Digestive Endoscopy 2015; 27 (Suppl. 1): 47–54
doi: 10.1111/den.12443
Clinical evaluation of new diagnostic modalities of EUS for pancreatobiliary diseases
Endoscopic ultrasonography using new functions for pancreatobiliary diseases: Current status and future perspectives Akio Katanuma,1 Hiroyuki Isayama2 and Amol Bapaye3 1
Center for Gastroenterology, Teine-Keijinkai Hospital, Sapporo, Japan; 2Department of Gastroenterology, Graduate School of Medicine, Tokyo University, Tokyo, Japan; and 3Department of Digestive Diseases and Endoscopy, Deenanath Mangeshkar Hospital and Research Center, Maharashtra, India
A new endoscopic ultrasound processor (EU-ME2 Premier Plus) has recently been developed. It improves fundamental imaging and enables three new functions; namely, tissue harmonic echo (THE), elastography, and contrast harmonic endoscopic ultrasonography (CH-EUS). However, many aspects regarding the usefulness of these three functions in the diagnosis of pancreatobiliary diseases remain unknown. In connection with and prior to the convening of Endoscopy Forum Japan 2014, endoscopic ultrasonography using EU-ME2 Premier Plus was carried out for pancreatic, bile duct, and gallbladder cases at 12 participating institutions (Japan [n = 10]; other Asian countries [n = 2]). A questionnaire survey was conducted regarding the usefulness of EU-ME2 Premier Plus for each EUS case. In addition, participants’ views were surveyed by asking them to vote as to whether or
INTRODUCTION
E
NDOSCOPIC ULTRASONOGRAPHY (EUS) is useful for the diagnosis and treatment of pancreatobiliary diseases. EUS plays important roles particularly for the detection of small lesions, differential diagnosis, and tumor staging, as well as for treatment involving various drainage techniques.1–4 Recently, a new EUS processor (EU-ME2 Premier Plus; Olympus Medical Systems Corp., Tokyo, Japan) has been developed. This processor is capable of three new functions; namely, tissue harmonic echo (THE), elastography, and contrast harmonic endoscopic ultrasonography (CH-EUS), the usefulness of which has been reported. THE provides high-quality images of cystic and solid lesions of the pancreas.5,6 Elastography is useful in differentiating between benign and malignant lesions.7–9 CH-EUS is beneficial for the differential diagnosis of pancreatic tumors.10–12
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Corresponding: Akio Katanuma, Center for Gastroenterology, Teine-Keijinkai Hospital, 1-40-1-12 Maeda, Teine, Sapporo 0068555, Japan. Email: [email protected] Received 8 December 2014; accepted 19 January 2015.
not the three functions of EU-ME2 Premier Plus were useful for several items under pancreatic, bile duct, and gallbladder indications. According to the participants’ views, THE (particularly THE-P mode) is essential for the diagnosis of cystic lesions. Many participants viewed elastography as useful in only extremely limited cases. Although CH-EUS was not considered useful for all cases, its indications covered a broad range. Additional studies are warranted to clarify the functions of EU-ME2 Premier Plus in more detail. Key words: contrast harmonic endoscopic ultrasonography, elastography, endoscopic ultrasonography, pancreatic cystic lesion, tissue harmonic echo
However, many aspects regarding the actual usefulness of these three new functions for the diagnosis of pancreatobiliary diseases still remain unknown, and a satisfactory consensus is far from being reached. Towards achieving a consensus, Endoscopy Forum Japan (EFJ) 2014 held in Otaru City, Hokkaido, Japan, became an important venue for discussing the usefulness of these new functions of EUS during the pancreatobiliary session. Important contents of the discussion are reported in the present article. In addition, we describe the current situation of EUS diagnosis in India. Also, we state our recommendations on the usefulness of the new functions of EU-ME2 Premier Plus.
PARTICIPATING INSTITUTIONS
R
ESEARCHERS FROM 10 Japanese high-volume centers and two Asian institutions participated and discussed their views at EFJ 2014. The participating doctors and their affiliations were as follows: Akio Katanuma (TeineKeijinkai Hospital), Hiroyuki Isayama (University of Tokyo), Goro Shibukawa (Fukushima Medical University, Aizu Medical Center), Shoumei Ryozawa (Saitama
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International Medical Center), Fumihide Itokawa (Tokyo Medical University), Ichiro Yasuda (Teikyo University School of Medicine University Hospital, Mizonokuchi), Eizaburo Ohno (Nagoya University), Masayuki Kitano (Kinki University), Hironari Kato (Okayama University), and Yusuke Ishida (Kurume University). Two Asian doctors outside Japan joined the session, Amol Bapaye (Deenanath Mangeshkar Hospital, India) and Anthony Teo (Prince of Wales Hospital, Hong Kong).
METHODS
B
EFORE THE CONVENING of EFJ 2014, EU-ME2 Premier Plus was used for the examination of patients with pancreatobiliary diseases at each participating institution. The following questions were asked in a survey for each of the 266 cases in which EU-ME2 Premier Plus was used. 1. Were the B-mode images obtained using EU-ME2 Premier Plus better than those obtained using the previous model (EU-ME1)? 2. Compared to the conventional B-mode, were the THE mode images obtained using EU-ME2 Premier Plus superior? 3. Was additional information obtained by THE mode compared with B-mode? During the EFJ 2014 session, the moderators (A.K. and H.I.) presented the following pancreatic, bile duct, and gallbladder indications (see below). The discussants then voted on the usefulness of the three new functions of EU-ME2 Premier Plus in relation to each indication by raising their hands according to the following scale: a, always useful; b, sometimes useful; c, limited indication; and d, not useful. 1. Pancreatic indications 1) Diagnosis of pancreatic cystic mass 2) Diagnosis of pancreatic solid mass 3) Diagnosis of the early stage of chronic pancreatitis 2. Bile duct indications 1) Detection of small bile duct stone 2) Differential diagnosis of bile duct stricture 3) Diagnosis of tumor extension of bile duct cancer 4) Diagnosis of ampullary cancer 3. Gallbladder indications 1) Detection of Rokitansky–Aschoff sinus (RAS) 2) Diagnosis of gallbladder polyp 3) Diagnosis of gallbladder cancer
RESULTS Questionnaire survey results
T
HE PRIOR QUESTIONNAIRE survey was conducted in all 12 participating institutions for 266 cases of EUS. These included 209 cases of EUS observation, 56 cases of
Figure 1 Fundamental B-mode image quality compared with EU-ME1 (Olympus Medical Systems Corp., Tokyo, Japan). , better; , equal; , worse.
a
b
Figure 2 Tissue harmonic echo (THE) image quality compared with B-mode. (a) THE-P, (b) THE-R. , better; , equal; , worse.
