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Mapping international practice patterns in EUS-guided tissue sampling: outcome of a global survey

Background and study aims: Although Endoscopic Ultrasound (EUS)-guided tissue sampling is widely used, the optimal sampling strategy remains subject of debate. We evaluated practice patterns within the international endosonographic community. Patients and methods: An online questionnaire was sent to 400 endosonographers from the United States, Europe, and Asia. Results: A total of 186 (47 %) endosonographers participated: United States 54 (29 %), Europe 85 (46 %), and Asia 47 (25 %). European (75 %) and Asian (84 %) respondents routinely check coagulation status, whereas US respondents only check on indication (64 %, P = 0.007). While propofol sedation is standard in the United States (83 %), conscious sedation is still widely used in Europe (52 %) and Asia (84 %, P < 0.001). Overall, the 22-gauge needle is most commonly used (52 %). For fine-needle aspiration (FNA) of solid pancreatic lesions, 22-gauge (45 %) and 25-gauge (49 %) needles are used equally. For fine-needle biopsy (FNB) of solid masses, the 25-gauge device is less favored than the 22-gauge FNA device (49 % versus 21 %). The 19-gauge needle is generally used for FNB of submucosal masses (62 %). Rapid on-site pathological evaluation (ROSE) is utilized more often by US (98 %) than by European and Asian respondents (51 %, P < 0.001). Cytolyt (52 %), formalin (15 %) and alcohol (15 %) are used for FNA specimen preservation in the United States and Europe, while saline (27 %) and alcohol (38 %) are widely used in Asia (P < 0.001). Conclusions: EUS-guided tissue sampling practices vary substantially within the international endosonographic community and differ considerably from recommendations expressed in guidelines. Because the clinical relevance of these variations is largely unknown, the outcome of this survey suggests a need for further studies.

Introduction ! Endoscopic ultrasound (EUS)-guided tissue sampling is a safe and accurate modality for diagnosing and staging lesions in and around the gastrointestinal tract [1]. It enables clinicians to obtain a tissue diagnosis during real-time imaging, using fine-needle aspiration (FNA) or fine-needle biopsy (FNB). The diagnostic accuracy of these sampling techniques ranges from 52 % to 98 % and is influenced by several factors including target lesion characteristics, operator skills, needle size and type, sampling techniques, presence of an on-site pathologist, and specimen handling and processing [2 -9]. To provide endosonographers with some guidance, both the American and European Society of Gastrointestinal Endoscopy (ASGE and ESGE) issued a set of guidelines [10 -16]. In 2011, the ESGE published practice guidelines on EUS-guided tissue sampling, covering its indications, learn-ing phase, techniques, complications, and results [11,12]. They were updated in 2013, adding two new techniques; elastography and contrast enhanced ultrasound [16]. The ASGE has issued practice guidelines concerning sedation, antibiotic prophylaxis, and prevention of adverse events. In addition, the Papanicolaou Society of Cytopathology (PSC), one of the leading societies in cancer cytopathology, published guidelines addressing EUS cytology techniques, terminology, ancillary studies, and post-procedure management [17,18].• " Table 1 compares their most important recommendations. Unfortunately, due to the limited number of well-conducted studies in this field, many of these recommendations lack firm scientific evidence. As a result, today's practice mainly relies on local hospital protocols, expert opinions, and personal preferences. Although EUS-guided tissue sampling is globally established, little is known about intercontinental variations in clinical practice. It is also unknown van  Background and study aims: Although Endoscopic Ultrasound (EUS)-guided tissue sampling is widely used, the optimal sampling strategy remains subject of debate. We evaluated practice patterns within the international endosonographic community. Patients and methods: An online questionnaire was sent to 400 endosonographers from the United States, Europe, and Asia. Results: A total of 186 (47 %) endosonographers participated: United States 54 (29 %), Europe 85 (46 %), and Asia 47 (25 %). European (75 %) and Asian (84 %) respondents routinely check coagulation status, whereas US respondents only check on indication (64 %, P = 0.007). While propofol sedation is standard in the United States (83 %), conscious sedation is still widely used in Europe (52 %) and Asia (84 %, P < 0.001). Overall, the 22gauge needle is most commonly used (52 %). For fine-needle aspiration (FNA) of solid pancreatic lesions, 22-gauge (45 %) and 25-gauge (49 %) needles are used equally. For fine-needle biopsy (FNB) of solid masses, the 25-gauge device is less favored than the 22-gauge FNA device (49 % versus 21 %). The 19-gauge needle is generally used for FNB of submucosal masses (62 %). Rapid onsite pathological evaluation (ROSE) is utilized more often by US (98 %) than by European and Asian respondents (51 %, P < 0.001). Cytolyt (52 %), formalin (15 %) and alcohol (15 %) are used for FNA specimen preservation in the United States and Europe, while saline (27 %) and alcohol (38 %) are widely used in Asia (P < 0.001). Conclusions: EUS-guided tissue sampling practices vary substantially within the international endosonographic community and differ considerably from recommendations expressed in guidelines. Because the clinical relevance of these variations is largely unknown, the outcome of this survey suggests a need for further studies.
how available practice guidelines are implemented in current local sampling routines. The purpose of this study, therefore, was to: 1) map the practice patterns in EUS-guided tissue sampling in today's endosonographic community; 2) identify differences and concordances between endosonographers from the United States, Europe and Asia; and 3) compare the current practice patterns to the guidelines of the ASGE and ESGE.

