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Colorectal endoscopic submucosal dissection (ESD)
Accepted Manuscript Colorectal endoscopic submucosal dissection (ESD) Lorenzo Fuccio, Thierry Ponchon
PII:
S1521-6918(17)30071-9
DOI:
10.1016/j.bpg.2017.07.003
Reference:
YBEGA 1529
To appear in:
Best Practice & Research Clinical Gastroenterology
Received Date: 23 May 2017 Revised Date:
29 June 2017
Accepted Date: 5 July 2017
Please cite this article as: Fuccio L, Ponchon T, Colorectal endoscopic submucosal dissection (ESD), Best Practice & Research Clinical Gastroenterology (2017), doi: 10.1016/j.bpg.2017.07.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Colorectal endoscopic submucosal dissection (ESD) Lorenzo Fuccio, MD, Associate Professora, Thierry Ponchon, MD, Professorb* a
Gastroenterology Unit, Department of Medical and Surgical Sciences, S.Orsola-Malpighi Hospital,
b
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University of Bologna, Bologna, Italy Gastroenterology and Endoscopy, Edouard Herriot Hospital, Lyon, France
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Keywords: endoscopic submucosal dissection, ESD, colon cancer, rectal cancer, relapse, training.
Conflict of interest statement: the authors declare no conflict of interest.
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Financial support: the authors did not receive any grant or other financial support for this article.
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Correspondence to:
Prof. Thierry Ponchon, MD
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Gastroenterology and Endoscopy, Edouard Herriot Hospital, Lyon, France
Email: [email protected]
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ACCEPTED MANUSCRIPT ABSTRACT Endoscopic submucosal dissection (ESD) is an interventional procedure for en-bloc resection of gastrointestinal lesions. ESD is a challenging and can involve a reasonable degree of risk, therefore case selection is of crucial importance, especially in the colo-rectum. This procedure should be mainly used for dissection of lesions when there is a high suspicion of superficial
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malignant invasion; several classifications have been proposed in order to better identify lesions suitable for ESD. However, case selection is still an issue, since only about 8-10% of dissected lesions are superficially invading cancer and most of cases involve benign or massively invading cancer. In addition, significant differences have been reported between Asian and Western countries
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in regard to main outcomes, and therefore measures should be adopted as soon as possible to reduce
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this discrepancy.
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ACCEPTED MANUSCRIPT Introduction Endoscopic submucosal dissection (ESD) is an interventional procedure suitable for en-bloc resection of gastrointestinal (GI) lesions. En-bloc resection has two principal advantages: it allows for a more accurate histological assessment, as it is possible to identify resection margins, and it represents an alternative to surgery for lesions with superficially invasive cancer. En-bloc resection
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also reduces the risk of post-procedure recurrence, especially for lesions greater than 20 mm in size, compared to standard piecemeal approaches, such as endoscopic mucosal resection (EMR).
Initially used for the upper GI tract 1, ESD indications have been extended in recent years to include colorectal lesions. The adequate selection of lesions suitable for ESD resection is crucial
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and several validated classifications (e.g. Kudo, Paris, NICE classifications) 2–4 have been proposed with the aim to predict the risk of malignancy and invasiveness of mucosal lesions. The principal criterion is that only lesions with invasion less than 1,000 µm into the submucosa should be
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considered suitable for ESD. Submucosa is usually subdivided into three layers of equivalent thickness: sm1, sm2 and sm3. Therefore, only lesions limited to the sm1 layer should be resected using ESD, while lesions with deeper invasion should be referred for surgery because of the risk of nodal involvement. Present data shows that lesions confined to the sm1 layer have risk of nodal metastasis below 1%, while this risk progressively increases to 6% with sm2 and 14% with sm3
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lesions3. In recent years, a lot of work has been done to identify invasiveness predictors in order to adequately select the best treatment strategy.
The morphology of colorectal lesions may help to predict the risk of submucosal invasion. Using the Paris classification, lesions may be distinguished as polypoid and non-polypoid types3,
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based on the arbitrary threshold of 2.5 mm in height (i.e. the height of closed biopsy forceps). Flat or slightly elevated lesions tend to spread laterally and when greater than 10 mm in size they are called Lateral Spreading Tumours (LST), which can be further classified as granular (LST-G) and
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non-granular (LST-NG) based on the presence or not of multiple nodules that create a slightly elevated broad-based mass3,5. Overall, LST-Gs with homogeneous patterns have a low risk of submucosal invasion (<2%), regardless of the size, while this risk increases with the presence of mixed-size nodules (i.e., the risk of submucosal invasion is greater than 30% for lesions >30 mm)6. LST-Gs with homogeneous patterns can be resected effectively using the EMR technique, while in cases involving mixed-size nodules, ESD should be considered, especially for larger (>30 mm) lesions. Similarly, LST-NGs should be considered for ESD because of substantially increased risk of submucosal invasion, which can range from 7% for lesions <20 mm up to 80% for lesions greater than 30 mm in size with a central pseudo-depression5. Truly depressed lesions present the highest risk of submucosal invasion and are generally referred to surgery. 3
ACCEPTED MANUSCRIPT The Kudo classification has shown a very good correlation between surface epithelium organization, or pit pattern explored in magnification with chromoscopy (e.g., 0.2% indigo carmine solution or other dyes) or narrow-band imaging (NBI) and submucosal invasion. Briefly, the Kudo classification includes seven patterns, which can be grouped into 3 categories: type I and type II (non-neoplastic); type IIIS, IIIL, and IV (low-grade and high-grade intramucosal tumours); and type
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V, with irregular (Vi) or non-structural (VN), amorphous surface (carcinoma with suspicion of submucosal invasion), which is also referred as the invasive pattern, because it is highly indicative of submucosal invasion deeper than 1000 µm. Otherwise, non-invasive patterns (i.e. IIIS, IIIL and IV) suggest intramucosal neoplasia or submucosal invasion less than 1000 µm, thus suitable for
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radical endoscopic treatment. The Kudo classification has been widely validated5.
The NBI International Colorectal Endoscopic (NICE) classification uses narrow-band imaging technology to help identify hyperplastic lesions, adenomas and deep invasive submucosal
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cancer by the analysis of three characteristics: colour, vascular and pit-patterns of lesions4. On the basis of these characteristics, three types of lesion have been categorized: type 1 (hyperplastic), type 2 (adenomas) and type 3 (deep submucosal invasive cancer). Brown to dark brown sometimes with patchy whiter areas, with disrupted or missing vessels and loss of surface pattern should be interpreted as highly suspicious for deep submucosal invasive cancer (type 3) [Table 1]. The
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presence of any one of the 3 criteria for deep submucosal invasion has a sensitivity of 94.9% and a negative predictive value of 95.9%. Furthermore, the NICE classification presents a high interobserver reproducibility, independent of the expertise of the endoscopist4. A recently published systematic review with a meta-analysis of 17 studies that assessed the accuracy of narrow-band
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imaging in the diagnosis of deep submucosal colorectal cancer showed that pooled sensitivity and specificity were 74% (95%CI 66%– 81 %) and 98% (95%CI 94%– 99 %) respectively and the area under the summary receiver operating characteristic curve (AUC) was 0.91 (95%CI 0.88 – 0.93)7.
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Notably, magnifying chromo-endoscopy seemed to perform slightly better than NBI in terms of pooled sensitivity, specificity and AUC, of 84% (95%CI 76%– 89 %), 97% (95%CI 94%– 99 %), and 0.97 (0.95 – 0.98), respectively7. However, the main limitation of the NICE classification is represented by the difficulty in differentiating high-grade dysplasia or superficial invasive carcinoma from low-grade dysplasia8,9. Therefore, in 2014, the Japanese NBI Expert Team (JNET), composed of Japanese specialized in magnifying colonoscopy, proposed a new NBI classification called JNET classification10 [Table 2]. The main differences between the NICE and the JNET classifications are that magnification is a criterion in the JNET classification with the result that NICE Type 2 has 2 subtypes (2A and 2B), and that the two main criteria are vessel and surface patterns, while color findings are not included 4
ACCEPTED MANUSCRIPT anymore. The diagnostic accuracy achieved when the JNET classification is used has been recently evaluated in a Japanese, single-center retrospective study involving 2,933 colorectal lesions (136 hyperplastic polyps/sessile serrated polyps, 1,926 low-grade dysplasias, 571 high-grade dysplasias, 87 superficial submucosal invasive carcinomas, and 213 deep submucosal invasive carcinomas)11. Overall, the results confirmed a weakness of this classification in the correct identification of high-
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grade dysplasia/superficial submucosal invasive cancer (type 2B) with sensitivity, specificity, positive and negative predictive values, and accuracy of 61.9%, 82.8%, 50.9%, 88.2%, and 78.1%, respectively. The JNET classification does not seem to add any additional benefit to the NICE classification; therefore, Sumimoto et al suggest utilizing additional tools to correctly evaluate
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lesions (e.g., pit-pattern assessment using chromoagents)11. Another reason limiting the widespread adoption of the JNET classification in Western countries is that the endoscopes with high-level, graduated optical magnification of 100-fold or more routinely used in Japanese tertiary referral
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centers are rarely used in Western countries: this high level of magnification is not possible with Olympus colonoscopes (e.g. Exera III CF-HQ190) used in Western countries12,13. A colorectal lesion characterized by slight crypt distortion but intact vascular structures (Kudo Vi, NICE type 2) should be considered for ESD resection as there might only be very superficial submucosal invasion, whereas the presence of severely disrupted type Vn pit pattern
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according to the Kudo classification, or type 3 pattern (absent/irregularly thickened vessels) in the NICE/JNET classification should be considered highly indicative for deep submucosal invasion and, after bioptic sampling and ink-tattooing, surgery should be considered,. At the National Cancer Center in Tokyo, Japan, which is the center where the ESD
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procedure has been developed and most performed, the established indications for colorectal ESD are non-granular LST > 20 mm and granular LST >30 mm, as well as residual or recurrent tumors >30 mm6,14. Rectal carcinoid tumors are considered for ESD when <20 mm in size. The same
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indications have been more recently recommended by the European Society of Gastrointestinal Endoscopy (ESGE)15.
The histological analysis of lesions dissected using ESD reported in literature shows that in both Asian and Western studies the majority of lesions are benign adenomas (i.e. low and highgrade dysplasias), while only 10-20% are malignant colorectal lesions [Table 3]16–26. A recently published Asian multicentre retrospective study, involving 1,259 colorectal tumors resected using ESD at 12 institutions, showed that 335 tumors (26.6%) were low-grade dysplasias, 667 tumors (53.0%) were high-grade dysplasias, 153 tumors (12.1%) were deep submucosal invasive carcinomas (≥1000 µm) and only 104 tumors (8.3%) were superficial submucosal invasive carcinomas (<1000 µm)19. This data is confirmed in almost all the published series in which 5
ACCEPTED MANUSCRIPT superficial invasive lesions (i.e. confined to the sm1 layer) represent no more than a half of the malignant lesions. This finding raises concerns about the ability of advanced endoscopic imaging to truly differentiate between superficial and deep submucosal invasive cancer in daily practice, i.e. clinical studies may misrepresent the diagnostic accuracy of these techniques.