EUS-guided fine-needle aspiration (EUS-FNA), and one case of EUS-guided treatment.
Imaging quality of fundamental B-mode images The B-mode images obtained using EU-ME2 Premier Plus were improved in 91% of the cases compared to those obtained using the previous EU-ME1 model (Fig. 1).
Imaging quality of tissue harmonic echo Comparison of the usefulness of the THE-P (penetration) mode and the B-mode for diagnosis showed that the THE-P mode was superior to the B-mode in 88% of the cases, comparable in 8%, and inferior in 4% (Fig. 2a). In contrast, the THE-R (resolution) mode was superior to the B-mode in only 48% of the cases, comparable in 28%, and inferior in 24% (Fig. 2b).
© 2015 The Authors Digestive Endoscopy © 2015 Japan Gastroenterological Endoscopy Society
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Additional information using tissue harmonic echo As to whether additional information was obtained compared with the B-mode, the responses showed that the information that was obtained by the THE-P and THE-R modes increased in 76% and 39% of the cases, were unchanged in 21% and 44%, and decreased in 4% and 21%, respectively (Fig. 3). THE-P mode was regarded as useful for pancreatic diseases in many cases, whereas THE-R mode was regarded as not very useful. This may be as a result of the fact that THE-P mode is superior in terms of the observation of more distant points owing to improved frequencies, and that THE-R mode allows adequate observation of only near points owing to penetration issues. a
b
EUS diagnosis using new techniques 49
Many comments obtained from the survey on prior case assessments indicated that THE-P mode was extremely useful for the observation of cysts or the inner parts of ductal organs such as the bile duct or gallbladder because of the reduced artifacts during observation. An important comment noted that THE-P mode was highly useful in depicting nodules and differentiation between nodules and mucus particularly in cases of intraductal papillary mucinous neoplasm. Many comments indicated that the outlines of solid lesions were clearly delineated. However, penetration depth was pointed out to be reduced in the case of a large lesion, making ultrasound images of distal regions partly unclear. In cases of chronic pancreatitis associated with calcification, clear images could not be obtained because of ultrasonic wave attenuation. In contrast, many commentators stated that THE-R mode was as useful as THE-P mode in the observation of cystic lesions and ductal organs. However, because of ultrasound attenuation, THE-R mode was useful only for the observation of regions proximal to the ultrasound probe and had limitations for the observation of distal regions.
Voting results on the usefulness of EU-ME2 Premier Plus functions Tissue harmonic echo
Figure 3 Additional information was obtained using tissue harmonic echo (THE) compared with B-mode. (a) THE-P, (b) THE-R. , better; , equal; , worse.
For pancreatic indications, all of the participants responded that theTHE function of EU-ME2 Premier Plus was always useful in the diagnosis of pancreatic cystic lesions. For solid lesions, the functions of EU-ME2 Premier Plus were regarded as useful by 92.3% of the participants, including 61.5% of those responding that the functions were always useful (Fig. 4). Although the
Figure 4 Voting results on the usefulness of tissue harmonic echo. , always useful; , sometimes useful; , limited indications; , not useful.
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usefulness of the THE function for solid lesions was slightly lower than that for cystic lesions, many participants stated that THE should also be used for solid lesions. For diagnosis of early-stage chronic pancreatitis, the functions were regarded as useful by 77% of the participants (Fig. 4). The results were divided in terms of their assessment. A possible factor for this was assumed to be the lack of an established disease concept regarding the early stage of chronic pancreatitis. However, some discussants indicated that THE made it easier to obtain findings on fibrotic changes of the pancreatic parenchyma in the early stage; thus, additional studies to clarify this issue are warranted. For bile duct indications, votes were taken on the usefulness of the new functions in terms of the detection of small bile duct stone, differential diagnosis of bile duct stricture, diagnosis of tumor extension for bile duct cancer, and diagnosis of ampullary cancer. Although no participant responded that the new functions were always useful, the majority of the participants indicated that THE was useful for all the items (Fig. 4). A possible explanation for this might be that, because the bile duct is a ductal organ, THE was expected to reduce artifacts and to more clearly delineate the border between the bile duct lumen and the surrounding tissue. However, although THE allows efficient observation, it remains unknown as to how useful THE is in terms of making a differential diagnosis and tumor staging, or to what extent THE allows differentiation between benign/ inflammatory changes and malignant changes. These issues necessitate future studies. For gallbladder indications, 71.4% of the participants responded that THE was always useful for the detection of RAS and the diagnosis of polyp. When the participants who responded that THE was sometimes useful were included, all of the participants indicated that THE should be carried out. For the diagnosis of gallbladder cancer, all of the participants responded that THE was always or sometimes useful; however, the proportion of those who responded that THE was always useful was smaller (46.2%) (Fig. 4). Regarding the detection of RAS, THE is assumed to provide clearly identifiable images because it reduces artifacts and emphasizes the lack of echo in the inner part of RAS.
