Herausgeber/Editor T. Seufferlein, Halle (Saale) Mitherausgeber/Co-Editor M. M. Dollinger, Halle (Saale) Redaktionsassistenz A. Berger, Halle (Saale)

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1 Zeitschrift für Gastroenterologie Sonderdruck für private Zwecke des Autors Offizielles Organ: Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten mit Sektion Gastroenterologische Endoskopie Gesellschaften: Österreichische Gesellschaft und Hepatologie Ungarische Gesellschaft und Hepatologie Norddeutsche Gesellschaft Gesellschaft Nordrhein-Westfalen Gesellschaft in Westfalen Südwestdeutsche Gesellschaft Gastroenterologische Arbeitsgemeinschaft Rheinland-Pfalz/ Saarland (GARPS) Gesellschaft in Bayern Mitteldeutsche Gesellschaft für Gastroenterologie Herausgeber/Editor T. Seufferlein, Halle (Saale) Mitherausgeber/Co-Editor M. M. Dollinger, Halle (Saale) Redaktionsassistenz A. Berger, Halle (Saale) Kooptierende Herausgeber/ Coopting Editors M. Trauner, Wien Z. Tulassay, Budapest Schriftleitung/Section Editors Berufsfragen/Weiterbildung: W. Schepp, München Chronisch entzündliche Darmerkrankungen: A. Stallmach, Jena Chirurgie: J. Werner, Heidelberg Endoskopie: R. Kiesslich, Mainz Kasuistiken: J. Mössner, Leipzig Kommentierte Referate: S. Müller-Lissner, Berlin Leber: S. Zeuzem, Frankfurt Ösophagus/Magen: P. Malfertheiner, Magdeburg Redaktionskomitee/ Editorial committee H.-D. Allescher, Garmisch-Partenkirchen C. Bruns, München M. Büchler, Heidelberg S. Feuerbach, Regensburg H. Koop, Berlin M. Lerch, Greifswald M. P. Manns, Hannover A. May, Wiesbaden M. Reinshagen, Braunschweig E. Roeb, Gießen R. M. Schmid, München A. Tannapfel, Bochum Indexed in Current Contents/Biosis Excerpta Medica/Embase Index Internacional de Gastroenterologia Index medicus/medline Impact Factor: Zeitschrift im Internet: Verlag Georg Thieme Verlag KG Rüdigerstraße Stuttgart Onkologie: A. Reinacher-Schick, Bochum Pädiatrische Gastroenterologie: H. Witt, München Sonografie: C. F. Dietrich, Bad Mergentheim Stoffwechsel: W. E. Schmidt, Bochum

2 Originalarbeit 199 Advanced Endosonographic Diagnostic Tools for Discrimination of Focal Chronic Pancreatitis and Pancreatic Carcinoma Elastography, Contrast Enhanced High Mechanical Index (CEHMI) and Low Mechanical Index (CELMI) Endosonography in Direct Comparison b Kontrastverstärkte Endosonografie mit 3D-Rekonstruktion zur Diagnostik der autoimmunen Pankreatitis Authors M. Hocke 1, A. Ignee 2, C. F. Dietrich 2 Affiliations Key words " gastroenteropancreatic tumours " endoscopic sonography " contrast media " pancreas " ultrasound elastography " Schlüsselwörter " Gastro-entero-pankreatische Tumoren " Endosonografie " Kontrastmittel " Pankreas " Sonografie Elastografie " received accepted Bibliography DOI /s Z Gastroenterol 2012; 50: Georg Thieme Verlag KG Stuttgart New York ISSN Correspondence PD Dr. Michael Hocke Department of Internal Medicine II, Hospital Meiningen Bergstraße Bad Meiningen Germany Tel.: ++49/3693/ Fax: ++49/3693/ Michael.hocke@klinikummeiningen.de 1 Department of Internal Medicine II, Hospital Meiningen, Bad Meiningen, Germany 2 Department of Internal Medicine II, Caritas Hospital, Bad Mergentheim, Germany Abstract New tools have recently emerged that further improve the diagnostic performance of high-end endosonography. Whilst elastography has been available for a while, contrast-enhancing techniques are still very young with little experience existing in this field. The latest development is contrast enhanced low mechanical index endosonography (CELMI-EUS) which became commercially available at the beginning of This technique requires contrast-specific software whereas the pre-existing