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Technique The standard technique for performing ESD in the colo-rectum does not differ from that used for lesions located in the upper GI. Briefly, after injecting the submucosa with a viscous solution (e.g. 0.1% sodium hyaluronate generally mixed with few drops of indigo carmine and
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adrenaline), a needle knife is used to incise the mucosa surrounding the lesion and to dissect it from the submucosal layer. A plastic cap is attached to the tip of the endoscope with the aim of retracting the flap of tissue and produce temporary haemostasis by compressing damaged large vessels, while
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coagulation is achieved with haemostatic forceps. Changing patient position may make it easier to pull the flap of tissue away from the dissection area and gain a better view of the submucosal plane. Finally, a circumferential incision is made and the submucosa is totally separated from the underlying muscle. An alternative to the standard technique is to create a submucosal pocket under the tumor after an initial mucosal incision, approximately 20 mm in length and approximately
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10 mm from the distal side of the tumor [Figure 1]. The main difference from the standard pocketcreation method is completion of the submucosal dissection under the lesion with a minimal mucosal incision. Once the submucosal pocket has been created, additional mucosal incisions and submucosal dissections are made to open the lower side (‘lower’ in terms of the direction of
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gravitational pull) of the pocket toward the proximal side. Finally, a mucosal incision and submucosal dissection of the upper side are performed in the same manner. The standard ESD technique is a challenging and time-consuming procedure, therefore an
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alternative, less challenging technique has also been proposed; it is called the hybrid knife-assisted technique27. This technique is based on the sequential use of an endoscopic knife to circumferentially incise the lesion and partially dissect the submucosal plane to undermine and expose the lesion and the subsequent use of a large snare to complete the en-bloc excision. With this technique, a clear lateral margin is reliably achieved and large lesions may be removed quickly and relatively simply. The main indication for this technique are scarred polyps where an en-bloc excision is difficult to achieve using the standard EMR technique because of the difficulty to obtain good lift28.
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ACCEPTED MANUSCRIPT The training issue Acquiring competency in the ESD procedure represents the main obstacle to the widespread adoption of this technique in Western countries. The better outcomes achieved by Asian countries are mainly explained by the different training programs, with significant focus on GI cancer epidemiology. To be more specific, Japanese tertiary referral centers adopt a step-up training
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procedure, beginning with a long period in which senior trainees, already skilled in therapeutic endoscopy, observe an ESD expert carrying out at least 40 procedures. In addition, animal cadavers are frequently used during this preliminary training phase. Thereafter, trainees are directly involved as assistants to the expert for about another 20 cases. Gastric lesions located in the antrum are the
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beginning of the hands-on part of the training program, with all procedures closely supervised by the expert, who can intervene if necessary. This type of lesion is ideal for trainees because the thick gastric wall reduces the risk of perforation and lesion location allows for easy access. In addition to
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the step-up training program, the ESD case-load also plays a pivotal role. Several studies have shown that all the main outcomes measures (i.e. en-bloc and R0 resection rates, procedure time and adverse-event rates) significantly improved in the mid-phase after the introduction of ESD in daily practice29. However, in Western countries it is rare for gastric lesions to be considered as candidates for endoscopic resection because they are almost always at an advanced stage at the time of
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diagnosis. In 2015, Yang et al. published a retrospective study in which a single endoscopist without previous experience with gastric ESD removed a total of 250 colorectal lesions from 236 patients using the ESD technique30. The results clearly demonstrated that all the main outcomes significantly improved over time, suggesting that 100 colorectal ESDs should be considered
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sufficient to reach adequate skill. The number of ESDs performed (i.e. >100), rectal location and the severity of fibrosis were identified as the factors significantly influencing the success rate. Unfortunately, this study evaluated the outcomes of a single endoscopist and has never been
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confirmed in different settings. Another important difference between Asian and Western countries is that in the latter ESD is very rarely taught during specialization training. Indeed, ESD is most frequently used by senior endoscopists, who have to find the time and resources to learn and then perform this time-consuming, risky and challenging procedure during their daily, busy practice. Several studies demonstrated that for equivalent-sized lesions, the procedural time for ESD may exceed by 3 to 4 times the time for a standard EMR31–33, thus introducing logistical issues because the long waiting-lists in Western endoscopy units do not allow for the routine use of timeconsuming procedures, further adding an obstacle to the widespread adoption of ESD in these countries.
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ACCEPTED MANUSCRIPT All the above considerations should always be remembered because they significantly limit the relevance of studies performed in Asian countries, which are only meaningful if they are validated in the context of Western medical practice. Like EMR and standard ESD techniques, the hybrid knife-assisted technique involves a medium length learning curve, and, similarly to these, about 100 procedures has been suggested as
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necessary to achieve adequate en-bloc resection rates, rising from 30% at the outset to more than 75% 34.
Clinical Outcomes
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R0 and en-bloc resection rates
A recently published systematic review and meta-analysis of 109 studies (97 studies
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evaluating the standard technique and 12 studies evaluating the hybrid one), involving more than 19,400 colorectal dissections, showed that ESD carried out with the standard technique achieves a pooled R0 resection rate of 82.9% (95%CI, 80.4%-85.1%) and an en-bloc resection rate of 91% (95%CI, 89.2%-92.5%)35.
As you would expect from a systematic review involving more than 100 studies, the heterogeneity between studies was very high and the authors of the present article investigated the
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topic using subgroup and meta-regression analyses so as to obtain more informative conclusions. The subgroup analysis was done for different parts of the world where the procedure was performed and revealed that the R0 resection rate in Western countries, i.e. Europe and North America, was 71.3% (95%CI, 66.2%-75.9%), which was significantly lower than that observed in Asian countries
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(85.6%; 95%CI, 83.3-87.7%). Doubtless, the number of ESDs performed per year per center may substantially contribute to the difference observed between Eastern and Western countries.
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However, Fuccio et al also performed a subgroup analysis on the basis of the number of procedures performed per year and found that high-volume centers, defined as those centers carrying out more than 2 ESDs per month, in Western countries still continued to present significantly lower R0 resection rates (72.0%; 95%CI 59.5%-81.8%) when compared with Asian high-volume centers (87.4%; 95%CI 85.2%-89.4%). Therefore, the difference between Asian and Western countries might not only be due to different procedure volume but also the training process carried out in these countries, as mentioned above. Indeed, in Asian countries expertise with ESD is generally acquired during a 3-year course following the traditional model of see one, do one, teach one
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and ESD for colorectal lesions represents the end of a step-up training process. In Western countries, as previously mentioned, this model is not feasible for several reasons (i.e. different epidemiology of GI neoplasms suitable for endoscopic resection, lack of time, insufficient number 8
ACCEPTED MANUSCRIPT of experts), therefore lower GI tract lesions frequently are the first lesions removed during the training program, especially those located in the rectum. A different use of image-enhanced magnified endoscopy and bioptic sampling for the pre-procedure assessment of ESD candidate lesions has been suggested as another possible explanation for the difference between Asian and Western countries38. Fibrosis owing to multiple bioptic sampling might increase the difficulty and
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the risk of adverse events associated with dissection, thus partly explaining the worse outcomes reported in Western countries.
Another interesting finding of the systematic review by Fuccio et al35, which was the result of a meta-regression analysis of factors influencing the between-study heterogeneity, was that there
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is a possible inverse association between rectal location and R0 resection rates. An increase in the number of rectal lesions resected resulted in a reduction of R0 resection rates. This finding indirectly confirms the previous observation that rectal lesions, especially in Western countries,
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frequently are the first lesions that are dealt with during training. In addition, because of the common belief that there is a lower risk of major ESD-related adverse events in regard to the rectum, endoscopists may be tempted to carry out ESD for lesions that are beyond their level of expertise.
The meta-analysis of the 12 studies evaluating the hybrid technique revealed quite disappointing results with an R0 resection rate of 60.6% (95%CIm 40.6%-77.5%) and an en-bloc
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resection rate of 68.4% (95%CI 51.7-81.3%)35. The subgroup analysis on the basis of the different parts of the world where the procedure was performed revealed not significantly higher rates in Asian countries (71.1%; 95%CI 43.3%-88.8%) in comparison with Western countries (44.4%; Studies on the use of the hybrid knife-assisted technique for the
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95%CI 24.6%-66.1%).
management of scarred polyps have showed interesting results, with an overall cure rate of 90% and
Safety
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a recurrence rate of 16%39.
ESD is a very challenging and risky procedure, and the most serious complications are perforation and bleeding40. Recently published meta-analysis by Fuccio et al35 shows that the pooled perforation rate using the standard technique was 5.2% (95%CI, 4.4%-6.1%) and again significant differences were observed between Asian and Western countries. The risk of perforation was significantly higher in Western (8.6%; 95%CI, 5.9%-12.2%) than in Asian countries (4.5; 95%CI, 3.9%-5.3%). Several risk factors for ESD-related perforations have been identified, such as location in the colon, tumor size, the presence of submucosal fibrosis and also the endoscopists’ expertise41,42. 9
ACCEPTED MANUSCRIPT Recently, a model able to predict the risk of perforation with good discrimination has been proposed by Hong et al41. The authors developed a nomogram called SELF, in which four variables, size, experience, location and fibrosis, are used to calculate the risk of perforation. For tumors located in the colon (vs. rectum), 2 points were given, one point for each 1-cm increment in tumor size, 2 additional points for the presence of submucosal fibrosis, while one point should be
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subtracted if the endoscopist’s experience is over 50 ESDs. A cut-off score of 4 points was determined; if the total score is 4 or below, the risk of perforation is considered low, about 4%, otherwise for scores above 4 the risk is substantially increased by 3 times (i.e. 11.6%). Despite several limitations, this predictive model is a very useful tool that can help in the decision making
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process, especially for endoscopists who are not highly experienced43.
The early recognition of perforation substantially improves patient outcomes. Use of carbon dioxide is mandatory during ESD, as it reduces the risk of perforation and also favors a
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conservative approach. Once a deep mural injury is detected, endoscopically placed clips (throughthe-scope, TTS) should be used to close the perforation, especially for those smaller than 15-20 mm40,44,45. It has been demonstrated that intra-procedural detection and clipping of perforations, is sufficient to avoid surgery in almost all cases44. The over-the-scope clip (OTSC) has been proposed as alternative to the TTS clip, when larger defects, up to 30 mm, are identified46,47; however, the
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need for scope withdrawal and reinsertion may compromise clinical success. Ma et al suggested several principles to follow to achieve an adequate and successful TTS clip placement and closure of mural defects40. Briefly, these were minimize gas insufflation in order to avoid or reduce tension on the defect, try to maintain the field clean by changing patient position, prevent peristalsis by
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administering anti-peristaltic agents, apply clips generally from left to right. Using an endoscopic suturing device was proposed for the closure of full-thickness colonic perforations. The endoscopic suturing device’s sutures allow close tissue approximation of the wall layers and complete closure
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of even large, deep mural defects after ESD48. Kantsevoy et al reported their experience with 16 patients using the Overstitch device (Apollo Endosurgery Inc, Austin, Tex)49. To perform endoscopic suturing closure, the colonoscope must be withdrawn and a double-channel endoscope preloaded with the suturing device is introduced. The wall defect is then closed with full-thickness sutures either with a continuous suture line or separate stitches. Although it was a retrospective study based on a small sample size, the results suggest that the endoscopic suture closure of colonic perforations is technically feasible and could reduce the need for surgery, especially if compared to closure with TTS clips. The rate of perforation with the hybrid technique is similar to that observed with the standard technique, 4.8% (95%CI, 2.4%-9.1%), without significant differences between 10
ACCEPTED MANUSCRIPT geographical regions. Similarly, the rate of delayed bleeding is about 4.0% (95%CI, 2.8-5.8%) and again without significant differences among regions. Overall, the need for surgery owing to severe adverse events was 1.0% (95% CI, 0.4%-2.3%). Therefore, based on the available evidence, the hybrid technique should not be considered safer than the standard technique. The rate of delayed bleeding (>48 hours) after ESD is about 2.7% (95%CI, 2.2%-3.2%),
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with a not significantly higher rate reported in Western (4.2%) vs. Asian (2.4%) countries. The risk factors for delayed bleeding are almost the same as for perforation, with the exception of lesions located in the rectum, which are associated with an increased risk of bleeding16,50.