EUS-elastography Elastography, a new imaging modality, was developed for making a differential diagnosis in EUS examinations, and was first reported in 2006 by Giovannini et al.7 Tissue stiffness is evaluated and the differences may be useful to differential diagnosis. This modality measures the elastic properties of tissues by applying slight compression to the tissue, and comparing the before and after compression images. Previous articles have reported the usefulness of EUS-elastography in differential diagnosis of pancreatic solid mass from pancreatic parenchyma, with clear recognition of the margin of a solid mass, and necrotic tissues in a solid mass.8,9
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Commercially available EUS-elastography is not able to evaluate quantitatively. It can evaluate relative stiffness compared with the surrounding tissue, including on the same screen. It is not an objective examination, and has some limitations. This imaging modality showed high sensitivity and low specificity, and can diagnose a solid mass, but it is difficult to distinguish the mass from fibrosis. For pancreatic indications, all participants voted that current EUS-elastography was not considered a useful modality (Fig. 5). We discussed cystic lesion, solid mass and early chronic pancreatitis, similar to the other modalities. Sometimes it was difficult to distinguish pancreatic cancer from chronic pancreatitis, and we discussed the availability of surveillance in chronic pancreatitis cases. Many participants thought that it was still difficult with current EUS-elastography to make a differential diagnosis of pancreatic cancer from chronic pancreatitis. For biliary and gallbladder indications, most participants thought that EUSelastography was not available. A requirement of EUSelastography development was to make it possible to evaluate quantitatively. If we can estimate the quantitative stiffness of region of interest (ROI), we can diagnose many diseases. Another problem with this imaging modality is that it is not covered by government insurance.
Contrast-harmonic EUS Contrast harmonic EUS was the modality used for evaluation of blood flow of tissue, and its aim was similar to that of contrast-enhanced CT (CE-CT). The information provided may make it possible to improve the detectability and understand the character of a tumor according to its vascularity. CH-EUS can also diagnose the vascularity of target tissue. When we use EUS, we obtain a Doppler image, but it detects only large vessels. Contrast for EUS is microbubbles and it can diagnose small vessels because of the high-resolution image of EUS. Therefore, CH-EUS can provide additional information to a CT image. CT, Doppler and CH-EUS are all complementary examinations. Kitano et al. made a classification of the pattern of enhancement for the diagnosis of pancreatic tumor as follows: no-enhancement, necrotic tissue; hypo-, ductal carcinoma; iso, focal pancreatitis; and hyper-, neuroendocrine tumor.12 Mass-forming autoimmune pancreatitis was sometimes very difficult to diagnose. EUS could detect the mass in the pancreatic parenchyma, but CH-EUS showed no difference between mass and pancreatic parenchyma. The image suggested that the mass was inflammatory pseudotumor. CH-EUS image can reveal the character of target tissue. There was another difficult diagnosis in intraductal papillary neoplasm (IPMN). Differential diagnosis between mural nodule and mucus clot was difficult in conventional EUS examination. CE-CT can detect or reveal the vascularity of a relatively large nodule, but this is impossible or difficult in a small nodule. CH-EUS can obtain a more precise image of these small nodular lesions, and diagnose differentially.
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Figure 5 Voting results on the usefulness of elastography. , always useful; , sometimes useful; , limited indications; , not useful.
Figure 6 Voting results on the usefulness of contrast harmonic endoscopic ultrasonography. , always useful; , sometimes useful; , limited indications; , not useful.
During voting for pancreatic indications, differential diagnosis for solid mass using CH-EUS was considered as sometimes useful (Fig. 6). We could get additional information blood flow information, and it may contribute to an understanding of the character of the mass lesion. However, CE-CT can obtain similar information and this information
is objective. EUS-FNA can obtain pathological information, therefore participants thought that CH-EUS was sometimes useful. Information from CH-EUS was complementary for both CE-CT and EUS-FNA. It revealed more information of small vessels than CE-CT. When EUS-FNA failed to show the correct diagnosis, findings of CH-EUS showed the next
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step. If CT-EUS suggested malignancy, we carried out EUSFNA again, but if CT-EUS did not suggest malignancy, we decided on observation. For a diagnosis of IPMN, CH-EUS was useful for differential diagnosis between mural nodule and mucus clot. CE-CT cannot detect such a small lesion and diagnose it. EUS is the choice for diagnosis of a mural nodule. CT-EUS may be useful for diagnosis of neoplastic lesions, but is not so useful for chronic pancreatitis. For biliary indications, stricture and tumor extension, neoplastic lesions were considered as sometimes useful or limited indications (Fig. 6). The value of CH-EUS was not as high for biliary indications compared to pancreatic indications. For gallbladder indications, RAS, polyps and cancer were good indications for CH-EUS (Fig. 6). There were limited indications of EUS-FNA for gallbladder diseases and small lesions were not suitable for CT diagnosis. Therefore, gallbladder elevated lesions were a good indication for CH-EUS.
EUS in India India has witnessed a significant growth in EUS technology in the last few years. According to a study from the EUS Working Group of India presented in abstract form in 2011, there were 72 medical institutions in India having access to EUS equipment, out of which 15 were high-volume centers.13 Approximately two-thirds of EUS procedures were for biliary-pancreatic indications. Approximately two-thirds of EUS procedures were carried out for diagnosis, whereas the rest were for FNA or therapy. In the last 3 years, many more centers across India have started EUS services; however, exact numbers are not available. According to experts and industry estimates, there are approximately 150 EUS installations across the country with an estimated 20% growth predicted every year for the next few years. Despite this broad installation base, there are only about 15 highvolume centers, which carry out more than 300 procedures annually.13 Utilization patterns for EUS in India indicate that approximately two-thirds of EUS procedures are carried out for diagnosis, whereas the rest are for FNA or therapy. Data from India on the role of EUS for biliary-pancreatic diseases is sparse. The majority of Indian publications in the last 4 years have focused on EUS-FNA or EUS-guided therapy.14–21 Two publications, both review articles by the Asian Consortium for EUS, deal with the utility of EUS for diagnosis of solid and cystic pancreatic lesions.22,23 Both emphasize the need for more data on this subject from all Asian countries including India. EUS imaging has improved in the last few years with the development of new technologies – THE, elastography and CH-EUS. The exact clinical impact and positioning of these technologies regarding improved diagnosis are still evolving.