technique of contrastenhanced high mechanical index endosonography (CEHMI-EUS) does not. The aim of this study was to compare these techniques in discriminating between focal chronic pancreatitis and pancreatic carcinoma. Included in the study were 58 patients with a pancreatic lesion (19 pancreatic cancer and 39 chronic pancreatitis) with a mean age of 60 ± 15 years. All patients were examined by one investigator (MH). All methods were performed within one examination and the result of each technique was noted before using the next. The gold standard was pathology following surgery, endoscopic fine-needle puncture, or oneyear follow-up when chronic pancreatitis was suspected. The consecutive results of specificity and sensitivity were 73.7 % and 61.5 % for B- mode endosonography; 94.7 % and 33.4 % for elastography; 84.2 % and 76.9 % for CELMI-EUS; and 89.5 % and 92.3 % for CEHMI-EUS. A combination of 3 of those methods could not improve on the result of CEHMI-EUS alone. This study shows that, despite the availability of new technologies, CEHMI-EUS is still the most reliable method for the differentiation of focal chronic pancreatitis and pancreatic carcinoma. However, understanding the advantages of the different methods might help to find the optimal indications for the use of the new techniques. Zusammenfassung Neue Möglichkeiten in der technischen Entwicklung haben die Endosonografie in der letzten Zeit vorangetrieben. Während mittlerweile Verfahren wie die Elastografie schon als etabliert gelten, sind die kontrastmittelvermittelten Verfahren jedoch weiterhin als neu zu betrachten, über deren Bedeutung auch bisher wenig bekannt ist. Die jüngste Entwicklung dabei entspricht der Endosonografie mit niedrig mechanischem Index (CELMI-EUS), welche kommerziell erst 2010 verfügbar wurde. Diese Technik erfordert eine spezielle Kontrastmittelsoftware, welches sie von der bisher ausgeübten kontrastverstärkten Endosonografie mit hohem mechanischen Index (CEHMI-EUS) unterscheidet. Der Sinn unserer Studie war, zu prüfen, welche Wertigkeit die einzelnen diagnostischen Tools bei der Unterscheidung von fokaler chronischer Pankreatitis vom Pankreaskarzinom besitzen. In unsere Studie wurde 58 Patienten im Alter von 60 ± 15 Jahren mit fokalen Pankreasläsionen eingeschlossen (19 Pankreaskarzinom und 39 chronische Pankreatitis). Alle Patienten wurden durch denselben Untersucher untersucht (MH). Alle Techniken kamen in einem Untersuchungsgang zur Anwendung und die Diagnosestellung erfolgte jeweils nach Abschluss eines Untersuchungsgangs. Als Goldstandard fungierte die postoperative Pathologie, das Resultat der Feinnadelpunktion und ein 1- jähriges Follow-up bei Patienten mit chronischer Pankreatitis. Die Spezifität und Sensitivität der einzelnen Verfahren betrugen für die B-mode Endosonografie 73,3% und 61,5%, für die Elastografie 94,7% und 33,4%, für die CELMI-EUS 84,2% und 76,9% und für die CEHMI-EUS 89,5% und 92,3%. Die Kombination von 3 dieser Methoden konnte das vom CEHMI-EUS erzielte Resultat nicht weiter verbessern. Die Studie konnte zeigen, dass der Wert der Gefäßanalyse mithilfe der kontrastverstärkten Endosonografie im Modus mit hohem mechanischen Index immer noch das zuverläs-