Selection of study subjects
An online questionnaire was sent out per e-mail to endosonographers from the United States, Europe, and Asia. Registered endosonographers were selected by 1) using the personal network of the research team, which consists of national and international experts in the field, and 2) performing a PubMed literature search to identify authors who have published on the topic of EUS-guided tissue sampling in the last 10 years. Not only first authors but all listed authors were approached. Consent to participate in the study was inferred from voluntary completion of the survey.

Questionnaire
The survey consisted of a maximum of 65 multiple-choice questions and was designed to take less than 10 minutes to complete (Appendix 1) and was divided into four sections. The first part focused on demographics including gender, age, country of residence, type and size of current practice, years of experience, training and familiarity with EUS and EUS-guided tissue sam-pling. The second part included questions regarding peri-procedural use of anticoagulants, antibiotics, and sedation. The third part contained questions on preferred equipment and sampling techniques and whether these preferences depend upon target lesion type (pancreatic solid or cystic mass, lymph node or submucosal mass). The final part of the survey examined practice patterns regarding tissue processing and analysis.

Questionnaire administration
All endosonographers were approached by e-mail with a study invitation and were provided with a personal, direct link to the survey. This link was inactivated once the survey was completed. A reminder was sent by e-mail, after 2, 4, and 6 weeks. Subjects who did not respond within 4 weeks thereafter were considered to be non-respondents.

Statistical analysis
Only completed surveys were used for data analysis. For comparison between continents, the Chi-squared or Kruskal Wallis test was applied. All reported P values are two-sided and a value < 0.05 was considered to be significant. Data were analysed with SPSS 22, Statistical Package for the Social Sciences, SPSS Inc., Chicago, Illinois. -EUS-FNA of solid lesions can be performed in patients on aspirin or NSAIDS, but not in patients on thienopyridines.

Antibiotic prophylaxis
-Recommended before sampling of cystic lesions.
-Recommended before sampling of cystic lesions.

Sedation
-Propofol provides more rapid onset of action and shorter recovery time.
No proof of higher patient satisfaction or better safety. Cost-effectiveness for average-risk patients is not proven.
-Propofol provides higher post-procedural patient satisfaction, decreases time to sedation and recovery.
No proof of cost-effectiveness.
-On-site anesthesiologist suggested in presence of patient-related risk factors.
-On-site anesthesiologist suggested in presence of patient-related risk factors.

Preprocedural practice patterns Coagulation status
In preparation for the procedure, most European (75 %) and Asian (84 %) respondents report that they "always check" coagulation status, while their US colleagues generally do so on indication (• " Table 3, P = 0.007). Acetylsalicylic acid is generally continued (77 %), but that differed between continents. US respondents always continue acetylsalicylic acid, as compared to 87 % of Euro-pean and 50 % of Asian respondents (• " Table 3, P < 0.001). Regarding the use of heparin, coumarin, and new oral anticoagulants (NOACs), there is little consensus. While heparin is discontinued by all US and most Asian respondents (94 %), it is stopped by 75 % of the Europeans (P = 0.022). The opposite is true for coumarin, which is stopped more often in Europe (86 %) than in the United States (46 %) and Asia (59 %, P = 0.003). In analogy, European respondents less often perform tissue sampling in patients with an international normalized ratio (INR) > 1.5 (11 %), as compared to non-European respondents (33 %, P = 0.008). Lastly, NOACs are discontinued by virtually all US (91 %) and European (88 %) endosonographers, as compared to 66 % of Asian respondents (P = 0.029).

Antibiotic prophylaxis
In all continents, the majority of respondents use antibiotic prophylaxis for EUS-guided tissue sampling (77 %); mostly depending on the indication (92 %), but some use antibiotics routinely (8 %). Of those endosonographers who report prescribing antibiotics on indication, virtually all use it when sampling a cystic  Original article E362 THIEME lesion (95 %) [12]. A minority prescribes antibiotics for other indications, such as a prosthetic cardiac valve, vascular graft, previous infective endocarditis, or congenital heart disease (< 39 %,• " Table  4). US physicians reported the lowest use of antibiotic prophylaxis.