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These latest advances and new functions are relatively new to India. Only a few centers (possibly less than 10) have access to these new advanced technologies. Implementation of these new technologies in India has a few unique challenges.
New EUS technologies in India Tissue harmonic echo Chronic pancreatitis, especially the tropical (non-alcoholic) type, is common in India. EUS imaging for diagnosis of early chronic pancreatitis using B-mode is often confusing as a result of the fact that many healthy individuals have hyperechoic strands or foci within the pancreas. It is as yet unknown whether these hyperechoic strands or foci are pathological features of early chronic pancreatitis or are only a variation of the normal anatomy of the pancreas in healthy Indian subjects. By its ability to reduce artifacts, THE may allow superior imaging of the pancreas in this group of patients, thus improving diagnosis.
EUS-elastography Pancreatic adenocarcinomas are typically hard tumors and therefore show up as hard (blue) areas on elastography. However, elastography has still not been shown to replace FNA in terms of diagnostic accuracy. The other limitation of EUS-elastography is that it is operator dependent and results often depend on the pressure exerted by the transducer on the tissue. In India, where these technologies are new, proper training in carrying out and interpreting elastography may be necessary before this technology can find universal application. At present, elastography remains at best a roadmap to guide the FNA needle in an optimum area to acquire representative tissue for cytology or biopsy.
Contrast harmonic endoscopic ultrasonography An important challenge to the use of CH-EUS in India is the limited availability of ultrasound contrast media. Sonovue™ (Bracco, Milan, Italy) is not readily available and is expensive, limiting its use to a select group of patients. Also, current endosonographers have limited experience in CH-EUS and therefore must be trained to interpret CH-EUS images.
Recommendations on the usefulness of the new functions of EU-ME2 Premier Plus Training of endosonographers for the optimum use of these technologies to obtain and interpret the resulting images is recommended. THE, especially P-mode, is most likely to gain widespread acceptance in near future because of its ease of use and low operator dependence. THE is superior in terms of depiction and observation of pancreatic cystic
© 2015 The Authors Digestive Endoscopy © 2015 Japan Gastroenterological Endoscopy Society
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lesions and ductal organs (i.e. bile duct and gallbladder) and appears to be an essential examination technique. However, the effectiveness of THE in terms of improved diagnostic performance remains to be definitively established through multicenter collaborative studies. Indication of current elastography without quantitative function was limited. In the near future, we should re-evaluate this modality with quantitative function. CH-EUS was useful for differential diagnosis in neoplastic lesions. We can obtain additional blood flow information with CH-EUS. However, we can get similar images with CE-CT and can obtain pathological information with EUSFNA. CH-EUS was complementary for both CE-CT and EUS-FNA. Government insurance does not approve this function nor covers the fee of contrast medium. Therefore, indication for CH-EUS is still controversial and it requires a prospective comparative study. Finally, any technological advance must be assessed in light of the clinical benefit that it can provide. Unless these technological advances in EUS imaging can replace tissue sampling, their utility remains limited to providing a roadmap for the optimum site for FNA.
ACKNOWLEDGMENT
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HE AUTHORS ARE indebted to Dr Edward Barroga, Associate Professor and Senior Medical Editor of Tokyo Medical University for reviewing and editing the manuscript.
CONFLICT OF INTERESTS
A
UTHORS DECLARE NO conflict of interests for this article.
REFERENCES 1 Kaufman AR, Sivak MV Jr. Endoscopic ultrasonography in the differential diagnosis of pancreatic disease. Gastrointest. Endosc. 1989; 35: 214–9. 2 Soriano A, Castells A, Ayuso C et al. Preoperative staging and tumor resectability assessment of pancreatic cancer: Prospective study comparing endoscopic ultrasonography, helical computed tomography, magnetic resonance imaging, and angiography. Am. J. Gastroenterol. 2004; 99: 492–501. 3 Gress FG, Hawes RH, Savides TJ et al. Role of EUS in the preoperative staging of pancreatic cancer: A large single-center experience. Gastrointest. Endosc. 1999; 50: 786–91. 4 Aslanian H, Salem R, Lee J, Andersen D, Robert M, Topazian M. EUS diagnosis of vascular invasion in pancreatic cancer: Surgical and histologic correlates. Am. J. Gastroenterol. 2005; 100: 1381–5.
