Current practice with endoscopic submucosal dissection in Europe: position statement from a panel of experts

• Introduction
• Current practice of upper and lower gastrointestinal ESD in Europe
• Training in ESD
• Quality standards
• Guidelines for ESD
• Registries
• Discussion with the Japanese experts
• Conclusions
• Acknowledgments
• References

Endoscopic submucosal dissection (ESD) is the gold standard technique for performing en bloc resection of large superficial tumors in the upper and lower gastrointestinal tract. Experience in Europe, however, is still limited and ESD is only performed in a few selected centers, with low volumes of cases, no description of training programs, and few published reports. In 2008, a panel of experts gathered in Rotterdam to discuss indications, training, and the wider use of ESD. The panel of experts and participants reached a consensus on five general statements: 1) ESD aims at treating mucosal cancer; 2) treatment aims for R0 resection; 3) ESD should meet quality standards; 4) ESD should be performed following national or European Society of Gastrointestinal Endoscopy (ESGE) guidelines or under institutional review board approval; and 5) ESD cases should be registered. Due to the high level of expertise needed to perform the technique safely, ESD should be performed in a step-up approach, starting with lesions presenting in the rectum or in the distal stomach, then colon, proximal stomach, and finally in the esophagus. Registration is advised either at the local site or at a national or ESGE level, and should include information on indication (Paris classification of lesion, location, and histological results prior to treatment), technique used (e. g. type of knife), results (en bloc and R0 resection), complications, and follow-up. The panel also agreed on minimal institutional requirements: good quality imaging, experienced histopathologist following the Japanese criteria (2-mm sections, micrometric invasion, vessel and lymphatic infiltration, etc), and dedicated endoscopic follow-up. Moreover, minimum training requirements were also defined: knowledge in indications and instruments, exposure to experts (currently all in Japan), hands-on experience in a model of isolated pig stomach and in live pigs, and management of complications. The experts did not reach a consensus on a minimum case load, or whether the technique should be restricted to expert centers.

Introduction

Endoscopic mucosal resection (EMR) was developed in Eastern countries such as Japan and Korea as a curative treatment for superficial carcinomas in the stomach and esophagus. In a 1984 publication, Tada et al. described for the first time the use of “strip-off biopsy” as a treatment option in early gastric carcinoma [1]. This was the start of the gradual acceptance of EMR as a therapeutic and diagnostic procedure in the upper gastrointestinal tract. The first EMR procedures for early esophageal carcinoma were carried out in the early 1990 s, again by Japanese endoscopists [2] [3]. It was only several years later that the first Western research groups published their experience with EMR for esophageal neoplasia [4] [5]. The reasons might have been fewer diagnoses of early cancers and a more frequent use of ablation techniques, such as argon plasma coagulation and photodynamic therapy.

The terms “EMR” or “mucosectomy” are in fact inappropriate, as resection includes a part of the submucosa. They should therefore be replaced by the term “endoscopic resection.” Different techniques have been developed for piecemeal or “en bloc” resection, such as cap assisted resection, band ligation, or more recently endoscopic submucosal dissection (ESD) and full thickness resection.

The ESD technique is a new endoscopic method using cutting devices, which removes the lesion by the following three steps: injection of fluid into the submucosa to elevate the lesion from the muscle layer; then precut of the surrounding mucosa of the lesion; and finally, dissection of the submucosal connective tissue beneath the lesion [6]. The major advantages of this technique compared with conventional EMR are that: the resected size and shape can be controlled; en bloc resection is possible even in a large lesion; and the lesions with ulcerative findings are also resectable. Nowadays, several knives, such as needle knife [7] [8], insulated tipped knife [9], hook-knife [10], triangle tipped knife [11], flex-knife [12], and flush-knife are available for ESD. In the largest prospective study published to date on this technique, en bloc removal was achieved in 89 % of the lesions if the lesions did not exceed 20 mm in diameter. From the point of view of tumor pathology, en bloc resection is certainly the ideal procedure [13] [14] [15].

Experience in ESD in European countries is still limited. Most endoscopists who carry out ESD were trained in Japan and are now slowly spreading their expertise in the Western world. ESD is performed in very few selected centers, with low volumes of cases, minimal training programs, and few published reports. It was therefore suggested that a meeting between European experts in ESD should be organized (“Experts meet experts,” Rotterdam, The Netherlands, 11 – 12 February 2008). The aims of the meeting were to discuss the current practice in upper gastrointestinal and colorectal ESD in Europe, the training program requirements, the role of registries, and to propose some guidelines or statements for proper and safe use of this promising technique. The questions specifically raised were as follows.