Intra-procedural bleeding is very frequent and its prevention and management represents one
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of the most important and time-consuming parts of the procedure. Appropriate settings on the electrosurgical unit during the pre-cut and dissection phases and coagulation of the exposed vessels during the procedure may reduce the risk. Bleeding vessels may be initially managed by utilizing
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the endoscope’s plastic cap to dab the bleeding vessel, executing a mechanical haemostasis in order to maintain the field clean, and then using a soft coagulation or coagulation grasper to coagulate the vessels. The prophylactic treatment of non-bleeding vessels at the end of the procedure has always been matter of debate, since there is no clear evidence that this practice may significantly reduce the risk of late-onset bleeding.
Electrocoagulation syndrome is definitively more common after ESD than EMR, and it
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occurs in about 1 in every 12 dissections51,52. This syndrome is due to transmural thermal injury to the colon wall and generally develops within 24-48 hours after the procedure, and it is characterized by fever, localized abdominal pain, no sign of intra-peritoneal air in X-rays and an increase in C-
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reactive protein and leukocytosis53. The two independent risk factors for electrocoagulation syndrome are the lesion size (> 30 mm) and lesion location in the colon, and either of these individual factors may increase the risk 5 to 7 times54. The treatment is conservative and based on
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the intravenous administration of fluids and antibiotics as well as bowel rest; the prognosis is generally favorable, with clinical remission normally occurring within 24 hours. The risk of post-ESD stenosis is very low. A recently published large retrospective study performed in Japan, involving 912 dissected lesions in 822 patients, reported an incidence of postESD stenosis of 0.49% (4 cases)55. Stenosis occurred only in patients with a circumferential mucosal defect of more than 90%, three cases were located in the rectum and stenosis developed within 3 months of the procedure. All the cases were easily managed by 1 to 3 sessions of endoscopic balloon dilation with the adjunct of steroid therapy (i.e. betamethasone steroid suppositories, 1.0 mg/day, for 90 days). Steroid therapy should be used only for cases considered at risk of early re-stenosis. Surgery was not indicated for any of these cases. 11
ACCEPTED MANUSCRIPT Overall, it should be noted that, based on the best available evidence, most of the adverse events occurring after ESD are generally managed endoscopically; indeed, the need for surgery due to severe complications has been estimated as 1.1% (95%CI, 0.8%-1.3%), but again with a significantly higher rate reported in Western countries (3.1%; 95%CI, 2.1%-4.7%) compared to
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Asian countries (0.8%; 95%CI, 0.6%-1.0%) 35.
The risk of recurrence after ESD
The rate of recurrence 12 months after standard ESD is low, about 2.0% (95% 1.3-3.0), but again with significant difference between Western (5.2%; 95%CI 3.3-8.1%) and Asian countries
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(1.1%; 95% 0.7-1.8%)35. A recently published retrospective, single-center, Japanese study involving 224 colorectal lesions dissected using ESD in 222 patients, reported after a median
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follow-up of 79 months a local recurrence rate of 1.5%56. Risk factors for recurrence were the type of resection (i.e., piecemeal vs. en bloc), incomplete resection detected at histology (i.e. complete resection defined as horizontal and vertical margins negative) and in cases of non-curative resection (i.e. complete resection and no risk of lymph node metastasis on histologic examination57). The risk of recurrence after EMR is definitely greater; a recently published systematic review by Hassan et al, involving 50 studies and 6,779 polyps larger than 2 cm, reported a
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recurrence rate during endoscopic surveillance of 13.8% (95% CI 12.9%-14.7%)58. Of note is that endoscopic treatment of post-EMR recurrence was successfully achieved in about 90% of cases and
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surgery was required for 4.2% of patients.
Comparison between ESD and EMR A meta-analysis of 8 studies published between 2005 and 2013 comparing ESD with EMR
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for the treatment of colorectal lesions showed that ESD achieved significantly better outcomes than EMR in regard to en-bloc resection and curative resection rates32. However, safety was definitely lower, since the rate of perforation during ESD (5.7%) was significantly higher than that reported using EMR (1.4%). In addition, the need for additional surgery was significantly higher after ESD; the main reason was massive submucosal invasion, suggesting a failure in the correct selection of cases suitable for ESD removal.
Conclusions ESD is an effective and safe procedure, at least in Asian countries. In Western countries initiatives should be introduced to improve the main outcomes. The lower occurrence of this 12
ACCEPTED MANUSCRIPT procedure in Western countries is also due to a different management of the same types of lesion. The correct selection of cases that are suitable for ESD instead of EMR is the main issue, since advance imaging endoscopy does not always guarantee an adequate differentiation between highgrade dysplasia, superficial submucosal invasive cancer and deep invasive cancer.
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evidence shows that ESD is mainly used for benign lesions (i.e. low- and high-grade adenomas),
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while malignant lesions represent less than 20% of dissected cases and, disappointingly, superficially invading lesions (i.e. confined to the sm1 layer), are no more than half of all cases (5%-10%). Therefore, every 10 ESDs used to treat (number needed to treat [NNT]) prevents the need for surgery for one patient with superficial invasion (sm1) in the Asian series, while in the
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European series one operation is prevented every 35 ESDs 59. This means that the above-mentioned criteria for case selection are not adequately and correctly implemented in clinical practice, and therefore diagnostic criteria need to be improved. Since the best available evidence has been
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published by tertiary referral centers, it can be presumed that there is worse performance in other settings (i.e. low-volume centers without internal auditing of main outcomes). The improvement of all the clinical outcomes in Western countries should represent the main goal for the near future; this can be achieved by referring patients to centers that are staffed with endoscopists skilled in
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ESD and by implementing certified and step-up training programs.
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ACCEPTED MANUSCRIPT Clinical Practice Points & Research Agenda •
Differences are still present between Asian and Western countries in regard to main outcomes measures (i.e., en-bloc and R0 resection rates, complication rates and risk of relapse).
•
Despite several validated classifications being proposed with the aim of helping case
still represent a minority of the lesions dissected.
A formal and certified step-up training program and a constantly performed internal audit of the main outcome measures should be promoted in each center, especially in Western
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countries.
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•
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selection identification of lesions highly suspicious for superficial malignant invasion, these
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ACCEPTED MANUSCRIPT REFERENCES
1.
Yamamoto H, Yube T, Isoda N, et al. A novel method of endoscopic mucosal resection using sodium hyaluronate. Gastrointest Endosc. 1999;50(2):251-256. http://www.ncbi.nlm.nih.gov/pubmed/10425422. Accessed May 22, 2017. Kudo S, Kashida H, Nakajima T, Tamura S, Nakajo K. Endoscopic diagnosis and treatment of early colorectal cancer. World J Surg. 1997;21(7):694-701.
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2.
http://www.ncbi.nlm.nih.gov/pubmed/9276699. Accessed May 22, 2017. 3.
The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and
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colon: November 30 to December 1, 2002. Gastrointest Endosc. 2003;58(6 Suppl):S3-43. http://www.ncbi.nlm.nih.gov/pubmed/14652541. Accessed May 22, 2017. 4.
Hayashi N, Tanaka S, Hewett DG, et al. Endoscopic prediction of deep submucosal invasive
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carcinoma: validation of the narrow-band imaging international colorectal endoscopic (NICE) classification. Gastrointest Endosc. 2013;78(4):625-632. doi:10.1016/j.gie.2013.04.185. 5.
Kudo S ei, Lambert R, Allen JI, et al. Nonpolypoid neoplastic lesions of the colorectal mucosa. Gastrointest Endosc. 2008;68(4 Suppl):S3-47. doi:10.1016/j.gie.2008.07.052. Uraoka T, Saito Y, Matsuda T, et al. Endoscopic indications for endoscopic mucosal
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6.
resection of laterally spreading tumours in the colorectum. Gut. 2006;55(11):1592-1597. doi:10.1136/gut.2005.087452. 7.
Zhang Q-W, Teng L-M, Zhang X-T, et al. Narrow-band imaging in the diagnosis of deep
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submucosal colorectal cancers: a systematic review and meta-analysis. Endoscopy. 2017;49(6):564-580. doi:10.1055/s-0043-103014. 8.
Tanaka S, Hayashi N, Oka S, Chayama K. Endoscopic Assessment of Colorectal Cancer with
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Superficial or Deep Submucosal Invasion Using Magnifying Colonoscopy. Clin Endosc. 2013;46(2):138. doi:10.5946/ce.2013.46.2.138. 9.
Tanaka S, Sano Y. Aim to unify the narrow band imaging (NBI) magnifying classification for colorectal tumors: current status in Japan from a summary of the consensus symposium in the 79th Annual Meeting of the Japan Gastroenterological Endoscopy Society. Dig Endosc. 2011;23 Suppl 1:131-139. doi:10.1111/j.1443-1661.2011.01106.x.
10.
Sano Y, Tanaka S, Kudo S-E, et al. Narrow-band imaging (NBI) magnifying endoscopic classification of colorectal tumors proposed by the Japan NBI Expert Team. Dig Endosc. 2016;28(5):526-533. doi:10.1111/den.12644.
11.
Sumimoto K, Tanaka S, Shigita K, et al. Clinical impact and characteristics of the narrow15
ACCEPTED MANUSCRIPT band imaging magnifying endoscopic classification of colorectal tumors proposed by the Japan NBI Expert Team. Gastrointest Endosc. 2017;85(4):816-821. doi:10.1016/j.gie.2016.07.035. 12.
Bhat YM, Abu Dayyeh BK, Chauhan SS, et al. High-definition and high-magnification endoscopes. Gastrointest Endosc. 2014;80(6):919-927. doi:10.1016/j.gie.2014.06.019. Hewett DG, Sakata S. Classifications for optical diagnosis of colorectal lesions: not
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13.
2B??with JNET. Gastrointest Endosc. 2017;85(4):822-828. doi:10.1016/j.gie.2017.01.004. 14.
Nakajima T, Saito Y, Tanaka S, et al. Current status of endoscopic resection strategy for
doi:10.1007/s00464-013-2903-x. 15.
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large, early colorectal neoplasia in Japan. Surg Endosc. 2013;27(9):3262-3270.
Pimentel-Nunes P, Dinis-Ribeiro M, Ponchon T, et al. Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy.
16.
M AN U
2015;47(9):829-854. doi:10.1055/s-0034-1392882.
Saito Y, Uraoka T, Yamaguchi Y, et al. A prospective, multicenter study of 1111 colorectal endoscopic submucosal dissections (with video). Gastrointest Endosc. 2010;72(6):12171225. doi:10.1016/j.gie.2010.08.004.
17.
Tamai N, Saito Y, Sakamoto T, Nakajima T, Matsuda T, Tajiri H. Safety and efficacy of
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colorectal endoscopic submucosal dissection in elders: clinical and follow-up outcomes. Int J Colorectal Dis. 2012;27(11):1493-1499. doi:10.1007/s00384-012-1514-7. 18.
Repici A, Hassan C, Pagano N, et al. High efficacy of endoscopic submucosal dissection for rectal laterally spreading tumors larger than 3 cm. Gastrointest Endosc. 2013;77(1):96-101.