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5 Ishikawa H, Hirooka Y, Itoh A et al. A comparison of image quality between tissue harmonic echo and fundamental imaging with an electronic radial scanning echoendoscope in the diagnosis of pancreatic diseases. Gastrointest. Endosc. 2003; 57: 931–6. 6 Matsumoto K, Katanuma A. Novel tissue harmonic echo clearly visualizes a case of intraductal papillary mucinous neoplasm with mural nodules. JOP 2014; 15: 274–5. 7 Giovannini M, Hookey LC, Bories E, Pesenti C, Monges G, Delpero JR. Endoscopic ultrasound elastography: The first step towards virtual biopsy? Preliminary results in 49 patients. Endoscopy 2006; 38: 344–8. 8 Itokawa F, Itoi T, Sofuni A et al. EUS elastography combined with the strain ratio of tissue elasticity for diagnosis of solid pancreatic masses. J. Gastroenterol. 2011; 46: 843–53. 9 Saftoiu A, Vilmann P, Gorunescu F et al. Accuracy of endoscopic ultrasound elastography used for differential diagnosis of focal pancreatic masses: A multicenter study. Endoscopy 2011; 43: 596–603. 10 Hocke M, Schulze E, Gottschalk P, Topalidis T, Dietrich CF. Contrast-enhanced endoscopic ultrasound in discrimination between focal pancreatitis and pancreatic cancer. World J. Gastroenterol. 2006; 12: 246–50. 11 Napoleon B, Alvarez-Sanchez MV, Gincoul R et al. Contrastenhanced harmonic endoscopic ultrasound in solid lesions of the pancreas: Results of a pilot study. Endoscopy 2010; 42: 564–70. 12 Kitano M, Kudo M, Yamao K et al. Characterization of small solid tumors in the pancreas: The value of contrast-enhanced harmonic endoscopic ultrasonography. Am. J. Gastroenterol. 2012; 107: 303–10. 13 Dhir V, Puri R, Sharma M et al. Utilization patterns of EUS and EUS guided FNA in India: A survey of the EUS Working Group of India. J. Gastroenterol. Hepatol. 2011; 26 (s5): 70. 14 Dhir V, Artifon EL, Gupta K et al. Multicenter study on endoscopic ultrasound-guided expandable biliary metal stent placement: Choice of access route, direction of stent insertion, and drainage route. Dig. Endosc. 2014; 26: 430–5. 15 Dhir V, Vivekanandarajah S, Bhandari S, Bapat M, Maydeo A. Endoscopic ultrasound-guided cholangiography and intraluminal needle puncture through a tight subhilar bile duct stricture for biliary stenting following failed ERCP. Endoscopy 2013; 45 (Suppl 2 UCTN): E5–6. 16 Dhir V, Bhandari S, Bapat M, Joshi N, Vivekanandarajah S, Maydeo A. Comparison of transhepatic and extrahepatic routes for EUS-guided rendezvous procedure for distal CBD obstruction. United European Gastroenterol J. 2013; 1: 103–8. 17 Bapaye A, Dubale N, Aher A. Comparison of endosonographyguided vs. percutaneous biliary stenting when papilla is inaccessible for ERCP. United European Gastroenterol J. 2013; 1: 285–93. 18 Puri R, Thandassery RB, Eloubeidi MA, Sud R. Diagnosis of isolated pancreatic tuberculosis: The role of EUS-guided FNA cytology. Gastrointest. Endosc. 2012; 75: 900–4. 19 Dhir V, Bhandari S, Bapat M, Maydeo A. Comparison of EUSguided rendezvous and precut papillotomy techniques for
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biliary access (with videos). Gastrointest. Endosc. 2012; 75: 354–9. 20 Bapaye A, Dubale N. Endoscopic ultrasound-guided antegrade dilation of a stenosed hepaticojejunostomy. Endoscopy 2012; 44 (Suppl 2 UCTN): E435–6. 21 Dhir V, Kwek BE, Bhandari S, Bapat M, Maydeo A. EUSguided biliary rendezvous using a short hydrophilic guidewire. J. Int. Gastroenterol. 2011; 1: 153–9.
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22 Kongkam P, Ang TL, Vu CK et al. Current status on the diagnosis and evaluation of pancreatic tumor in Asia with particular emphasis on the role of endoscopic ultrasound. J. Gastroenterol. Hepatol. 2013; 28: 924–30. 23 Lim LG, Itoi T, Lim WC et al. Current status on the diagnosis and management of pancreatic cysts in the Asia-Pacific region: Role of endoscopic ultrasound. J. Gastroenterol. Hepatol. 2011; 26: 1702–8.
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doi: 10.1111/den.12443
Clinical evaluation of new diagnostic modalities of EUS for pancreatobiliary diseases
Endoscopic ultrasonography using new functions for pancreatobiliary diseases: Current status and future perspectives Akio Katanuma,1 Hiroyuki Isayama2 and Amol Bapaye3 1
Center for Gastroenterology, Teine-Keijinkai Hospital, Sapporo, Japan; 2Department of Gastroenterology, Graduate School of Medicine, Tokyo University, Tokyo, Japan; and 3Department of Digestive Diseases and Endoscopy, Deenanath Mangeshkar Hospital and Research Center, Maharashtra, India
A new endoscopic ultrasound processor (EU-ME2 Premier Plus) has recently been developed. It improves fundamental imaging and enables three new functions; namely, tissue harmonic echo (THE), elastography, and contrast harmonic endoscopic ultrasonography (CH-EUS). However, many aspects regarding the usefulness of these three functions in the diagnosis of pancreatobiliary diseases remain unknown. In connection with and prior to the convening of Endoscopy Forum Japan 2014, endoscopic ultrasonography using EU-ME2 Premier Plus was carried out for pancreatic, bile duct, and gallbladder cases at 12 participating institutions (Japan [n = 10]; other Asian countries [n = 2]). A questionnaire survey was conducted regarding the usefulness of EU-ME2 Premier Plus for each EUS case. In addition, participants’ views were surveyed by asking them to vote as to whether or
INTRODUCTION
E
NDOSCOPIC ULTRASONOGRAPHY (EUS) is useful for the diagnosis and treatment of pancreatobiliary diseases. EUS plays important roles particularly for the detection of small lesions, differential diagnosis, and tumor staging, as well as for treatment involving various drainage techniques.1–4 Recently, a new EUS processor (EU-ME2 Premier Plus; Olympus Medical Systems Corp., Tokyo, Japan) has been developed. This processor is capable of three new functions; namely, tissue harmonic echo (THE), elastography, and contrast harmonic endoscopic ultrasonography (CH-EUS), the usefulness of which has been reported. THE provides high-quality images of cystic and solid lesions of the pancreas.5,6 Elastography is useful in differentiating between benign and malignant lesions.7–9 CH-EUS is beneficial for the differential diagnosis of pancreatic tumors.10–12
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Corresponding: Akio Katanuma, Center for Gastroenterology, Teine-Keijinkai Hospital, 1-40-1-12 Maeda, Teine, Sapporo 0068555, Japan. Email: [email protected] Received 8 December 2014; accepted 19 January 2015.
not the three functions of EU-ME2 Premier Plus were useful for several items under pancreatic, bile duct, and gallbladder indications. According to the participants’ views, THE (particularly THE-P mode) is essential for the diagnosis of cystic lesions. Many participants viewed elastography as useful in only extremely limited cases. Although CH-EUS was not considered useful for all cases, its indications covered a broad range. Additional studies are warranted to clarify the functions of EU-ME2 Premier Plus in more detail. Key words: contrast harmonic endoscopic ultrasonography, elastography, endoscopic ultrasonography, pancreatic cystic lesion, tissue harmonic echo
However, many aspects regarding the actual usefulness of these three new functions for the diagnosis of pancreatobiliary diseases still remain unknown, and a satisfactory consensus is far from being reached. Towards achieving a consensus, Endoscopy Forum Japan (EFJ) 2014 held in Otaru City, Hokkaido, Japan, became an important venue for discussing the usefulness of these new functions of EUS during the pancreatobiliary session. Important contents of the discussion are reported in the present article. In addition, we describe the current situation of EUS diagnosis in India. Also, we state our recommendations on the usefulness of the new functions of EU-ME2 Premier Plus.