• Should ESD be performed only after prior experience with conventional EMR? What minimum number of total endoscopic resection procedures should be performed?

• Should ESD be performed only under formal guidelines/institutional review board (IRB) protocols?

• What are the minimum training requirements in terms of number of procedures attended, number of hands-on courses, and the need for supervised procedures?

• Is there a stepwise approach for ESD training? How many gastric/rectal ESD procedures should be performed before procedures in the colon and esophagus are attempted?

• Can we define a minimum yearly case load?

• Should all cases be centrally registered?

Current practice of upper and lower gastrointestinal ESD in Europe

Dr. Mario Ribeiro (Porto, Portugal) reviewed all databases (Pubmed and Institute for Scientific Information [ISI], and proceedings from United European Gastroenterology Week [UEGW] and Digestive Diseases Week [DDW]) and questioned ESD experts on their personal experience. The results focused on indications, type and location of the lesions, results of R0, en bloc resections, recurrences, and complications such as bleeding and perforations. Only a handful of abstracts and two full papers were found describing limited case series [16] [17] [18] [19] [20]. All ESD experts had practiced EMR before carrying out ESD procedures. The responses showed that most esophageal lesions are removed by EMR and not ESD techniques and that the ESD practice is limited to under 30 cases among experts present at the meeting [21]. In the stomach, more than 50 cases had been reported in 2008 [19] [20] and about 70 patients had been treated by the experts at the meeting. Feasibility rates were between 75 % and 100 %, R0 resection was performed in more than 85 % of cases, and en bloc was successful in 80 %, with complications rates between 10 % and 20 %. These results are comparable to the Japanese experience reporting R0 (i. e. clear resection margins) and en bloc resections in more than 80 %, complication rates of ∼12 %, and low recurrence rates after en bloc ESD [15] [22] [23] [24].

The report on colonic and rectal ESD was presented by Dr. Alessandro Repici (Milan, Italy) who explained that colonic lesions are usually larger than upper gastrointestinal lesions, they are more frequently elevated, the colonic wall is thinner with a higher risk of perforation, the vascular network is different with lower bleeding risk, and there is less room for scope maneuverability and retroflexed vision. Reports on colonic ESD in Europe are still limited to his own series [25] [26] and case series from Belgium and the UK [27] [28] [29].

Training in ESD

ESD is a complex interventional procedure involving several risks and diverse instrumentation. There are both endoscopic and oncologic limitations, and a limited number of suitable patients are available, the result being that the procedure should only be performed by an experienced interventional endoscopist. The learning curve from novice level, to learner, competent, proficient, and finally expert levels should be as steep as possible and supported by adequate training programs. Dr. Jelle Haringsma (Rotterdam, The Netherlands) proposed structured training with the following steps:

• acquire basic knowledge

• see experts at work, namely in Japan

• assist in procedures

• training on animal models – isolated pig stomach and live pigs

• procedures on patients

• continued training.

Basic knowledge means disease knowledge, instrument knowledge, use of the electrosurgical unit, and familiarity with indications, limitations, risks, and outcomes of ESD. At present, training on models mainly relies on the pig model, which is comparable in size and wall structure with some differences in the mucosal thickness, submucosal suppleness, and different electrocoagulation settings than in clinical human practice. In animal models, a minimum of 30 resections reaching a resection speed of 30 minutes for a lesion with maximum diameter of 5 cm, and management of complications, were suggested as aims of training.

Emphasis is also put on a training continuum with books, DVDs, journals, conferences, live demonstrations (master classes and courses), and visits to expert centers.

The impact of the learning curve on R0 and en bloc resection was illustrated by the Klinikum Augsburg experience on more than 71 ESD procedures [30] [31]. During the early experience (2003 – 2006) to the more expert phase of treatment (2007) the en bloc resection rate increased from 77.1 % to 86.1 %, and R0 from 65 % to 72 % of procedures, respectively.

The role of adequate training is of course to influence the spread of this technique in Europe, to set standards for training and certification, to promote quality management, and to limit complications inherent to early learning.