19.
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doi:10.1016/j.gie.2012.08.036.
Boda K, Oka S, Tanaka S, et al. Clinical outcomes of endoscopic submucosal dissection for colorectal tumors: a large multicenter retrospective study of Hiroshima GI Endoscopy
20.
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Research Group. Gastrointest Endosc. 2017. doi:10.1016/j.gie.2017.05.051. Hurlstone DP, Atkinson R, Sanders DS, Thomson M, Cross SS, Brown S. Achieving R0 resection in the colorectum using endoscopic submucosal dissection. Br J Surg. 2007;94(12):1536-1542. doi:10.1002/bjs.5720. 21.
Isomoto H, Nishiyama H, Yamaguchi N, et al. Clinicopathological factors associated with clinical outcomes of endoscopic submucosal dissection for colorectal epithelial neoplasms. Endoscopy. 2009;41(8):679-683. doi:10.1055/s-0029-1214979.
22.
Yoshida N, Naito Y, Kugai M, et al. Efficient hemostatic method for endoscopic submucosal dissection of colorectal tumors. World J Gastroenterol. 2010;16(33):4180-4186. http://www.ncbi.nlm.nih.gov/pubmed/20806436. Accessed May 26, 2017. 16
ACCEPTED MANUSCRIPT 23.
Nakajima T, Saito Y, Tanaka S, et al. Current status of endoscopic resection strategy for large, early colorectal neoplasia in Japan. Surg Endosc. 2013;27(9):3262-3270. doi:10.1007/s00464-013-2903-x.
24.
Thorlacius H, Uedo N, Toth E. Implementation of Endoscopic Submucosal Dissection for Early Colorectal Neoplasms in Sweden. Gastroenterol Res Pract. 2013;2013:1-6.
25.
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doi:10.1155/2013/758202. Takeuchi Y, Iishi H, Tanaka S, et al. Factors associated with technical difficulties and adverse events of colorectal endoscopic submucosal dissection: retrospective exploratory factor analysis of a multicenter prospective cohort. Int J Colorectal Dis. 2014;29(10):1275-
26.
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1284. doi:10.1007/s00384-014-1947-2.
Lee E-J, Lee JB, Lee SH, Youk EG. Endoscopic treatment of large colorectal tumors: comparison of endoscopic mucosal resection, endoscopic mucosal resection-precutting, and
doi:10.1007/s00464-012-2164-0. 27.
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endoscopic submucosal dissection. Surg Endosc. 2012;26(8):2220-2230.
Toyonaga T, Man-I M, Morita Y, Azuma T. Endoscopic submucosal dissection (ESD) versus simplified/hybrid ESD. Gastrointest Endosc Clin N Am. 2014;24(2):191-199. doi:10.1016/j.giec.2013.11.004.
Longcroft-Wheaton G, Bhandari P. Management of early colonic neoplasia: where are we
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28.
now and where are we heading? Expert Rev Gastroenterol Hepatol. 2017;11(3):1-10. doi:10.1080/17474124.2017.1279051. 29.
SAITO Y, KAWANO H, TAKEUCHI Y, et al. CURRENT STATUS OF COLORECTAL
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ENDOSCOPIC SUBMUCOSAL DISSECTION IN JAPAN AND OTHER ASIAN COUNTRIES: PROGRESSING TOWARDS TECHNICAL STANDARDIZATION. Dig Endosc. 2012;24:67-72. doi:10.1111/j.1443-1661.2012.01282.x. Yang D-H, Jeong GH, Song Y, et al. The Feasibility of Performing Colorectal Endoscopic
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30.
Submucosal Dissection Without Previous Experience in Performing Gastric Endoscopic Submucosal Dissection. Dig Dis Sci. 2015;60(11):3431-3441. doi:10.1007/s10620-0153755-0. 31.
Klein A, Bourke MJ. Advanced Polypectomy and Resection Techniques. Gastrointest Endosc Clin N Am. 2015;25(2):303-333. doi:10.1016/j.giec.2014.11.005.
32.
Fujiya M, Tanaka K, Dokoshi T, et al. Efficacy and adverse events of EMR and endoscopic submucosal dissection for the treatment of colon neoplasms: a meta-analysis of studies comparing EMR and endoscopic submucosal dissection. Gastrointest Endosc. 2015;81(3):583-595. doi:10.1016/j.gie.2014.07.034. 17
ACCEPTED MANUSCRIPT 33.
Heitman SJ, Bourke MJ. Endoscopic submucosal dissection and EMR for large colorectal polyps: ?the perfect is the enemy of good? Gastrointest Endosc. 2017;86(1):87-89. doi:10.1016/j.gie.2017.03.022.
34.
Bhattacharyya R, Chedgy FJ, Kandiah K, Longcroft-Wheaton G, Bhandari P. Knife-assisted snare resection (KAR) of large and refractory colonic polyps at a Western centre: Feasibility,
2016;4(3):466-473. doi:10.1177/2050640615615301. 35.
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safety and efficacy study to guide future practice. United Eur Gastroenterol J.
Fuccio L, Hassan C, Ponchon T, et al. Clinical outcomes after endoscopic submucosal dissection for colorectal neoplasia: a systematic review and meta-analysis. Gastrointest
36.
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Endosc. February 2017. doi:10.1016/j.gie.2017.02.024.
Yamamoto Y, Fujisaki J, Ishiyama A, Hirasawa T, Igarashi M. Current status of training for endoscopic submucosal dissection for gastric epithelial neoplasm at Cancer Institute
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Hospital, Japanese Foundation for Cancer Research, a famous Japanese hospital. Dig Endosc. 2012;24 Suppl 1:148-153. doi:10.1111/j.1443-1661.2012.01278.x. 37.
Draganov P V, Coman RM, Gotoda T. Training for complex endoscopic procedures: how to incorporate endoscopic submucosal dissection skills in the West? Expert Rev Gastroenterol Hepatol. 2014;8(2):119-121. doi:10.1586/17474124.2014.864552. Saito Y, Bhatt A, Matsuda T. Colorectal endoscopic submucosal dissection and its journey to
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38.
the West. Gastrointest Endosc. 2017;86(1):90-92. doi:10.1016/j.gie.2017.03.1548. 39.
Chedgy F, Bhattacharyya R, Kandiah K, Longcroft-Wheaton G, Bhandari P. Knife-assisted snare resection: a novel technique for resection of scarred polyps in the colon. Endoscopy.
40.
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2016;48(3):277-280. doi:10.1055/s-0035-1569647. Ma MX, Bourke MJ. Complications of endoscopic polypectomy, endoscopic mucosal resection and endoscopic submucosal dissection in the colon. Best Pract Res Clin
41.
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Gastroenterol. 2016;30(5):749-767. doi:10.1016/j.bpg.2016.09.009. Hong SN, Byeon JS, Lee B-I, et al. Prediction model and risk score for perforation in patients undergoing colorectal endoscopic submucosal dissection. Gastrointest Endosc. 2016;84(1):98-108. doi:10.1016/j.gie.2015.12.011. 42.
Yoshida N, Wakabayashi N, Kanemasa K, et al. Endoscopic submucosal dissection for colorectal tumors: technical difficulties and rate of perforation. Endoscopy. 2009;41(9):758761. doi:10.1055/s-0029-1215028.
43.
Kantsevoy S V. A new tool to estimate the risk of perforations during colorectal endoscopic submucosal dissection. Gastrointest Endosc. 2016;84(1):109-114. doi:10.1016/j.gie.2016.03.1495. 18
ACCEPTED MANUSCRIPT 44.
Yang D-H, Byeon J-S, Lee K-H, et al. Is endoscopic closure with clips effective for both diagnostic and therapeutic colonoscopy-associated bowel perforation? Surg Endosc. 2010;24(5):1177-1185. doi:10.1007/s00464-009-0746-2.
45.
Magdeburg R, Sold M, Post S, Kaehler G. Differences in the endoscopic closure of colonic perforation due to diagnostic or therapeutic colonoscopy. Scand J Gastroenterol.
46.
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2013;48(7):862-867. doi:10.3109/00365521.2013.793737. Weiland T, Fehlker M, Gottwald T, Schurr MO. Performance of the OTSC System in the endoscopic closure of iatrogenic gastrointestinal perforations: a systematic review. Surg Endosc. 2013;27(7):2258-2274. doi:10.1007/s00464-012-2754-x.
Singhal S, Changela K, Papafragkakis H, Anand S, Krishnaiah M, Duddempudi S. Over the
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47.
Scope Clip. J Clin Gastroenterol. 2013;47(9):749-756. doi:10.1097/MCG.0b013e318296ecb9.
Kantsevoy S V., Bitner M, Mitrakov AA, Thuluvath PJ. Endoscopic suturing closure of large
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48.
mucosal defects after endoscopic submucosal dissection is technically feasible, fast, and eliminates the need for hospitalization (with videos). Gastrointest Endosc. 2014;79(3):503507. doi:10.1016/j.gie.2013.10.051. 49.
Kantsevoy S V., Bitner M, Hajiyeva G, et al. Endoscopic management of colonic
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perforations: clips versus suturing closure (with videos). Gastrointest Endosc. 2016;84(3):487-493. doi:10.1016/j.gie.2015.08.074. 50.
Terasaki M, Tanaka S, Shigita K, et al. Risk factors for delayed bleeding after endoscopic submucosal dissection for colorectal neoplasms. Int J Colorectal Dis. 2014;29(7):877-882.
51.
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doi:10.1007/s00384-014-1901-3.
Yamashina T, Takeuchi Y, Uedo N, et al. Features of electrocoagulation syndrome after endoscopic submucosal dissection for colorectal neoplasm. J Gastroenterol Hepatol.
52.
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2016;31(3):615-620. doi:10.1111/jgh.13052. Hong MJ, Kim JH, Lee S-Y, Sung I-K, Park HS, Shim CS. Prevalence and Clinical Features of Coagulation Syndrome After Endoscopic Submucosal Dissection for Colorectal Neoplasms. Dig Dis Sci. 2015;60(1):211-216. doi:10.1007/s10620-014-3484-9. 53.
Cha J, Lim K, Lee S, et al. Clinical outcomes and risk factors of post-polypectomy coagulation syndrome: a multicenter, retrospective, case-control study. Endoscopy. 2013;45(3):202-207. doi:10.1055/s-0032-1326104.
54.
Jung D, Youn YH, Jahng J, Kim J-H, Park H. Risk of electrocoagulation syndrome after endoscopic submucosal dissection in the colon and rectum. Endoscopy. 2013;45(9):714-717. doi:10.1055/s-0033-1344555. 19
ACCEPTED MANUSCRIPT 55.
Hayashi T, Kudo S-E, Miyachi H, et al. Management and risk factor of stenosis after endoscopic submucosal dissection for colorectal neoplasms. Gastrointest Endosc. December 2016. doi:10.1016/j.gie.2016.11.032.
56.
Shigita K, Oka S, Tanaka S, et al. Long-term outcomes after endoscopic submucosal dissection for superficial colorectal tumors. Gastrointest Endosc. 2017;85(3):546-553.
57.
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doi:10.1016/j.gie.2016.07.044. Watanabe T, Itabashi M, Shimada Y, et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2014 for treatment of colorectal cancer. Int J Clin Oncol. 2015;20(2):207-239. doi:10.1007/s10147-015-0801-z.