3 200 Originalarbeit sigste Verfahren zur Unterscheidung von fokaler chronischer Pankreatitis vom Pankreaskarzinom darstellt. Das Verständnis der Vorteile der neuen Verfahren eröffnet jedoch mit Sicherheit neue Indikationsstellungen für neue Verfahren wie die kontrastverstärkte Endosonografie im niedrig mechanischen Index-Modus. b The differentiation of focal chronic pancreatitis from pancreatic cancer is still a major challenge in clinical medicine [1 3]. In the last few years, endosonography has been shown to be useful as a tool that adds to the diagnostic options [4, 5]. New techniques have evolved that offer additional information to B-mode ultrasound. Elastography is able to measure tissue stiffness and has been seen as the method of choice to discriminate between malignant and benign tissue [6]. The combination of power Doppler or colour Doppler endosonography in high mechanical index mode (CEHMI-EUS) with the application of an ultrasound contrast agent reveals the unique behaviour of tissue vascularisation and has therefore also proved useful for discrimination [7 9]. The latest commercially available technique is contrast-enhanced low mechanical index endosonography (CELMI-EUS) which allows observation of contrast enhancer inflow in the pancreatic microvessels without bubble destruction [10 12]. In this preliminary study, we tried to determine which of these new techniques is the most reliable to differentiate between chronic inflammatory processes of the pancreas and ductal adenocarcinoma of the pancreas, the most common malignant tumour. Introduction Patients and Methods We included 58 consecutive patients (Jan to Dec. 2010) in our study (39 male, 19 female) with a mean age of 60 ± 15 years. All patients were suspected of having a solid pancreatic tumour from a previous abdominal ultrasound or CT scan, without a definitive diagnosis. Because of the secondary referral status of the investigator, the ultrasound and CT scans were mostly done outside the hospital and so were not part of the present study. The procedure was always performed in the same way, using a Hitachi HI VISION Preirus ultrasound machine in combination with a Pentax endoscopic ultrasound probe, with the patient under sedation with disoprivane. Using endoscopic ultrasound, the lesion was targeted and measured. The lesion was diagnosed with B-mode ultrasound using the criteria previously published [7]. After this diagnosis, the lesion was analysed with the help of elastography, comparing the lesion to the surrounding normal pancreatic tissue where possible. Mostly blue coding of the lesion, noted over a period of 2 minutes, was classified as pancreatic cancer, mostly red and green coding of the lesion over a period of 2 minutes was classified as focal chronic pancreatitis. The next analysis involved contrast-enhanced low mechanical index endosonography. The machine was switched into the low mechanical index mode (commercial software of Hitachi) and 4.8 ml of Sonovue (Bracco, Italy) were injected followed by a flush with 10 ml saline. The analysis was made over a period of another 2 minutes following the visible influx of the contrast agent. Hypo-enhancement in comparison to the surrounding pancreatic tissue was considered an indication of pancreatic cancer and iso- or hyper-enhancement was considered to be focal chronic pancreatitis. Following this analysis, the machine was switched into high mechanical index mode with the settings previously described [9]. A further 4.8 ml of Sonovue were injected followed by another 10 ml saline flush and the vessel analysis was made with the help of the colour Doppler mode and PW Doppler analysis over a further period of 2 minutes after the influx of the contrast enhancer. Finally, if necessary, the lesion was punctured with help of a 22-G endoscopic ultrasound needle to acquire a cytological specimen for further analysis. When the diagnostic procedure in total had become too long and the patient became unsettled, the fine needle puncture of the lesion was postponed to the following day. The surgical decision was made referring to the results of all diagnostic procedures, favouring the CEHMI-EUS result where discrepancies existed since this was the method which proved to be the most reliable. 