Quality standards

Clinical results were summarized by Dr. Jacques Bergman (Amsterdam, The Netherlands). Results are mainly reported as Japanese series, with high rates of complete en bloc resections, and remarkably few complications, most of which were managed endoscopically [32]. ESD is technically demanding and the average procedure time is measured in hours rather than minutes. Endoscopic resection is widely performed in Japan and it is therefore easier for young endoscopists to learn the technique. The difficulty of the ESD technique largely depends on location and size of the lesion, and the presence of fibrosis [33]. The rate of curative en bloc resection, the procedure times, and the perforation rates were shown to be significantly lower in the lower part of the stomach compared with the middle and upper parts. Lesions located in the distal stomach and rectum may be easier and safer to treat using ESD during the learning curve [15]. Once expertise is reached in these locations, endoscopists in training may move to the proximal stomach and finally to the colon and esophagus. Most experts in Japan set the level of expertise at 50 cases to be proficient [34]. In Europe, however, most superficial lesions arise in Barrett’s mucosa and in the colon. In these locations other techniques are competing with ESD. The question, therefore, is how do endoscopists learn ESD in Europe? It seems it would take more than 5 years even in high volume centers to collect 50 gastric ESD cases, as early gastric cancers are rare in the distal stomach. One might therefore suggest abandoning ESD in Europe; however, most endoscopic experts are well aware that ESD is an important evolutionary step in endoscopic surgery, bringing new ideas, skills, devices, and disposables that will take therapeutic endoscopy to a higher level.

How can we propose quality control and guidelines for ESD if we have no guidelines for endoscopic treatment of early neoplasia in general? We should start with the basics: ESD should follow a national guideline or an IRB-approved research protocol; in cases where there is none, ESD should only be performed under IRB approval (comparable with guidelines for natural orifice transluminal endoscopic surgery). Proposed guidelines should include IRB approval, good quality imaging, an experienced histopathologist available, a dedicated endoscopic follow-up, a training program, a minimum case load per year (10 – 20 ESDs per year was suggested), and prospective registration (ideally a centralized registry). Quality control for ESD should provide some guarantee that the right endoscopists are doing the appropriate procedures for their level of expertise.

At a minimum, a “position statement” should be proposed in the absence of national or European guidelines. This statement should include the minimum training requirements, stepwise expansion of ESD (distal stomach or rectum as a first step and esophagus and colon as a second step), and prospective registration.

Guidelines for ESD

Dr. Thierry Ponchon (Lyon, France) questioned the place and setting of ESD guidelines, as there are currently no guidelines for EMR and also because we cannot strictly recommend ESD at present without appropriate training and expertise in Europe. Even if we cannot recommend ESD, ESD is an optimal option in some cases and ESD has some advantages over EMR. At the very least, if we do not strictly recommend ESD, we must distinguish endoscopic treatment aiming at R0 (clear margins) from endoscopic treatment not aiming at R0. Piecemeal resection does not aim for R0 resection, as lateral and deep margins cannot be properly assessed by the pathologist. What are the risks associated with not achieving an R0 resection: a higher risk of recurrence [22] [23], and the risk of leaving in situ or destroying an invasive carcinoma. Indeed the risk of recurrence increases with the diameter of the lesion and with a piecemeal rather than en bloc removal of a tumor [14] [35] [36] [37] [38] [39] [40] [41]. This is a relative risk and follow-up must be organized. Leaving an invasive carcinoma in place or destroying an invasive carcinoma is more damaging because it induces a risk of lymph node metastasis. This risk will depend on the depth of invasion of the submucosa (1000 µm in the colon and 500 µm in the stomach). Guidelines for ESD should therefore form part of European Society of Gastrointestinal Endoscopy (ESGE) or international guidelines on EMR, defining indications in the various parts of the digestive tract, and separating when we should aim for an R0 resection and specifically use ESD. Guidelines for ESD should also cover guidelines on pathological examination of the specimen, including longitudinal sections every 2 mm, micrometric measurement of the depth of invasion, and vessel and lymphatic infiltration.

Registries

Dr. Soren Meisner (Copenhagen, Denmark) underlined the advantages and disadvantages of cohort studies (registries). The advantages of registries are that:

• they are ethically safe

• subjects can be matched

• they can establish timing and directionality of events

• eligibility criteria and outcome assessments can be standardized

• they are administratively easier and cheaper than a randomized controlled trial (RCT).