Sedation and anesthesia
Almost all endosonographers sedate their patients during EUSguided tissue sampling (98 %). Propofol is generally used in the United States (83 %), whereas conscious sedation is still used by 52 % of European and 84 % of Asian respondents (P < 0.001). All US respondents who use propofol have anesthesia personnel in the endoscopy room (100 %), compared to only 66 % in Europe and 50 % in Asia (P < 0.001).

Sampling techniques and equipment
Target lesion size While half of the respondents perform EUS-FNA, regardless of the lesion diameter, the other half has a preferred minimum size of 0.5 cm (32 %), 1 cm (17 %), or 2 cm (1 %). For EUS-FNB, most respondents confine to a minimum size of 1 cm (59 %). European respondents perform EUS-FNB of lesions < 1 cm more often (51 %) than non-European respondents (34 %, P = 0.014). Needle size The gross of respondents prefers a specific needle size for FNA (84 %) and FNB (75 %), depending on the position of the scope or the location of the target lesion (66 %). Overall, the 22-gauge needle is most popular (• " Table 5). However, for FNA of solid pancreatic lesions, 22-gauge (45 %) and 25-gauge (49 %) needles are used equally, and for FNA of submucosal lesions, besides the 22-gauge (44 %), the 19-gauge needle (49 %) is frequently used. For FNB of submucosal masses, most respondents use the 19-gauge needle (62 %). Responses did not differ between continents. Number of passes Generally, respondents perform two to three needle passes for FNA (49 %) and FNB (57 %). Most respondents adjust the number of passes according to the target lesion. In pancreatic cysts, a single pass is performed for FNA (81 %) and FNB (76 %). For FNA of solid pancreatic masses, two to three (46 %) or more than three needle passes are performed (50 %). For FNB of solid pancreatic masses, most respondents report carrying out only two to three passes (70 %). A minority report doing more than three passes (26 %). Asian respondents vary their number of needle passes less often (47 %) than European (69 %) and US respondents (63 %, P = 0.037). Sampling technique Fanning is the preferred needle motion technique for FNA (64 %). For FNB, fanning (44 %) and only moving "to and fro" (46 %) are favored equally. To increase the yield of EUS-FNA, most endosonographers apply suction with a syringe (47 %) or use the slow-pull technique (42 %). Most respondents use dry instead of wet suction (93 %). Also for FNB, most endosonogra-  and Asia (55 %, P < 0.001). Reasons for omitting ROSE included "limited pathology staffing" (74 %), "disbelieve in its additive value" (32 %), "high costs" (24 %), and "additional procedure time" (24 %).
Ancillary techniques The majority of respondents apply the cellblock technique (85 %). In the United States, almost all endosonographers use cellblock (96 %), while it is used to a lesser extent in Europe (85 %) and Asia (70 %, P = 0.002). Immunohistochemical analysis is also available for most respondents (96 %), and generally used for diagnosing and staging submucosal masses (91 %), solid pancreatic lesions (75 %) and lymph nodes (70 %).