Hassan C, Repici A, Sharma P, et al. Efficacy and safety of endoscopic resection of large
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58.
colorectal polyps: a systematic review and meta-analysis. Gut. 2016;65(5):806-820. doi:10.1136/gutjnl-2014-308481.
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Rex DK, Hassan CC, Dewitt JM. Colorectal endoscopic submucosal dissection in the United States: Why do we hear so much about it and do so little of it? Gastrointest Endosc.
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2017;85(3):554-558. doi:10.1016/j.gie.2016.09.015.
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ACCEPTED MANUSCRIPT Figure 1 – Pocket-creation method. Laterally spreading tumor, granular type (LST-G), 5 x 4 cm in size, at the recto-sigmoid junction, developed in a patient with long-standing ulcerative colitis [a]. A submucosal pocket was created under the tumor after an initial mucosal incision, approximately 10 mm from the distal side of the tumor, [b]. Once the submucosal pocket had been created [c],
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additional mucosal incisions and submucosal dissections were made to open the lower side (‘lower’ in terms of the direction of gravitational pull) of the pocket toward the proximal side [d]. Finally, a mucosal incision and submucosal dissection of the upper side were performed in the same manner
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adenoma with low-grade dysplasia; vertical and lateral margins were free of neoplasia.
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ACCEPTED MANUSCRIPT Table 1 – NBI International Colorectal Endoscopic (NICE) Classification Type 1
Type 2
Type 3
Color
Same or lighter than background
Browner relative to background (verify color arises from vessels)
Brown to dark brown relative to background; sometimes patchy whiter areas
Vessels
None, or isolated lacy vessels across the lesion
Brown vessels surrounding white structures
Area(s) disrupted or lacking vessels
Surface pattern
Dark or white spots of uniform size, or homogeneous absence of pattern
Oval, tubular or branched white structure/s surrounded by brown vessels
Amorphous or absent surface pattern
Most likely pathology
Hyperplastic
Adenoma
Deep submucosal invasive cancer
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Characteristics
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ACCEPTED MANUSCRIPT Table 2 – Japanese NBI Expert Team (JNET) Classification Type 2A
Type 2B
Type 3
Vessel pattern
Invisible
Regular caliber Regular distribution (meshed/spiral pattern)
Variable caliber Irregular distribution
Loose vessel areas Interruption of thick vessels
Surface pattern
Regular dark or white spots Similar to surrounding normal mucosa
Regular (tubular/branched/ papillary)
-Irregular or obscure
Amorphous areas
Most likely histology
Hyperplastic polyp/Sessile serrated polyp
Low-grade intramucosal neoplasia
High-grade intramucosal neoplasia/Superfic ial submucosal invasive cancer
Deep submucosal invasive cancer
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Type I
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ACCEPTED MANUSCRIPT Table 3 – Histology of dissected lesions. Region Europe Asia Asia Asia Asia Asia Asia Europe Europe Asia Asia
Design Prospective Retrospective Prospective Retrospective Retrospective Retrospective Prospective Prospective Retrospective Retrospective Retrospective
Lesions 42 292 1111 250 635 874 816 40 29 816 1259
Adenomas (n) 40 265 875 231 485 736 660 38 24 661 1002
sm1 (n) 1 18 112 7 68 74 88 2 3 88 104
sm2 or deeper (n) 1 9 101 12 71 58 62 0 2 67 153
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Publication year 2007 2009 2010 2010 2012 2012 2013 2013 2013 2014 2017
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Author (Reference) Hurlstone DP et al (14) Isomoto H et al (15) Saito Y et al (10) Yoshida N et al (16) Tamai N et al (11) Lee E-J et al (20) Nakajima T et al (17) Repici A et al (12) Thorlacius H et al (18) Takeuchi Y et al (19) Boda K et al (13)
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PII:
S1521-6918(17)30071-9
DOI:
10.1016/j.bpg.2017.07.003
Reference:
YBEGA 1529
To appear in:
Best Practice & Research Clinical Gastroenterology
Received Date: 23 May 2017 Revised Date:
29 June 2017
Accepted Date: 5 July 2017
Please cite this article as: Fuccio L, Ponchon T, Colorectal endoscopic submucosal dissection (ESD), Best Practice & Research Clinical Gastroenterology (2017), doi: 10.1016/j.bpg.2017.07.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Colorectal endoscopic submucosal dissection (ESD) Lorenzo Fuccio, MD, Associate Professora, Thierry Ponchon, MD, Professorb* a
Gastroenterology Unit, Department of Medical and Surgical Sciences, S.Orsola-Malpighi Hospital,
b
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University of Bologna, Bologna, Italy Gastroenterology and Endoscopy, Edouard Herriot Hospital, Lyon, France
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Keywords: endoscopic submucosal dissection, ESD, colon cancer, rectal cancer, relapse, training.
Conflict of interest statement: the authors declare no conflict of interest.
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Financial support: the authors did not receive any grant or other financial support for this article.
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Correspondence to:
Prof. Thierry Ponchon, MD
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Gastroenterology and Endoscopy, Edouard Herriot Hospital, Lyon, France
Email: [email protected]
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ACCEPTED MANUSCRIPT ABSTRACT Endoscopic submucosal dissection (ESD) is an interventional procedure for en-bloc resection of gastrointestinal lesions. ESD is a challenging and can involve a reasonable degree of risk, therefore case selection is of crucial importance, especially in the colo-rectum. This procedure should be mainly used for dissection of lesions when there is a high suspicion of superficial
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malignant invasion; several classifications have been proposed in order to better identify lesions suitable for ESD. However, case selection is still an issue, since only about 8-10% of dissected lesions are superficially invading cancer and most of cases involve benign or massively invading cancer. In addition, significant differences have been reported between Asian and Western countries
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in regard to main outcomes, and therefore measures should be adopted as soon as possible to reduce
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this discrepancy.
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ACCEPTED MANUSCRIPT Introduction Endoscopic submucosal dissection (ESD) is an interventional procedure suitable for en-bloc resection of gastrointestinal (GI) lesions. En-bloc resection has two principal advantages: it allows for a more accurate histological assessment, as it is possible to identify resection margins, and it represents an alternative to surgery for lesions with superficially invasive cancer. En-bloc resection
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also reduces the risk of post-procedure recurrence, especially for lesions greater than 20 mm in size, compared to standard piecemeal approaches, such as endoscopic mucosal resection (EMR).
Initially used for the upper GI tract 1, ESD indications have been extended in recent years to include colorectal lesions. The adequate selection of lesions suitable for ESD resection is crucial
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and several validated classifications (e.g. Kudo, Paris, NICE classifications) 2–4 have been proposed with the aim to predict the risk of malignancy and invasiveness of mucosal lesions. The principal criterion is that only lesions with invasion less than 1,000 µm into the submucosa should be
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considered suitable for ESD. Submucosa is usually subdivided into three layers of equivalent thickness: sm1, sm2 and sm3. Therefore, only lesions limited to the sm1 layer should be resected using ESD, while lesions with deeper invasion should be referred for surgery because of the risk of nodal involvement. Present data shows that lesions confined to the sm1 layer have risk of nodal metastasis below 1%, while this risk progressively increases to 6% with sm2 and 14% with sm3
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lesions3. In recent years, a lot of work has been done to identify invasiveness predictors in order to adequately select the best treatment strategy.
The morphology of colorectal lesions may help to predict the risk of submucosal invasion. Using the Paris classification, lesions may be distinguished as polypoid and non-polypoid types3,
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based on the arbitrary threshold of 2.5 mm in height (i.e. the height of closed biopsy forceps). Flat or slightly elevated lesions tend to spread laterally and when greater than 10 mm in size they are called Lateral Spreading Tumours (LST), which can be further classified as granular (LST-G) and
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non-granular (LST-NG) based on the presence or not of multiple nodules that create a slightly elevated broad-based mass3,5. Overall, LST-Gs with homogeneous patterns have a low risk of submucosal invasion (<2%), regardless of the size, while this risk increases with the presence of mixed-size nodules (i.e., the risk of submucosal invasion is greater than 30% for lesions >30 mm)6. LST-Gs with homogeneous patterns can be resected effectively using the EMR technique, while in cases involving mixed-size nodules, ESD should be considered, especially for larger (>30 mm) lesions. Similarly, LST-NGs should be considered for ESD because of substantially increased risk of submucosal invasion, which can range from 7% for lesions <20 mm up to 80% for lesions greater than 30 mm in size with a central pseudo-depression5. Truly depressed lesions present the highest risk of submucosal invasion and are generally referred to surgery. 3
ACCEPTED MANUSCRIPT The Kudo classification has shown a very good correlation between surface epithelium organization, or pit pattern explored in magnification with chromoscopy (e.g., 0.2% indigo carmine solution or other dyes) or narrow-band imaging (NBI) and submucosal invasion. Briefly, the Kudo classification includes seven patterns, which can be grouped into 3 categories: type I and type II (non-neoplastic); type IIIS, IIIL, and IV (low-grade and high-grade intramucosal tumours); and type
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V, with irregular (Vi) or non-structural (VN), amorphous surface (carcinoma with suspicion of submucosal invasion), which is also referred as the invasive pattern, because it is highly indicative of submucosal invasion deeper than 1000 µm. Otherwise, non-invasive patterns (i.e. IIIS, IIIL and IV) suggest intramucosal neoplasia or submucosal invasion less than 1000 µm, thus suitable for
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radical endoscopic treatment. The Kudo classification has been widely validated5.
The NBI International Colorectal Endoscopic (NICE) classification uses narrow-band imaging technology to help identify hyperplastic lesions, adenomas and deep invasive submucosal
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cancer by the analysis of three characteristics: colour, vascular and pit-patterns of lesions4. On the basis of these characteristics, three types of lesion have been categorized: type 1 (hyperplastic), type 2 (adenomas) and type 3 (deep submucosal invasive cancer). Brown to dark brown sometimes with patchy whiter areas, with disrupted or missing vessels and loss of surface pattern should be interpreted as highly suspicious for deep submucosal invasive cancer (type 3) [Table 1]. The
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presence of any one of the 3 criteria for deep submucosal invasion has a sensitivity of 94.9% and a negative predictive value of 95.9%. Furthermore, the NICE classification presents a high interobserver reproducibility, independent of the expertise of the endoscopist4. A recently published systematic review with a meta-analysis of 17 studies that assessed the accuracy of narrow-band
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imaging in the diagnosis of deep submucosal colorectal cancer showed that pooled sensitivity and specificity were 74% (95%CI 66%– 81 %) and 98% (95%CI 94%– 99 %) respectively and the area under the summary receiver operating characteristic curve (AUC) was 0.91 (95%CI 0.88 – 0.93)7.