20 of the 58 patients received surgery and the pathological result was used as the gold standard. If operation was not an option, endoscopic fine needle cytology was performed and, in the cases of suspected chronic pancreatitis, a follow-up of at least 6 months was made. According to the results the sensitivity and specificity of every method were calculated. In a second step the sensitivity and specificity of a combination of methods were calculated. The combinations used were: B-mode endosonography + elastography + CELMI-EUS; B-mode endosonography + elastography + CEHMI- EUS; elastography + CELMI-EUS + CEHMI-EUS and B-mode endosonography + CEHMI-EUS + CELMI-EUS. In those calculations at least two concordant results estimated the final result. Results Fourteen of 19 patients with pancreatic cancer and 24 of 39 patients with chronic pancreatitis were correctly classified with B- mode endosonography. Using elastography, according to the stiffness of the lesion, nearly all the pancreatic cancer patients were classified correctly (18 of 19). However, elastography failed to correctly classify the patients with chronic pancreatitis with only 13 of 39 patients identified. Contrast-enhanced low mechanical index endosonography achieved reliable results with the correct diagnosis of 16 of 19 patients with pancreatic cancer and 30 of 39 patients with chronic pancreatitis. The overall best modality was, however, contrast-enhanced high mechanical index endosonography with PW Doppler analysis which correctly diagnosed 17 of 19 patients with pancreatic cancer and 36 of 39 patients with chronic pancreatitis. The results are summarized in " Table 1. In a second step we tested if the result could be improved by combination of the methods used. Using the combinations B-mode + elastography + CEHMI-EUS achieved a sensitivity of 89.5 % and specificity of 59.0 %. B-mode + elastography + CELMI-EUS achieved a sensitivity of 89.5 % and specificity of 64.1 % and elastography + CELMI-EUS + CEHMI-EUS achieved a sensitivity of 94.7 % and a specificity of 74.3 %. The best result was achieved by the combination of B-mode + CELMI-EUS + CEHMI + EUS with a

4 Originalarbeit 201 B-mode elastography CELMI CEHMI pancreatic cancer wrongly diagnosed correctly diagnosed chronic focal pancreatitis wrongly diagnosed correctly diagnosed sensitivity specificity Table1 Results of the diagnostic methods in direct competition. btable2 B-mode + Elasto + CELMI B-mode + Elasto + CEHMI Elasto + CELMI + CEHMI pancreatic cancer wrongly diagnosed correctly diagnosed chronic focal pancreatitis wrongly diagnosed correctly diagnosed sensitivity specificity B-mode + CEHMI + CELMI Results of combined methods for discrimination of chronic pancreatitis and pancreatic carcinoma, at least two concordant methods ruled the result of the combination. Fig. 1 a Elastographic image of a pancreatic carcinoma, the surrounding tissue appears softer (coded red and green) then the tumour itself (mostly coded blue). b Contrast enhanced low mechanical index endosonographic image of the same tumour, the surrounding tissue takes up the contrast agent whereas in the tumour no contrast enhancement is visible. In the middle of the picture collaterals are visible. c Contrast enhanced high mechanical index endosonography with PW Doppler analysis of the same tumour. Only two vessels are enhanced within the lesion in colour Doppler ultrasound and both vessels showed arterial signals. No venous signal could be detected within the tumour.