!
To the best of our knowledge, no study has investigated practice trends in EUS-FNA guided tissue sampling with respect to the current ASGE and ESGE guidelines. This survey identified substantial intercontinental differences in EUS-guided tissue sampling. Interestingly, some routines vary considerably from the recommendations expressed in existing guidelines. We found that sedation with propofol is custom in the United States, but not in Asia and Europe. In the past, conscious sedation was standard of care, but procedures have become lengthier and more complex, requiring higher doses of sedatives. Propofol is appreciated as an alternative, because it provides a deep level of sedation with a short recovery time. However, costs may be higher, due to the need of aneasthesiological assistance in most countries [13,19,20]. Because cost-effectiveness of sedation with propofol has not been established, the American and European Society of Gastroenterology do not take a stand on this subject [11,13]. Although we did not ask participants for the reasons behind their choice, previous studies have suggested that the increased use of propofol in the United States is caused by: 1) the believe that it improves the diagnostic accuracy of EUS-guided tissue sampling; 2) efforts to offset falling procedure reimbursements; and 3) marketing strategies of anesthesiologists [13,21,22].
The second interesting finding involves differences in anticoagulation and antiplatelet management. While respondents from the United States generally check coagulation status on indication only, European and Asian respondents do this more routinely. Interestingly, the practice of the US respondents, rather than that of the Europeans, seems to follow the ESGE guidelines, which recommend checking coagulation status only in selected patients, that is, those using anticoagulant or antiplatelet therapy or who have a (family) history of a bleeding disorder. Both the ASGE and ESGE recommend not discontinuing acetylsalicylic acid, while all other anticoagulation and antiplatelet therapy should be stopped [12,23]. In contrast to US respondents, not all European and Asian respondents adhere to this recommendation. One explanation might be that US physicians adhere to guidelines more promptly, possibly as a consequence of an increased chance for malpractice claims in the United States [24,25]. The relatively high number of Asian respondents who discontinue acetylsalicylic acid may be a reflection of the fact that bleeding risks are weighted more heavily in Asia. It has been suggested that Asians are more susceptible to bleeding complications, while whites are more at risk for thromboembolic events [26]. However, the Japan Gastroenterological Endoscopy Society has recently revised their guidelines, emphasizing the thromboembolism risks of discontinuation of antithrombotic agents [27]. Therefore, a shift toward continuance of acetylsalicylic acid is to be expected. Another interesting finding of this survey is that for solid pancreatic masses, endosonographers report performing fewer needle passes with FNB than with FNA. This finding is line with recently published data about using FNB to establish a diagnosis in solid pancreatic masses [28 -31]. The ESGE recommends performing at least five passes for FNA of solid pancreatic masses, in the absence of ROSE. Neither the ASGE not the ESGE recommend a minimum number of passes for FNB. Also noteworthy is that, overall, most respondents reported using the 22-gauge needle more often than the 25-gauge needle. This finding is especially interesting, since two recent meta-analyses found no differences between the two needles, with regard to diagnostic accuracy, the number of needle passes, or complications [8,32]. In fact, a trend towards better performance of the 25-gauge needle for FNA of solid pancreatic masses was observed in these studies. The ESGE guideline states that, although there is no difference in diagnostic yield and safety profiles, the 25-gauge needle performs somewhat better with regard to number of required needle passes, presumably due to its higher flexibility [12]. The Papanicolaou Society of Cytopathology (PSC), recommends adapting the needle size to the target lesion. For highly vascular lesions and lymph nodes they recommend a 25-gauge needle, for mucinous cysts a 22-gauge needle, and for fibrotic or stromal-rich lesions, a 19-gauge needle [17]. Another important outcome of this survey is the intercontinental variation in use of rapid on-site pathological evaluation. Whereas virtually all US respondents use ROSE, only half of the European and Asian respondents do. Respondents who refrain from using ROSE state that they consider it too time consuming and that reimbursement for pathology services is too low. However, more than two-thirds of our respondents also mention that they have doubts with regard to the added benefit of ROSE, which might be influenced by ESGE recommendations of the ESGE stating that ROSE should only be implemented at sites where specimen adequacy rates are below 90 % or during the learning curve of EUS-FNA [12,33]. In contrast, the PSC recommends the use of ROSE whenever possible [17]. The last, but certainly not least remarkable finding concerns the preservation of the tissue samples. After procurement, EUS-FNA specimens are susceptible to damage by colonizing bacteria and to autolysis by enzyme activity. To halt these processes, it must be placed in a fixative (e. g., formalin, CytoRich Red, Cytolyt) or physiologic solution (e. g., saline, Hanks' salt solution). Although most of the respondents use formalin to preserve histologic samples, there is no consensus regarding preservation of cytological samples. While a majority of the Asian respondents store cytology in alcohol or saline, their European and US colleagues store it in Cytolyt. Although there are currently no guidelines on this topic, we did not expect to find such striking differences among the three continents. It would be interesting to investigate the influence of preservation methods on the specimen's quality and diagnostic accuracy, as this aspect is under-investigated so far. Our survey has some potential limitations. First, it seems conceivable that our results have been subject to a response bias, given our response rate of 47 %. Although our response rate still falls at the high end of the spectrum of responses for online surveys amongst physicians (1 -10), it might have caused a selection towards the more active, academic endosonographers. Although most respondents indeed reported to work in high-volume academic centers, only 61 % had participated in a formal EUS training program. This could have accounted for the low adherence to the practice guidelines. Currently, the ESGE and ASGE advise that a dedicated fellowship should last 6 to 24 months [12,34]. However, they also acknowledge that there is a lack of sufficient EUStraining and training capacity in Europe and the United States [35,36]. Because most respondents in the current study are EUS experts, the number of formally trained endosonographers and the adherence to the guidelines is likely to be even lower in nonacademic, low-volume centers. Last, a reporting or goodwill bias is likely to exist, since that is inevitable for retrospective surveys that are based on self-reporting. If respondents indeed gave an expected answer rather than a true answer, that would only strengthen our main conclusion that practice patterns for EUSguided tissue sampling differ and are not congruent with the guidelines.
In conclusion, this survey shows that there is considerable intercontinental variation in the practice of EUS-guided tissue sampling. Despite of the growing number of studies in the field of EUS-guided tissue sampling, the optimal sampling strategy remains subject to debate. Moreover, some routines vary considerably from recommendations stated in existing guidelines. Further studies are required to determine the relevance and impact of various practices on outcome and safety. Pending these outcomes, cost-effectiveness studies may be required to support the implementation of a certain sampling strategies.