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Notably, magnifying chromo-endoscopy seemed to perform slightly better than NBI in terms of pooled sensitivity, specificity and AUC, of 84% (95%CI 76%– 89 %), 97% (95%CI 94%– 99 %), and 0.97 (0.95 – 0.98), respectively7. However, the main limitation of the NICE classification is represented by the difficulty in differentiating high-grade dysplasia or superficial invasive carcinoma from low-grade dysplasia8,9. Therefore, in 2014, the Japanese NBI Expert Team (JNET), composed of Japanese specialized in magnifying colonoscopy, proposed a new NBI classification called JNET classification10 [Table 2]. The main differences between the NICE and the JNET classifications are that magnification is a criterion in the JNET classification with the result that NICE Type 2 has 2 subtypes (2A and 2B), and that the two main criteria are vessel and surface patterns, while color findings are not included 4
ACCEPTED MANUSCRIPT anymore. The diagnostic accuracy achieved when the JNET classification is used has been recently evaluated in a Japanese, single-center retrospective study involving 2,933 colorectal lesions (136 hyperplastic polyps/sessile serrated polyps, 1,926 low-grade dysplasias, 571 high-grade dysplasias, 87 superficial submucosal invasive carcinomas, and 213 deep submucosal invasive carcinomas)11. Overall, the results confirmed a weakness of this classification in the correct identification of high-
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grade dysplasia/superficial submucosal invasive cancer (type 2B) with sensitivity, specificity, positive and negative predictive values, and accuracy of 61.9%, 82.8%, 50.9%, 88.2%, and 78.1%, respectively. The JNET classification does not seem to add any additional benefit to the NICE classification; therefore, Sumimoto et al suggest utilizing additional tools to correctly evaluate
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lesions (e.g., pit-pattern assessment using chromoagents)11. Another reason limiting the widespread adoption of the JNET classification in Western countries is that the endoscopes with high-level, graduated optical magnification of 100-fold or more routinely used in Japanese tertiary referral
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centers are rarely used in Western countries: this high level of magnification is not possible with Olympus colonoscopes (e.g. Exera III CF-HQ190) used in Western countries12,13. A colorectal lesion characterized by slight crypt distortion but intact vascular structures (Kudo Vi, NICE type 2) should be considered for ESD resection as there might only be very superficial submucosal invasion, whereas the presence of severely disrupted type Vn pit pattern
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according to the Kudo classification, or type 3 pattern (absent/irregularly thickened vessels) in the NICE/JNET classification should be considered highly indicative for deep submucosal invasion and, after bioptic sampling and ink-tattooing, surgery should be considered,. At the National Cancer Center in Tokyo, Japan, which is the center where the ESD
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procedure has been developed and most performed, the established indications for colorectal ESD are non-granular LST > 20 mm and granular LST >30 mm, as well as residual or recurrent tumors >30 mm6,14. Rectal carcinoid tumors are considered for ESD when <20 mm in size. The same
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indications have been more recently recommended by the European Society of Gastrointestinal Endoscopy (ESGE)15.
The histological analysis of lesions dissected using ESD reported in literature shows that in both Asian and Western studies the majority of lesions are benign adenomas (i.e. low and highgrade dysplasias), while only 10-20% are malignant colorectal lesions [Table 3]16–26. A recently published Asian multicentre retrospective study, involving 1,259 colorectal tumors resected using ESD at 12 institutions, showed that 335 tumors (26.6%) were low-grade dysplasias, 667 tumors (53.0%) were high-grade dysplasias, 153 tumors (12.1%) were deep submucosal invasive carcinomas (≥1000 µm) and only 104 tumors (8.3%) were superficial submucosal invasive carcinomas (<1000 µm)19. This data is confirmed in almost all the published series in which 5
ACCEPTED MANUSCRIPT superficial invasive lesions (i.e. confined to the sm1 layer) represent no more than a half of the malignant lesions. This finding raises concerns about the ability of advanced endoscopic imaging to truly differentiate between superficial and deep submucosal invasive cancer in daily practice, i.e. clinical studies may misrepresent the diagnostic accuracy of these techniques.
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Technique The standard technique for performing ESD in the colo-rectum does not differ from that used for lesions located in the upper GI. Briefly, after injecting the submucosa with a viscous solution (e.g. 0.1% sodium hyaluronate generally mixed with few drops of indigo carmine and
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adrenaline), a needle knife is used to incise the mucosa surrounding the lesion and to dissect it from the submucosal layer. A plastic cap is attached to the tip of the endoscope with the aim of retracting the flap of tissue and produce temporary haemostasis by compressing damaged large vessels, while
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coagulation is achieved with haemostatic forceps. Changing patient position may make it easier to pull the flap of tissue away from the dissection area and gain a better view of the submucosal plane. Finally, a circumferential incision is made and the submucosa is totally separated from the underlying muscle. An alternative to the standard technique is to create a submucosal pocket under the tumor after an initial mucosal incision, approximately 20 mm in length and approximately
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10 mm from the distal side of the tumor [Figure 1]. The main difference from the standard pocketcreation method is completion of the submucosal dissection under the lesion with a minimal mucosal incision. Once the submucosal pocket has been created, additional mucosal incisions and submucosal dissections are made to open the lower side (‘lower’ in terms of the direction of
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gravitational pull) of the pocket toward the proximal side. Finally, a mucosal incision and submucosal dissection of the upper side are performed in the same manner. The standard ESD technique is a challenging and time-consuming procedure, therefore an
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alternative, less challenging technique has also been proposed; it is called the hybrid knife-assisted technique27. This technique is based on the sequential use of an endoscopic knife to circumferentially incise the lesion and partially dissect the submucosal plane to undermine and expose the lesion and the subsequent use of a large snare to complete the en-bloc excision. With this technique, a clear lateral margin is reliably achieved and large lesions may be removed quickly and relatively simply. The main indication for this technique are scarred polyps where an en-bloc excision is difficult to achieve using the standard EMR technique because of the difficulty to obtain good lift28.
6
ACCEPTED MANUSCRIPT The training issue Acquiring competency in the ESD procedure represents the main obstacle to the widespread adoption of this technique in Western countries. The better outcomes achieved by Asian countries are mainly explained by the different training programs, with significant focus on GI cancer epidemiology. To be more specific, Japanese tertiary referral centers adopt a step-up training
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procedure, beginning with a long period in which senior trainees, already skilled in therapeutic endoscopy, observe an ESD expert carrying out at least 40 procedures. In addition, animal cadavers are frequently used during this preliminary training phase. Thereafter, trainees are directly involved as assistants to the expert for about another 20 cases. Gastric lesions located in the antrum are the
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beginning of the hands-on part of the training program, with all procedures closely supervised by the expert, who can intervene if necessary. This type of lesion is ideal for trainees because the thick gastric wall reduces the risk of perforation and lesion location allows for easy access. In addition to
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the step-up training program, the ESD case-load also plays a pivotal role. Several studies have shown that all the main outcomes measures (i.e. en-bloc and R0 resection rates, procedure time and adverse-event rates) significantly improved in the mid-phase after the introduction of ESD in daily practice29. However, in Western countries it is rare for gastric lesions to be considered as candidates for endoscopic resection because they are almost always at an advanced stage at the time of
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diagnosis. In 2015, Yang et al. published a retrospective study in which a single endoscopist without previous experience with gastric ESD removed a total of 250 colorectal lesions from 236 patients using the ESD technique30. The results clearly demonstrated that all the main outcomes significantly improved over time, suggesting that 100 colorectal ESDs should be considered
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sufficient to reach adequate skill. The number of ESDs performed (i.e. >100), rectal location and the severity of fibrosis were identified as the factors significantly influencing the success rate. Unfortunately, this study evaluated the outcomes of a single endoscopist and has never been
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confirmed in different settings. Another important difference between Asian and Western countries is that in the latter ESD is very rarely taught during specialization training. Indeed, ESD is most frequently used by senior endoscopists, who have to find the time and resources to learn and then perform this time-consuming, risky and challenging procedure during their daily, busy practice. Several studies demonstrated that for equivalent-sized lesions, the procedural time for ESD may exceed by 3 to 4 times the time for a standard EMR31–33, thus introducing logistical issues because the long waiting-lists in Western endoscopy units do not allow for the routine use of timeconsuming procedures, further adding an obstacle to the widespread adoption of ESD in these countries.
7
ACCEPTED MANUSCRIPT All the above considerations should always be remembered because they significantly limit the relevance of studies performed in Asian countries, which are only meaningful if they are validated in the context of Western medical practice. Like EMR and standard ESD techniques, the hybrid knife-assisted technique involves a medium length learning curve, and, similarly to these, about 100 procedures has been suggested as
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necessary to achieve adequate en-bloc resection rates, rising from 30% at the outset to more than 75% 34.
Clinical Outcomes
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R0 and en-bloc resection rates
A recently published systematic review and meta-analysis of 109 studies (97 studies
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evaluating the standard technique and 12 studies evaluating the hybrid one), involving more than 19,400 colorectal dissections, showed that ESD carried out with the standard technique achieves a pooled R0 resection rate of 82.9% (95%CI, 80.4%-85.1%) and an en-bloc resection rate of 91% (95%CI, 89.2%-92.5%)35.
As you would expect from a systematic review involving more than 100 studies, the heterogeneity between studies was very high and the authors of the present article investigated the
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topic using subgroup and meta-regression analyses so as to obtain more informative conclusions. The subgroup analysis was done for different parts of the world where the procedure was performed and revealed that the R0 resection rate in Western countries, i.e. Europe and North America, was 71.3% (95%CI, 66.2%-75.9%), which was significantly lower than that observed in Asian countries
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(85.6%; 95%CI, 83.3-87.7%). Doubtless, the number of ESDs performed per year per center may substantially contribute to the difference observed between Eastern and Western countries.
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However, Fuccio et al also performed a subgroup analysis on the basis of the number of procedures performed per year and found that high-volume centers, defined as those centers carrying out more than 2 ESDs per month, in Western countries still continued to present significantly lower R0 resection rates (72.0%; 95%CI 59.5%-81.8%) when compared with Asian high-volume centers (87.4%; 95%CI 85.2%-89.4%). Therefore, the difference between Asian and Western countries might not only be due to different procedure volume but also the training process carried out in these countries, as mentioned above. Indeed, in Asian countries expertise with ESD is generally acquired during a 3-year course following the traditional model of see one, do one, teach one
36,37
and ESD for colorectal lesions represents the end of a step-up training process. In Western countries, as previously mentioned, this model is not feasible for several reasons (i.e. different epidemiology of GI neoplasms suitable for endoscopic resection, lack of time, insufficient number 8
ACCEPTED MANUSCRIPT of experts), therefore lower GI tract lesions frequently are the first lesions removed during the training program, especially those located in the rectum. A different use of image-enhanced magnified endoscopy and bioptic sampling for the pre-procedure assessment of ESD candidate lesions has been suggested as another possible explanation for the difference between Asian and Western countries38. Fibrosis owing to multiple bioptic sampling might increase the difficulty and
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the risk of adverse events associated with dissection, thus partly explaining the worse outcomes reported in Western countries.
Another interesting finding of the systematic review by Fuccio et al35, which was the result of a meta-regression analysis of factors influencing the between-study heterogeneity, was that there
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is a possible inverse association between rectal location and R0 resection rates. An increase in the number of rectal lesions resected resulted in a reduction of R0 resection rates. This finding indirectly confirms the previous observation that rectal lesions, especially in Western countries,
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frequently are the first lesions that are dealt with during training. In addition, because of the common belief that there is a lower risk of major ESD-related adverse events in regard to the rectum, endoscopists may be tempted to carry out ESD for lesions that are beyond their level of expertise.
The meta-analysis of the 12 studies evaluating the hybrid technique revealed quite disappointing results with an R0 resection rate of 60.6% (95%CIm 40.6%-77.5%) and an en-bloc
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resection rate of 68.4% (95%CI 51.7-81.3%)35. The subgroup analysis on the basis of the different parts of the world where the procedure was performed revealed not significantly higher rates in Asian countries (71.1%; 95%CI 43.3%-88.8%) in comparison with Western countries (44.4%; Studies on the use of the hybrid knife-assisted technique for the
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95%CI 24.6%-66.1%).
management of scarred polyps have showed interesting results, with an overall cure rate of 90% and
Safety
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a recurrence rate of 16%39.