The disadvantages are that:

• controls may be difficult to identify

• exposure may be linked to a hidden confounder

• blinding is difficult

• randomization is not present

• for rare disease, large sample sizes or long follow-up are necessary.

Cohort studies will provide level 2b evidence in evaluation of therapy. A registry such as the ESD registry proposed at the ESGE research Committee (www.esge.com/research.html) might provide the opportunity of establishing timing and directionality of events (bleeding, perforation, stricture, recurrence, sedation related complications, etc.). Eligibility criteria and outcome assessments can be standardized (ESD: pathology, adjuvant therapy, follow-up schedules etc.), and a registry is administratively easier and cheaper than conducting an RCT. The registry should however be user-friendly and avoid the use of too strict criteria.

Discussion with the Japanese experts

ESD has definite advantages over EMR: large en bloc resections, fewer local recurrences, and more precise and complete histological assessment [15] [36] [42] [43] [44] [45] [46]. Dr. Takuji Gotoda summarized the expansion of indications for resection to larger or deeper lesions with a low risk of metastasis [42]. In the stomach no lymph nodes were seen in large series of patients with intestinal well differentiated mucosal cancer without ulcer and no size limit, with ulcer with size less than 30 mm, and in patients with submucosal cancer limited to sm1 infiltration (< 500 µm deep in the submucosa starting from the muscularis mucosae) and less than 30 mm in diameter [47].

Drs. Tsuneo Oyama and Akiko Takahashi explained that in the esophagus, squamous cell carcinoma staged m1 (carcinoma in situ) or m2 have a zero risk of lymph node metastasis. According to the Japan Esophageal Society 2002 guidelines for the treatment of esophageal cancer (www.esophagus.jp/pdf_files/esophagus200212.pdf), the absolute indication for EMR is therefore defined as m1-m2 esophageal cancer, whereas the relative indication is defined as m3-sm1 esophageal cancer. The incidence of lymph node metastasis of esophageal cancer relates closely to the depth of invasion, vascular invasion, and tissue type. Invasion of the muscularis mucosae (m3) carries a risk of 9.3 % and submucosal invasion a risk from 19 % (sm1) to 54 % (sm2 – 3) [10]. En bloc resection is essential for investigating these parameters. The rate of en bloc resection of esophageal EMR was as low as 23 % – 57 % because the resected area was limited to 15.1 – 23.9 mm. Conversely, en bloc resection was achieved in 95 % of ESD procedures and the perforation rate was low at 0 %. Piecemeal resection may not permit an adequate histopathological examination and may cause a high local recurrence rate.

For Barrett’s adenocarcinoma, as for gastric cancer, mucosal lesions have no risk of lymph node metastasis. The data in cases of submucosal invasion are more contradictory, with some authors reporting a high rate of 41 % for lymph node metastasis [48] and others [49] [50] reporting a low risk for sm1 invasion, similar to that in gastric cancer.

In the colon ESD has some advantages, such as better control of the shape and size of the resected specimen, and the possibility to perform en bloc and R0 resections even for large tumors or tumors that lift poorly due to fibrosis. The recurrence rate can be decreased to 0 % with ESD compared with 18 % for piecemeal EMR. But ESD does carry some disadvantages too: it requires two or more assistants, it is a time consuming procedure, and it carries a higher risk of bleeding and a slightly higher probability of perforation. The procedure time has been compared in the treatment of colorectal neoplasia at the National Cancer Center in Tokyo: operation time increased from 29 minutes (range 3 – 120 minutes) with EMR to 100 minutes (18 – 390 minutes) with ESD [15]. The results in colonic ESD were presented by Dr. Mitsuhiro Fujishiro. En bloc resection rate was 93.0 %; delayed bleeding was 0.8 %; blood transfusion rate was 0.4 %; perforation occurred in 5.4 % (immediate 5.0 %, delayed 0.4 % needing laparotomy); local recurrence occurred in 1.7 %; and distant recurrence in 0 %; there were no colorectal cancer related deaths [24]. Some complications may be preventable by technical improvements and accumulation of knowledge. Most complications may be rescued by appropriate endoscopic therapy with intensive medical management. However, there is no way to prevent and manage the rare complication of delayed perforation, which still requires surgical rescue at the present time [24].

Although ESD seems to be a promising technique that is applicable to colorectal epithelial neoplasm, when determining whether colorectal ESD is indicated, it is important to weigh the potential benefits against the risks. This may be different for each endoscopist and for each lesion. Currently, it may be better to resect some large flat colorectal epithelial neoplasms using a method such as piecemeal EMR or colorectal resection when expertise with ESD is still limited.