5 202 Originalarbeit b specificity of 94.7 % and a sensitivity of 84.6 %. The results are summarized in " Table 2. A typical picture sequence of correctly diagnosed pancreatic cancer and chronic pancreatitis is shown in " Fig. 1 and " Fig. 2. Fig. 2 a Elastographic image of a focal chronic pancreatitis, the pseudotumour itself is mostly coded green and red indicating soft tissue. b Contrast enhanced low mechanical index endosonography of the same lesion, a clear contrast uptake can be visualised. c Contrast enhanced high mechanical Discussion An indeterminate pancreatic lesion is still a challenge in clinical practice. However, all diagnostic tools have significantly improved in the last few years and as a result, cystic lesions and occasionally, tumours are not as hard to differentiate from pancreatic adenocarcinoma as they were a quarter of a century ago [13, 14]. However, we still face the challenge of discrimination of focal inflammatory processes from adenocarcinomas because of the multiple similarities of these lesions [15]. This is the reason behind the development of even more exciting techniques in all diagnostic areas of medicine. Endosonography still has the advantage of the highest resolution in comparison to all other methods [16]. However, until recently we were lacking a vital tool that is already a standard method in percutaneous index endosonography with PW Doppler analysis. A clear venous vessel spectrum is visible. Because the vessel analysis did not pick up the venous vessel in the first 40 seconds, the typical netlike vessel system of the lesion is already fading in this picture. ultrasound, this is the technique of contrast-enhanced ultrasound [17, 18]. Low mechanical index contrast-enhanced ultrasound should be able to produce similar contrast-enhancing behaviour in a lesion as those seen by CT or MRI scans. The advantage of having the possibility of low mechanical index contrast ultrasound with a high frequency probe as used in endosonography is being able to combine a high resolution method with a real-time contrast enhancing method [19]. Because there is little knowledge of the value of all three modern methods (elastography, CELMI and CEHMI-EUS), we aimed to make a direct comparison of them in the differentiation of focal chronic pancreatitis and pancreatic carcinoma. According to the literature, B-mode endoscopic ultrasound is not able to discriminate these two pancreatic diseases from each other. Additionally, elastography has not proved useful in differentiation according to the literature [20, 21]. In our study we observed a high sensitivity for this method, however, the specificity was very low and therefore the technique cannot be recommended in clinical practice. It has to be mentioned that the specificity in our study was markedly lower than in a recently published multi-centre study, this might be due to the fact that in our study

6 Originalarbeit 203 no post-processing software was used, and we did not include as many patients [22]. Other study groups achieved even higher accuracy but in those studies patients with chronic pancreatitis were not included [23]. The major problem with elastography imaging in this setting is the hard nature of the pancreatic tissue of some patients with chronic pancreatitis. Some studies indicate that this behaviour could be a factor of time from onset of the disease, as bthe tissue stiffens due to the increase of fibrotic tissue as repair mechanisms [24, 25]. In our study CELMI-EUS seems to be an option for discrimination of focal chronic pancreatitis from adenocarcinoma of the pancreas. However, in some patients with chronic pancreatitis, the method failed because of the lack of a contrast-enhancing effect. We suspect that those patients had a high percentage of fibrotic tissue within the lesion and therefore could not take up the contrast agent. The method also failed in the 3 patients who had a hyper-enhancing pancreatic cancer. The combination of 3 methods could not improve the overall result of the CEHMI-EUS alone. In our study the most reliable combination with a slightly increased sensitivity in comparison to the CEHMI-EUS was the combination of B-mode endosonography, CEHMI and CELMI-EUS. Despite the progress of elastography and CELMI-EUS, CEHMI-EUS proved the most reliable in direct comparison with the other methods and even with a combination of methods. Exploring the unique behaviour of the vascularisation by using CEHMI-EUS still seems to be the best discriminatory method. In our opinion, further development of this method would be worthwhile. It should be mentioned that the design of the study with just one investigator could have had an influence to the results. The advantage of the setting used was a high grade of standardisation in the use of the different methods. The disadvantage might be the knowledge of the investigator of the result of the previous used method. To minimise the influence of that knowledge, all investigations were stored as video frames and could be analysed by a second reader later on. CELMI-EUS however does have a clear indication in EUS diagnosis, for example, for discrimination of cystic lesions of the pancreas. Visualising the contrast-enhancing effect of the cystic wall is much easier using CELMI-EUS then any other method and should be the method of choice in the future. Ongoing studies on the topic will demonstrate this. References 01 Pickartz T, Mayerle J, Kraft M et al. Chronic pancreatitis as a risk factor for the development of pancreatic cancer diagnostic challenges. Med Klin 2010; 105: (in German). 02 Wang J, Su T, Jia N et al. Computed tomographic and magnetic resonance imaging presentations of pancreatitis maldiagnosed as pancreatic carcinoma. Pancreas 2010; 39: Boll DT, Merkle EM. 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