PARTICIPATING INSTITUTIONS
R
ESEARCHERS FROM 10 Japanese high-volume centers and two Asian institutions participated and discussed their views at EFJ 2014. The participating doctors and their affiliations were as follows: Akio Katanuma (TeineKeijinkai Hospital), Hiroyuki Isayama (University of Tokyo), Goro Shibukawa (Fukushima Medical University, Aizu Medical Center), Shoumei Ryozawa (Saitama
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International Medical Center), Fumihide Itokawa (Tokyo Medical University), Ichiro Yasuda (Teikyo University School of Medicine University Hospital, Mizonokuchi), Eizaburo Ohno (Nagoya University), Masayuki Kitano (Kinki University), Hironari Kato (Okayama University), and Yusuke Ishida (Kurume University). Two Asian doctors outside Japan joined the session, Amol Bapaye (Deenanath Mangeshkar Hospital, India) and Anthony Teo (Prince of Wales Hospital, Hong Kong).
METHODS
B
EFORE THE CONVENING of EFJ 2014, EU-ME2 Premier Plus was used for the examination of patients with pancreatobiliary diseases at each participating institution. The following questions were asked in a survey for each of the 266 cases in which EU-ME2 Premier Plus was used. 1. Were the B-mode images obtained using EU-ME2 Premier Plus better than those obtained using the previous model (EU-ME1)? 2. Compared to the conventional B-mode, were the THE mode images obtained using EU-ME2 Premier Plus superior? 3. Was additional information obtained by THE mode compared with B-mode? During the EFJ 2014 session, the moderators (A.K. and H.I.) presented the following pancreatic, bile duct, and gallbladder indications (see below). The discussants then voted on the usefulness of the three new functions of EU-ME2 Premier Plus in relation to each indication by raising their hands according to the following scale: a, always useful; b, sometimes useful; c, limited indication; and d, not useful. 1. Pancreatic indications 1) Diagnosis of pancreatic cystic mass 2) Diagnosis of pancreatic solid mass 3) Diagnosis of the early stage of chronic pancreatitis 2. Bile duct indications 1) Detection of small bile duct stone 2) Differential diagnosis of bile duct stricture 3) Diagnosis of tumor extension of bile duct cancer 4) Diagnosis of ampullary cancer 3. Gallbladder indications 1) Detection of Rokitansky–Aschoff sinus (RAS) 2) Diagnosis of gallbladder polyp 3) Diagnosis of gallbladder cancer
RESULTS Questionnaire survey results
T
HE PRIOR QUESTIONNAIRE survey was conducted in all 12 participating institutions for 266 cases of EUS. These included 209 cases of EUS observation, 56 cases of
Figure 1 Fundamental B-mode image quality compared with EU-ME1 (Olympus Medical Systems Corp., Tokyo, Japan). , better; , equal; , worse.
a
b
Figure 2 Tissue harmonic echo (THE) image quality compared with B-mode. (a) THE-P, (b) THE-R. , better; , equal; , worse.
EUS-guided fine-needle aspiration (EUS-FNA), and one case of EUS-guided treatment.
Imaging quality of fundamental B-mode images The B-mode images obtained using EU-ME2 Premier Plus were improved in 91% of the cases compared to those obtained using the previous EU-ME1 model (Fig. 1).
Imaging quality of tissue harmonic echo Comparison of the usefulness of the THE-P (penetration) mode and the B-mode for diagnosis showed that the THE-P mode was superior to the B-mode in 88% of the cases, comparable in 8%, and inferior in 4% (Fig. 2a). In contrast, the THE-R (resolution) mode was superior to the B-mode in only 48% of the cases, comparable in 28%, and inferior in 24% (Fig. 2b).
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Additional information using tissue harmonic echo As to whether additional information was obtained compared with the B-mode, the responses showed that the information that was obtained by the THE-P and THE-R modes increased in 76% and 39% of the cases, were unchanged in 21% and 44%, and decreased in 4% and 21%, respectively (Fig. 3). THE-P mode was regarded as useful for pancreatic diseases in many cases, whereas THE-R mode was regarded as not very useful. This may be as a result of the fact that THE-P mode is superior in terms of the observation of more distant points owing to improved frequencies, and that THE-R mode allows adequate observation of only near points owing to penetration issues. a
b
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Many comments obtained from the survey on prior case assessments indicated that THE-P mode was extremely useful for the observation of cysts or the inner parts of ductal organs such as the bile duct or gallbladder because of the reduced artifacts during observation. An important comment noted that THE-P mode was highly useful in depicting nodules and differentiation between nodules and mucus particularly in cases of intraductal papillary mucinous neoplasm. Many comments indicated that the outlines of solid lesions were clearly delineated. However, penetration depth was pointed out to be reduced in the case of a large lesion, making ultrasound images of distal regions partly unclear. In cases of chronic pancreatitis associated with calcification, clear images could not be obtained because of ultrasonic wave attenuation. In contrast, many commentators stated that THE-R mode was as useful as THE-P mode in the observation of cystic lesions and ductal organs. However, because of ultrasound attenuation, THE-R mode was useful only for the observation of regions proximal to the ultrasound probe and had limitations for the observation of distal regions.
Voting results on the usefulness of EU-ME2 Premier Plus functions Tissue harmonic echo
Figure 3 Additional information was obtained using tissue harmonic echo (THE) compared with B-mode. (a) THE-P, (b) THE-R. , better; , equal; , worse.