ESD is a very challenging and risky procedure, and the most serious complications are perforation and bleeding40. Recently published meta-analysis by Fuccio et al35 shows that the pooled perforation rate using the standard technique was 5.2% (95%CI, 4.4%-6.1%) and again significant differences were observed between Asian and Western countries. The risk of perforation was significantly higher in Western (8.6%; 95%CI, 5.9%-12.2%) than in Asian countries (4.5; 95%CI, 3.9%-5.3%). Several risk factors for ESD-related perforations have been identified, such as location in the colon, tumor size, the presence of submucosal fibrosis and also the endoscopists’ expertise41,42. 9
ACCEPTED MANUSCRIPT Recently, a model able to predict the risk of perforation with good discrimination has been proposed by Hong et al41. The authors developed a nomogram called SELF, in which four variables, size, experience, location and fibrosis, are used to calculate the risk of perforation. For tumors located in the colon (vs. rectum), 2 points were given, one point for each 1-cm increment in tumor size, 2 additional points for the presence of submucosal fibrosis, while one point should be
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subtracted if the endoscopist’s experience is over 50 ESDs. A cut-off score of 4 points was determined; if the total score is 4 or below, the risk of perforation is considered low, about 4%, otherwise for scores above 4 the risk is substantially increased by 3 times (i.e. 11.6%). Despite several limitations, this predictive model is a very useful tool that can help in the decision making
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process, especially for endoscopists who are not highly experienced43.
The early recognition of perforation substantially improves patient outcomes. Use of carbon dioxide is mandatory during ESD, as it reduces the risk of perforation and also favors a
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conservative approach. Once a deep mural injury is detected, endoscopically placed clips (throughthe-scope, TTS) should be used to close the perforation, especially for those smaller than 15-20 mm40,44,45. It has been demonstrated that intra-procedural detection and clipping of perforations, is sufficient to avoid surgery in almost all cases44. The over-the-scope clip (OTSC) has been proposed as alternative to the TTS clip, when larger defects, up to 30 mm, are identified46,47; however, the
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need for scope withdrawal and reinsertion may compromise clinical success. Ma et al suggested several principles to follow to achieve an adequate and successful TTS clip placement and closure of mural defects40. Briefly, these were minimize gas insufflation in order to avoid or reduce tension on the defect, try to maintain the field clean by changing patient position, prevent peristalsis by
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administering anti-peristaltic agents, apply clips generally from left to right. Using an endoscopic suturing device was proposed for the closure of full-thickness colonic perforations. The endoscopic suturing device’s sutures allow close tissue approximation of the wall layers and complete closure
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of even large, deep mural defects after ESD48. Kantsevoy et al reported their experience with 16 patients using the Overstitch device (Apollo Endosurgery Inc, Austin, Tex)49. To perform endoscopic suturing closure, the colonoscope must be withdrawn and a double-channel endoscope preloaded with the suturing device is introduced. The wall defect is then closed with full-thickness sutures either with a continuous suture line or separate stitches. Although it was a retrospective study based on a small sample size, the results suggest that the endoscopic suture closure of colonic perforations is technically feasible and could reduce the need for surgery, especially if compared to closure with TTS clips. The rate of perforation with the hybrid technique is similar to that observed with the standard technique, 4.8% (95%CI, 2.4%-9.1%), without significant differences between 10
ACCEPTED MANUSCRIPT geographical regions. Similarly, the rate of delayed bleeding is about 4.0% (95%CI, 2.8-5.8%) and again without significant differences among regions. Overall, the need for surgery owing to severe adverse events was 1.0% (95% CI, 0.4%-2.3%). Therefore, based on the available evidence, the hybrid technique should not be considered safer than the standard technique. The rate of delayed bleeding (>48 hours) after ESD is about 2.7% (95%CI, 2.2%-3.2%),
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with a not significantly higher rate reported in Western (4.2%) vs. Asian (2.4%) countries. The risk factors for delayed bleeding are almost the same as for perforation, with the exception of lesions located in the rectum, which are associated with an increased risk of bleeding16,50.
Intra-procedural bleeding is very frequent and its prevention and management represents one
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of the most important and time-consuming parts of the procedure. Appropriate settings on the electrosurgical unit during the pre-cut and dissection phases and coagulation of the exposed vessels during the procedure may reduce the risk. Bleeding vessels may be initially managed by utilizing
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the endoscope’s plastic cap to dab the bleeding vessel, executing a mechanical haemostasis in order to maintain the field clean, and then using a soft coagulation or coagulation grasper to coagulate the vessels. The prophylactic treatment of non-bleeding vessels at the end of the procedure has always been matter of debate, since there is no clear evidence that this practice may significantly reduce the risk of late-onset bleeding.
Electrocoagulation syndrome is definitively more common after ESD than EMR, and it
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occurs in about 1 in every 12 dissections51,52. This syndrome is due to transmural thermal injury to the colon wall and generally develops within 24-48 hours after the procedure, and it is characterized by fever, localized abdominal pain, no sign of intra-peritoneal air in X-rays and an increase in C-
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reactive protein and leukocytosis53. The two independent risk factors for electrocoagulation syndrome are the lesion size (> 30 mm) and lesion location in the colon, and either of these individual factors may increase the risk 5 to 7 times54. The treatment is conservative and based on
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the intravenous administration of fluids and antibiotics as well as bowel rest; the prognosis is generally favorable, with clinical remission normally occurring within 24 hours. The risk of post-ESD stenosis is very low. A recently published large retrospective study performed in Japan, involving 912 dissected lesions in 822 patients, reported an incidence of postESD stenosis of 0.49% (4 cases)55. Stenosis occurred only in patients with a circumferential mucosal defect of more than 90%, three cases were located in the rectum and stenosis developed within 3 months of the procedure. All the cases were easily managed by 1 to 3 sessions of endoscopic balloon dilation with the adjunct of steroid therapy (i.e. betamethasone steroid suppositories, 1.0 mg/day, for 90 days). Steroid therapy should be used only for cases considered at risk of early re-stenosis. Surgery was not indicated for any of these cases. 11
ACCEPTED MANUSCRIPT Overall, it should be noted that, based on the best available evidence, most of the adverse events occurring after ESD are generally managed endoscopically; indeed, the need for surgery due to severe complications has been estimated as 1.1% (95%CI, 0.8%-1.3%), but again with a significantly higher rate reported in Western countries (3.1%; 95%CI, 2.1%-4.7%) compared to
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Asian countries (0.8%; 95%CI, 0.6%-1.0%) 35.
The risk of recurrence after ESD
The rate of recurrence 12 months after standard ESD is low, about 2.0% (95% 1.3-3.0), but again with significant difference between Western (5.2%; 95%CI 3.3-8.1%) and Asian countries
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(1.1%; 95% 0.7-1.8%)35. A recently published retrospective, single-center, Japanese study involving 224 colorectal lesions dissected using ESD in 222 patients, reported after a median
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follow-up of 79 months a local recurrence rate of 1.5%56. Risk factors for recurrence were the type of resection (i.e., piecemeal vs. en bloc), incomplete resection detected at histology (i.e. complete resection defined as horizontal and vertical margins negative) and in cases of non-curative resection (i.e. complete resection and no risk of lymph node metastasis on histologic examination57). The risk of recurrence after EMR is definitely greater; a recently published systematic review by Hassan et al, involving 50 studies and 6,779 polyps larger than 2 cm, reported a
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recurrence rate during endoscopic surveillance of 13.8% (95% CI 12.9%-14.7%)58. Of note is that endoscopic treatment of post-EMR recurrence was successfully achieved in about 90% of cases and
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surgery was required for 4.2% of patients.
Comparison between ESD and EMR A meta-analysis of 8 studies published between 2005 and 2013 comparing ESD with EMR
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for the treatment of colorectal lesions showed that ESD achieved significantly better outcomes than EMR in regard to en-bloc resection and curative resection rates32. However, safety was definitely lower, since the rate of perforation during ESD (5.7%) was significantly higher than that reported using EMR (1.4%). In addition, the need for additional surgery was significantly higher after ESD; the main reason was massive submucosal invasion, suggesting a failure in the correct selection of cases suitable for ESD removal.
Conclusions ESD is an effective and safe procedure, at least in Asian countries. In Western countries initiatives should be introduced to improve the main outcomes. The lower occurrence of this 12
ACCEPTED MANUSCRIPT procedure in Western countries is also due to a different management of the same types of lesion. The correct selection of cases that are suitable for ESD instead of EMR is the main issue, since advance imaging endoscopy does not always guarantee an adequate differentiation between highgrade dysplasia, superficial submucosal invasive cancer and deep invasive cancer.
Available
evidence shows that ESD is mainly used for benign lesions (i.e. low- and high-grade adenomas),
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while malignant lesions represent less than 20% of dissected cases and, disappointingly, superficially invading lesions (i.e. confined to the sm1 layer), are no more than half of all cases (5%-10%). Therefore, every 10 ESDs used to treat (number needed to treat [NNT]) prevents the need for surgery for one patient with superficial invasion (sm1) in the Asian series, while in the
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European series one operation is prevented every 35 ESDs 59. This means that the above-mentioned criteria for case selection are not adequately and correctly implemented in clinical practice, and therefore diagnostic criteria need to be improved. Since the best available evidence has been
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published by tertiary referral centers, it can be presumed that there is worse performance in other settings (i.e. low-volume centers without internal auditing of main outcomes). The improvement of all the clinical outcomes in Western countries should represent the main goal for the near future; this can be achieved by referring patients to centers that are staffed with endoscopists skilled in
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ESD and by implementing certified and step-up training programs.
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ACCEPTED MANUSCRIPT Clinical Practice Points & Research Agenda •
Differences are still present between Asian and Western countries in regard to main outcomes measures (i.e., en-bloc and R0 resection rates, complication rates and risk of relapse).
•
Despite several validated classifications being proposed with the aim of helping case
still represent a minority of the lesions dissected.
A formal and certified step-up training program and a constantly performed internal audit of the main outcome measures should be promoted in each center, especially in Western
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countries.
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•
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selection identification of lesions highly suspicious for superficial malignant invasion, these
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ACCEPTED MANUSCRIPT REFERENCES
1.
Yamamoto H, Yube T, Isoda N, et al. A novel method of endoscopic mucosal resection using sodium hyaluronate. Gastrointest Endosc. 1999;50(2):251-256. http://www.ncbi.nlm.nih.gov/pubmed/10425422. Accessed May 22, 2017. Kudo S, Kashida H, Nakajima T, Tamura S, Nakajo K. Endoscopic diagnosis and treatment of early colorectal cancer. World J Surg. 1997;21(7):694-701.
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2.
http://www.ncbi.nlm.nih.gov/pubmed/9276699. Accessed May 22, 2017. 3.
The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and
SC
colon: November 30 to December 1, 2002. Gastrointest Endosc. 2003;58(6 Suppl):S3-43. http://www.ncbi.nlm.nih.gov/pubmed/14652541. Accessed May 22, 2017. 4.
Hayashi N, Tanaka S, Hewett DG, et al. Endoscopic prediction of deep submucosal invasive
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carcinoma: validation of the narrow-band imaging international colorectal endoscopic (NICE) classification. Gastrointest Endosc. 2013;78(4):625-632. doi:10.1016/j.gie.2013.04.185. 5.
