They found that real-time imaging using EUS angiography is useful for evaluating the vascularity of various pancreatic lesions, especially small ones. However, EUS angiography is performed during angiography, a technique that is more invasive than EUS.

Second-generation intravenous ultrasound contrast agents (UCA) including Sonazoid (GE Healthcare Japan, Tokyo, Japan), resonate with a low acoustic power ultrasound beam and produce harmonic components. Because EUS with a small electronic scanning transducer radiates an ultrasound beam of low acoustic power, second-generation intravenous UCAs are suitable for contrast-enhanced harmonic EUS, which can visualize tissue microcirculation by selective depiction of second harmonic components from the UCAs. In 2008, together with Olympus Co. Ltd. (Tokyo, Japan) and Aloka Co. Ltd. (Tokyo, Japan), Kitano et al. developed an EUS system equipped with contrast-enhanced harmonic EUS (CH-EUS) and succeeded in visualizing parenchymal perfusion and microvasculature in the pancreas and depicting pancreatic cancers as lesions with hypo-enhancement (Figs 1,3). Using this technology, they prospectively evaluated how accurately CH-EUS characterizes pancreatic lesions and showed CH-EUS was superior to multidetector CT in diagnosing small (≤2 cm) carcinomas (P < 0.05).11

Typical image of pancreatic cancer on contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS). Conventional EUS (left) shows a hypoechoic area (arrowheads) of 15 mm in diameter at the body of the pancreas. CH-EUS (right) indicates that the area has hypo-enhancement (arrowheads) compared with the surrounding tissue of the pancreas.

Recent advances in microflow imaging, depicting Doppler signals without motion artifacts, improved the ability to detect microflow in small vessels (Fig. 1). Using this novel technology in EUS (Detective Flow Imaging), Yamashita et al.12 succeeded in depicting intratumoral vessels in gastrointestinal stromal tumors without using contrast enhancement. Currently, vascular imaging with EUS has been an essential modality for characterization of tumors detected by EUS.

Development of EUS elastography for diagnosis of chronic pancreatitis

The electronic scanning technology allowed EUS elastography including two methods of different mechanical properties: strain elastography (SE) and shear-wave elastography (SWE). In SE, tissue hardness is depicted by color scales representing the tissue deformation in response to strain. Since EUS-SE was reported in 2006, it has contributed to the diagnosis of solid pancreatic masses and chronic pancreatitis (Fig. 1). Itoh et al.13 first performed semi-quantitative measurement of tissue hardness using EUS-SE, demonstrating that histology-determined fibrosis grade of the resected pancreas was significantly correlated with all four quantification parameters of mean, standard deviation, skewness and kurtosis. Although these SE parameters semi-quantitatively reflect tissue hardness, their values depend on the regions of interest. In 2019, EUS-SWE was developed for the quantitative measurement of tissue hardness (Fig. 1). Ohno et al.14 succeeded in measuring the shear-wave velocity generated at the edge of the push pulse, which is more reliable for obtaining absolute quantitative measurement of tissue hardness (Figs 1,4). Yamashita et al.15 first demonstrated that EUS-SWE is useful for measuring tissue hardness in chronic pancreatitis, and that shear-wave velocity correlated with exocrine and/or endocrine dysfunctions reflecting severity of chronic pancreatitis. Development of these novel technologies allowed us to estimate fibrosis in chronic pancreatitis.

Measurement of shear-wave velocity in early chronic pancreatitis. Median value of shear-wave velocity among 10 times of measurement at the region of interest (yellow square) is 3.86 m/s (displayed in white square), which indicates that pancreatic tissue is hard.

Conclusion

Since it was first reported, EUS has developed to become an accurate diagnostic method for pancreatobiliary diseases. Currently, EUS is recommended as an essential diagnostic method in clinical management guidelines for pancreatic cancer and intraductal papillary mucinous neoplasm as well as being a part of the Japanese diagnostic criteria for early chronic pancreatitis.

Conflict of interest

Author M.K. is an Associate Editor of Digestive Endoscopy, and has received honoraria from Olympus for lectures and research funding from Boston Scientific outside the submitted work.

Funding Information

None.

References

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