For pancreatic indications, all of the participants responded that theTHE function of EU-ME2 Premier Plus was always useful in the diagnosis of pancreatic cystic lesions. For solid lesions, the functions of EU-ME2 Premier Plus were regarded as useful by 92.3% of the participants, including 61.5% of those responding that the functions were always useful (Fig. 4). Although the
Figure 4 Voting results on the usefulness of tissue harmonic echo. , always useful; , sometimes useful; , limited indications; , not useful.
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usefulness of the THE function for solid lesions was slightly lower than that for cystic lesions, many participants stated that THE should also be used for solid lesions. For diagnosis of early-stage chronic pancreatitis, the functions were regarded as useful by 77% of the participants (Fig. 4). The results were divided in terms of their assessment. A possible factor for this was assumed to be the lack of an established disease concept regarding the early stage of chronic pancreatitis. However, some discussants indicated that THE made it easier to obtain findings on fibrotic changes of the pancreatic parenchyma in the early stage; thus, additional studies to clarify this issue are warranted. For bile duct indications, votes were taken on the usefulness of the new functions in terms of the detection of small bile duct stone, differential diagnosis of bile duct stricture, diagnosis of tumor extension for bile duct cancer, and diagnosis of ampullary cancer. Although no participant responded that the new functions were always useful, the majority of the participants indicated that THE was useful for all the items (Fig. 4). A possible explanation for this might be that, because the bile duct is a ductal organ, THE was expected to reduce artifacts and to more clearly delineate the border between the bile duct lumen and the surrounding tissue. However, although THE allows efficient observation, it remains unknown as to how useful THE is in terms of making a differential diagnosis and tumor staging, or to what extent THE allows differentiation between benign/ inflammatory changes and malignant changes. These issues necessitate future studies. For gallbladder indications, 71.4% of the participants responded that THE was always useful for the detection of RAS and the diagnosis of polyp. When the participants who responded that THE was sometimes useful were included, all of the participants indicated that THE should be carried out. For the diagnosis of gallbladder cancer, all of the participants responded that THE was always or sometimes useful; however, the proportion of those who responded that THE was always useful was smaller (46.2%) (Fig. 4). Regarding the detection of RAS, THE is assumed to provide clearly identifiable images because it reduces artifacts and emphasizes the lack of echo in the inner part of RAS.
EUS-elastography Elastography, a new imaging modality, was developed for making a differential diagnosis in EUS examinations, and was first reported in 2006 by Giovannini et al.7 Tissue stiffness is evaluated and the differences may be useful to differential diagnosis. This modality measures the elastic properties of tissues by applying slight compression to the tissue, and comparing the before and after compression images. Previous articles have reported the usefulness of EUS-elastography in differential diagnosis of pancreatic solid mass from pancreatic parenchyma, with clear recognition of the margin of a solid mass, and necrotic tissues in a solid mass.8,9
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Commercially available EUS-elastography is not able to evaluate quantitatively. It can evaluate relative stiffness compared with the surrounding tissue, including on the same screen. It is not an objective examination, and has some limitations. This imaging modality showed high sensitivity and low specificity, and can diagnose a solid mass, but it is difficult to distinguish the mass from fibrosis. For pancreatic indications, all participants voted that current EUS-elastography was not considered a useful modality (Fig. 5). We discussed cystic lesion, solid mass and early chronic pancreatitis, similar to the other modalities. Sometimes it was difficult to distinguish pancreatic cancer from chronic pancreatitis, and we discussed the availability of surveillance in chronic pancreatitis cases. Many participants thought that it was still difficult with current EUS-elastography to make a differential diagnosis of pancreatic cancer from chronic pancreatitis. For biliary and gallbladder indications, most participants thought that EUSelastography was not available. A requirement of EUSelastography development was to make it possible to evaluate quantitatively. If we can estimate the quantitative stiffness of region of interest (ROI), we can diagnose many diseases. Another problem with this imaging modality is that it is not covered by government insurance.
Contrast-harmonic EUS Contrast harmonic EUS was the modality used for evaluation of blood flow of tissue, and its aim was similar to that of contrast-enhanced CT (CE-CT). The information provided may make it possible to improve the detectability and understand the character of a tumor according to its vascularity. CH-EUS can also diagnose the vascularity of target tissue. When we use EUS, we obtain a Doppler image, but it detects only large vessels. Contrast for EUS is microbubbles and it can diagnose small vessels because of the high-resolution image of EUS. Therefore, CH-EUS can provide additional information to a CT image. CT, Doppler and CH-EUS are all complementary examinations. Kitano et al. made a classification of the pattern of enhancement for the diagnosis of pancreatic tumor as follows: no-enhancement, necrotic tissue; hypo-, ductal carcinoma; iso, focal pancreatitis; and hyper-, neuroendocrine tumor.12 Mass-forming autoimmune pancreatitis was sometimes very difficult to diagnose. EUS could detect the mass in the pancreatic parenchyma, but CH-EUS showed no difference between mass and pancreatic parenchyma. The image suggested that the mass was inflammatory pseudotumor. CH-EUS image can reveal the character of target tissue. There was another difficult diagnosis in intraductal papillary neoplasm (IPMN). Differential diagnosis between mural nodule and mucus clot was difficult in conventional EUS examination. CE-CT can detect or reveal the vascularity of a relatively large nodule, but this is impossible or difficult in a small nodule. CH-EUS can obtain a more precise image of these small nodular lesions, and diagnose differentially.
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Figure 5 Voting results on the usefulness of elastography. , always useful; , sometimes useful; , limited indications; , not useful.
Figure 6 Voting results on the usefulness of contrast harmonic endoscopic ultrasonography. , always useful; , sometimes useful; , limited indications; , not useful.