Concerning the management of complications, Dr. Naohisa Yahagi reviewed the rate of bleeding and perforation with ESD, pointing out that ESD is a longer procedure needing skillful techniques and associated with a higher risk of complications [51]. In a large series of ESD, perforation accounted for 4 % of ESD procedures and delayed bleeding for 4 % (1.7 % with more expertise in the recent cases) [39]. The perforation rate was related to the location of the lesion (upper stomach 7 % vs. 1 % for lower stomach), and to the presence of ulcer fibrosis (6 % with ulcer fibrosis vs. 3 % without). Most gastric perforations can be treated endoscopically: in a series of 2460 patients treated with ESD, 121 suffered a perforation and endoscopic closure was successful in 98.3 % of cases [52]. In the colon, use of ESD similarly and significantly increases the risk of perforation to 6 % compared with a 1 % risk with EMR, without any differences in the bleeding complications. Most perforations can also be treated endoscopically [24] [51].

Conclusions

The panel, which included the faculty, the Japanese experts, and the participants agreed to propose some statements on indications, training, and quality control of ESD.

The following statements were accepted by all experts and participants at the meeting.

• ESD aims at treating mucosal cancer.

• ESD aims, more precisely, at R0 resection.

• ESD should meet quality standards.

• ESD should be performed following national or ESGE guidelines or under IRB approval.

• ESD cases should be registered.

Due to the high level of expertise needed to perform the technique safely, ESD should be performed in a step-up approach after prior experience with conventional EMR, starting with lesions presenting in the rectum, then in the distal stomach, colon, proximal stomach, and finally in the esophagus. Registration is advised either at the local site or at a national or ESGE level, and should include information on indication, technique used, results (en bloc and R0 resection), complications, and follow-up. The panel also agreed on minimum institutional requirements: good quality imaging, experienced histopathologist available following the Japanese criteria (2-mm sections, micrometric invasion, vessel and lymphatic infiltration, pinning down the specimen, etc.), and dedicated endoscopic follow-up. The endoscopist should be able to deal with bleeding and perforation complications and to have access to acute surgery and intensive care units, if needed [52]. A multidisciplinary approach to treatment should be taken.

A better acceptance of ESD requires improvement of the technique to allow an easier, faster, and safer approach. There is a strong demand for structured training courses and limitations of human cases to selected centers that participate in prospective trials. A close collaboration between Western and Asian centers is recommended for improvement of the ESD technique and its clinical application [53].

The minimum training requirements are based on knowledge in indications and instruments, exposure to experts (observation of at least 15 live procedures, visits to expert centers), hands-on experience in a model of isolated pig stomach and in live pigs (minimum of five ESD resections), and management of complications. The isolated pig stomach is a good model for the treatment of perforation whereas the live pig can be used to teach how to deal with bleeding and perforations. The experts did not reach a consensus on a minimal case load, or whether the technique should be restricted to expert centers.

Acknowledgments

The “Experts meet experts” meeting was held in Rotterdam, The Netherlands, 11 – 12 February 2008 and was supported by an unrestricted grant from Olympus. Invited experts from Japan: M. Fujishiro, T. Gotoda, I. Oda, T. Oyama, A. Takahashi, and N. Yahagi. Participants: P. Bhandari, A. Bialek, R. Bisschops, R. Cestari, M. Heinerman, P. Houke, S. Koch, H. Messmann, A. Parra Blanco, A. Polidouru, and A. Schaefer.

Competing interests: None

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• 52 Ikehara H, Gotoda T, Ono H. et al . Gastric perforation during endoscopic resection for gastric carcinoma and the risk of peritoneal dissemination.  Br J Surg. 2007;  94 992-995
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  CrossrefPubMedSearch in Google Scholar

P. H. DeprezMD, PhD 

Gastroenterology
Cliniques Universitaires Saint-Luc

Av. Hippocrate 10
B-1200 Brussels, Belgium

Fax: +32-2-7648927

Email: pdeprez@uclouvain.be

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P. H. DeprezMD, PhD 

Gastroenterology
Cliniques Universitaires Saint-Luc

Av. Hippocrate 10
B-1200 Brussels, Belgium

Fax: +32-2-7648927

Email: pdeprez@uclouvain.be