During voting for pancreatic indications, differential diagnosis for solid mass using CH-EUS was considered as sometimes useful (Fig. 6). We could get additional information blood flow information, and it may contribute to an understanding of the character of the mass lesion. However, CE-CT can obtain similar information and this information
is objective. EUS-FNA can obtain pathological information, therefore participants thought that CH-EUS was sometimes useful. Information from CH-EUS was complementary for both CE-CT and EUS-FNA. It revealed more information of small vessels than CE-CT. When EUS-FNA failed to show the correct diagnosis, findings of CH-EUS showed the next
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step. If CT-EUS suggested malignancy, we carried out EUSFNA again, but if CT-EUS did not suggest malignancy, we decided on observation. For a diagnosis of IPMN, CH-EUS was useful for differential diagnosis between mural nodule and mucus clot. CE-CT cannot detect such a small lesion and diagnose it. EUS is the choice for diagnosis of a mural nodule. CT-EUS may be useful for diagnosis of neoplastic lesions, but is not so useful for chronic pancreatitis. For biliary indications, stricture and tumor extension, neoplastic lesions were considered as sometimes useful or limited indications (Fig. 6). The value of CH-EUS was not as high for biliary indications compared to pancreatic indications. For gallbladder indications, RAS, polyps and cancer were good indications for CH-EUS (Fig. 6). There were limited indications of EUS-FNA for gallbladder diseases and small lesions were not suitable for CT diagnosis. Therefore, gallbladder elevated lesions were a good indication for CH-EUS.
EUS in India India has witnessed a significant growth in EUS technology in the last few years. According to a study from the EUS Working Group of India presented in abstract form in 2011, there were 72 medical institutions in India having access to EUS equipment, out of which 15 were high-volume centers.13 Approximately two-thirds of EUS procedures were for biliary-pancreatic indications. Approximately two-thirds of EUS procedures were carried out for diagnosis, whereas the rest were for FNA or therapy. In the last 3 years, many more centers across India have started EUS services; however, exact numbers are not available. According to experts and industry estimates, there are approximately 150 EUS installations across the country with an estimated 20% growth predicted every year for the next few years. Despite this broad installation base, there are only about 15 highvolume centers, which carry out more than 300 procedures annually.13 Utilization patterns for EUS in India indicate that approximately two-thirds of EUS procedures are carried out for diagnosis, whereas the rest are for FNA or therapy. Data from India on the role of EUS for biliary-pancreatic diseases is sparse. The majority of Indian publications in the last 4 years have focused on EUS-FNA or EUS-guided therapy.14–21 Two publications, both review articles by the Asian Consortium for EUS, deal with the utility of EUS for diagnosis of solid and cystic pancreatic lesions.22,23 Both emphasize the need for more data on this subject from all Asian countries including India. EUS imaging has improved in the last few years with the development of new technologies – THE, elastography and CH-EUS. The exact clinical impact and positioning of these technologies regarding improved diagnosis are still evolving.
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These latest advances and new functions are relatively new to India. Only a few centers (possibly less than 10) have access to these new advanced technologies. Implementation of these new technologies in India has a few unique challenges.
New EUS technologies in India Tissue harmonic echo Chronic pancreatitis, especially the tropical (non-alcoholic) type, is common in India. EUS imaging for diagnosis of early chronic pancreatitis using B-mode is often confusing as a result of the fact that many healthy individuals have hyperechoic strands or foci within the pancreas. It is as yet unknown whether these hyperechoic strands or foci are pathological features of early chronic pancreatitis or are only a variation of the normal anatomy of the pancreas in healthy Indian subjects. By its ability to reduce artifacts, THE may allow superior imaging of the pancreas in this group of patients, thus improving diagnosis.
EUS-elastography Pancreatic adenocarcinomas are typically hard tumors and therefore show up as hard (blue) areas on elastography. However, elastography has still not been shown to replace FNA in terms of diagnostic accuracy. The other limitation of EUS-elastography is that it is operator dependent and results often depend on the pressure exerted by the transducer on the tissue. In India, where these technologies are new, proper training in carrying out and interpreting elastography may be necessary before this technology can find universal application. At present, elastography remains at best a roadmap to guide the FNA needle in an optimum area to acquire representative tissue for cytology or biopsy.
Contrast harmonic endoscopic ultrasonography An important challenge to the use of CH-EUS in India is the limited availability of ultrasound contrast media. Sonovue™ (Bracco, Milan, Italy) is not readily available and is expensive, limiting its use to a select group of patients. Also, current endosonographers have limited experience in CH-EUS and therefore must be trained to interpret CH-EUS images.
Recommendations on the usefulness of the new functions of EU-ME2 Premier Plus Training of endosonographers for the optimum use of these technologies to obtain and interpret the resulting images is recommended. THE, especially P-mode, is most likely to gain widespread acceptance in near future because of its ease of use and low operator dependence. THE is superior in terms of depiction and observation of pancreatic cystic
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lesions and ductal organs (i.e. bile duct and gallbladder) and appears to be an essential examination technique. However, the effectiveness of THE in terms of improved diagnostic performance remains to be definitively established through multicenter collaborative studies. Indication of current elastography without quantitative function was limited. In the near future, we should re-evaluate this modality with quantitative function. CH-EUS was useful for differential diagnosis in neoplastic lesions. We can obtain additional blood flow information with CH-EUS. However, we can get similar images with CE-CT and can obtain pathological information with EUSFNA. CH-EUS was complementary for both CE-CT and EUS-FNA. Government insurance does not approve this function nor covers the fee of contrast medium. Therefore, indication for CH-EUS is still controversial and it requires a prospective comparative study. Finally, any technological advance must be assessed in light of the clinical benefit that it can provide. Unless these technological advances in EUS imaging can replace tissue sampling, their utility remains limited to providing a roadmap for the optimum site for FNA.
ACKNOWLEDGMENT
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HE AUTHORS ARE indebted to Dr Edward Barroga, Associate Professor and Senior Medical Editor of Tokyo Medical University for reviewing and editing the manuscript.
CONFLICT OF INTERESTS
A
UTHORS DECLARE NO conflict of interests for this article.
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