Kudo S ei, Lambert R, Allen JI, et al. Nonpolypoid neoplastic lesions of the colorectal mucosa. Gastrointest Endosc. 2008;68(4 Suppl):S3-47. doi:10.1016/j.gie.2008.07.052. Uraoka T, Saito Y, Matsuda T, et al. Endoscopic indications for endoscopic mucosal
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6.
resection of laterally spreading tumours in the colorectum. Gut. 2006;55(11):1592-1597. doi:10.1136/gut.2005.087452. 7.
Zhang Q-W, Teng L-M, Zhang X-T, et al. Narrow-band imaging in the diagnosis of deep
EP
submucosal colorectal cancers: a systematic review and meta-analysis. Endoscopy. 2017;49(6):564-580. doi:10.1055/s-0043-103014. 8.
Tanaka S, Hayashi N, Oka S, Chayama K. Endoscopic Assessment of Colorectal Cancer with
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Superficial or Deep Submucosal Invasion Using Magnifying Colonoscopy. Clin Endosc. 2013;46(2):138. doi:10.5946/ce.2013.46.2.138. 9.
Tanaka S, Sano Y. Aim to unify the narrow band imaging (NBI) magnifying classification for colorectal tumors: current status in Japan from a summary of the consensus symposium in the 79th Annual Meeting of the Japan Gastroenterological Endoscopy Society. Dig Endosc. 2011;23 Suppl 1:131-139. doi:10.1111/j.1443-1661.2011.01106.x.
10.
Sano Y, Tanaka S, Kudo S-E, et al. Narrow-band imaging (NBI) magnifying endoscopic classification of colorectal tumors proposed by the Japan NBI Expert Team. Dig Endosc. 2016;28(5):526-533. doi:10.1111/den.12644.
11.
Sumimoto K, Tanaka S, Shigita K, et al. Clinical impact and characteristics of the narrow15
ACCEPTED MANUSCRIPT band imaging magnifying endoscopic classification of colorectal tumors proposed by the Japan NBI Expert Team. Gastrointest Endosc. 2017;85(4):816-821. doi:10.1016/j.gie.2016.07.035. 12.
Bhat YM, Abu Dayyeh BK, Chauhan SS, et al. High-definition and high-magnification endoscopes. Gastrointest Endosc. 2014;80(6):919-927. doi:10.1016/j.gie.2014.06.019. Hewett DG, Sakata S. Classifications for optical diagnosis of colorectal lesions: not
RI PT
13.
2B??with JNET. Gastrointest Endosc. 2017;85(4):822-828. doi:10.1016/j.gie.2017.01.004. 14.
Nakajima T, Saito Y, Tanaka S, et al. Current status of endoscopic resection strategy for
doi:10.1007/s00464-013-2903-x. 15.
SC
large, early colorectal neoplasia in Japan. Surg Endosc. 2013;27(9):3262-3270.
Pimentel-Nunes P, Dinis-Ribeiro M, Ponchon T, et al. Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy.
16.
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2015;47(9):829-854. doi:10.1055/s-0034-1392882.
Saito Y, Uraoka T, Yamaguchi Y, et al. A prospective, multicenter study of 1111 colorectal endoscopic submucosal dissections (with video). Gastrointest Endosc. 2010;72(6):12171225. doi:10.1016/j.gie.2010.08.004.
17.
Tamai N, Saito Y, Sakamoto T, Nakajima T, Matsuda T, Tajiri H. Safety and efficacy of
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colorectal endoscopic submucosal dissection in elders: clinical and follow-up outcomes. Int J Colorectal Dis. 2012;27(11):1493-1499. doi:10.1007/s00384-012-1514-7. 18.
Repici A, Hassan C, Pagano N, et al. High efficacy of endoscopic submucosal dissection for rectal laterally spreading tumors larger than 3 cm. Gastrointest Endosc. 2013;77(1):96-101.
19.
EP
doi:10.1016/j.gie.2012.08.036.
Boda K, Oka S, Tanaka S, et al. Clinical outcomes of endoscopic submucosal dissection for colorectal tumors: a large multicenter retrospective study of Hiroshima GI Endoscopy
20.
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Research Group. Gastrointest Endosc. 2017. doi:10.1016/j.gie.2017.05.051. Hurlstone DP, Atkinson R, Sanders DS, Thomson M, Cross SS, Brown S. Achieving R0 resection in the colorectum using endoscopic submucosal dissection. Br J Surg. 2007;94(12):1536-1542. doi:10.1002/bjs.5720. 21.
Isomoto H, Nishiyama H, Yamaguchi N, et al. Clinicopathological factors associated with clinical outcomes of endoscopic submucosal dissection for colorectal epithelial neoplasms. Endoscopy. 2009;41(8):679-683. doi:10.1055/s-0029-1214979.
22.
Yoshida N, Naito Y, Kugai M, et al. Efficient hemostatic method for endoscopic submucosal dissection of colorectal tumors. World J Gastroenterol. 2010;16(33):4180-4186. http://www.ncbi.nlm.nih.gov/pubmed/20806436. Accessed May 26, 2017. 16
ACCEPTED MANUSCRIPT 23.
Nakajima T, Saito Y, Tanaka S, et al. Current status of endoscopic resection strategy for large, early colorectal neoplasia in Japan. Surg Endosc. 2013;27(9):3262-3270. doi:10.1007/s00464-013-2903-x.
24.
Thorlacius H, Uedo N, Toth E. Implementation of Endoscopic Submucosal Dissection for Early Colorectal Neoplasms in Sweden. Gastroenterol Res Pract. 2013;2013:1-6.
25.
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doi:10.1155/2013/758202. Takeuchi Y, Iishi H, Tanaka S, et al. Factors associated with technical difficulties and adverse events of colorectal endoscopic submucosal dissection: retrospective exploratory factor analysis of a multicenter prospective cohort. Int J Colorectal Dis. 2014;29(10):1275-
26.
SC
1284. doi:10.1007/s00384-014-1947-2.
Lee E-J, Lee JB, Lee SH, Youk EG. Endoscopic treatment of large colorectal tumors: comparison of endoscopic mucosal resection, endoscopic mucosal resection-precutting, and
doi:10.1007/s00464-012-2164-0. 27.
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endoscopic submucosal dissection. Surg Endosc. 2012;26(8):2220-2230.
Toyonaga T, Man-I M, Morita Y, Azuma T. Endoscopic submucosal dissection (ESD) versus simplified/hybrid ESD. Gastrointest Endosc Clin N Am. 2014;24(2):191-199. doi:10.1016/j.giec.2013.11.004.
Longcroft-Wheaton G, Bhandari P. Management of early colonic neoplasia: where are we
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28.
now and where are we heading? Expert Rev Gastroenterol Hepatol. 2017;11(3):1-10. doi:10.1080/17474124.2017.1279051. 29.
SAITO Y, KAWANO H, TAKEUCHI Y, et al. CURRENT STATUS OF COLORECTAL
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ENDOSCOPIC SUBMUCOSAL DISSECTION IN JAPAN AND OTHER ASIAN COUNTRIES: PROGRESSING TOWARDS TECHNICAL STANDARDIZATION. Dig Endosc. 2012;24:67-72. doi:10.1111/j.1443-1661.2012.01282.x. Yang D-H, Jeong GH, Song Y, et al. The Feasibility of Performing Colorectal Endoscopic
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30.
Submucosal Dissection Without Previous Experience in Performing Gastric Endoscopic Submucosal Dissection. Dig Dis Sci. 2015;60(11):3431-3441. doi:10.1007/s10620-0153755-0. 31.
Klein A, Bourke MJ. Advanced Polypectomy and Resection Techniques. Gastrointest Endosc Clin N Am. 2015;25(2):303-333. doi:10.1016/j.giec.2014.11.005.
32.
Fujiya M, Tanaka K, Dokoshi T, et al. Efficacy and adverse events of EMR and endoscopic submucosal dissection for the treatment of colon neoplasms: a meta-analysis of studies comparing EMR and endoscopic submucosal dissection. Gastrointest Endosc. 2015;81(3):583-595. doi:10.1016/j.gie.2014.07.034. 17
ACCEPTED MANUSCRIPT 33.
Heitman SJ, Bourke MJ. Endoscopic submucosal dissection and EMR for large colorectal polyps: ?the perfect is the enemy of good? Gastrointest Endosc. 2017;86(1):87-89. doi:10.1016/j.gie.2017.03.022.
34.
Bhattacharyya R, Chedgy FJ, Kandiah K, Longcroft-Wheaton G, Bhandari P. Knife-assisted snare resection (KAR) of large and refractory colonic polyps at a Western centre: Feasibility,
2016;4(3):466-473. doi:10.1177/2050640615615301. 35.
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safety and efficacy study to guide future practice. United Eur Gastroenterol J.
Fuccio L, Hassan C, Ponchon T, et al. Clinical outcomes after endoscopic submucosal dissection for colorectal neoplasia: a systematic review and meta-analysis. Gastrointest
36.
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Endosc. February 2017. doi:10.1016/j.gie.2017.02.024.
Yamamoto Y, Fujisaki J, Ishiyama A, Hirasawa T, Igarashi M. Current status of training for endoscopic submucosal dissection for gastric epithelial neoplasm at Cancer Institute
M AN U
Hospital, Japanese Foundation for Cancer Research, a famous Japanese hospital. Dig Endosc. 2012;24 Suppl 1:148-153. doi:10.1111/j.1443-1661.2012.01278.x. 37.
Draganov P V, Coman RM, Gotoda T. Training for complex endoscopic procedures: how to incorporate endoscopic submucosal dissection skills in the West? Expert Rev Gastroenterol Hepatol. 2014;8(2):119-121. doi:10.1586/17474124.2014.864552. Saito Y, Bhatt A, Matsuda T. Colorectal endoscopic submucosal dissection and its journey to
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38.
the West. Gastrointest Endosc. 2017;86(1):90-92. doi:10.1016/j.gie.2017.03.1548. 39.
Chedgy F, Bhattacharyya R, Kandiah K, Longcroft-Wheaton G, Bhandari P. Knife-assisted snare resection: a novel technique for resection of scarred polyps in the colon. Endoscopy.
40.
EP
2016;48(3):277-280. doi:10.1055/s-0035-1569647. Ma MX, Bourke MJ. Complications of endoscopic polypectomy, endoscopic mucosal resection and endoscopic submucosal dissection in the colon. Best Pract Res Clin
41.
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Gastroenterol. 2016;30(5):749-767. doi:10.1016/j.bpg.2016.09.009. Hong SN, Byeon JS, Lee B-I, et al. Prediction model and risk score for perforation in patients undergoing colorectal endoscopic submucosal dissection. Gastrointest Endosc. 2016;84(1):98-108. doi:10.1016/j.gie.2015.12.011. 42.
Yoshida N, Wakabayashi N, Kanemasa K, et al. Endoscopic submucosal dissection for colorectal tumors: technical difficulties and rate of perforation. Endoscopy. 2009;41(9):758761. doi:10.1055/s-0029-1215028.
43.
Kantsevoy S V. A new tool to estimate the risk of perforations during colorectal endoscopic submucosal dissection. Gastrointest Endosc. 2016;84(1):109-114. doi:10.1016/j.gie.2016.03.1495. 18
ACCEPTED MANUSCRIPT 44.
Yang D-H, Byeon J-S, Lee K-H, et al. Is endoscopic closure with clips effective for both diagnostic and therapeutic colonoscopy-associated bowel perforation? Surg Endosc. 2010;24(5):1177-1185. doi:10.1007/s00464-009-0746-2.
45.
Magdeburg R, Sold M, Post S, Kaehler G. Differences in the endoscopic closure of colonic perforation due to diagnostic or therapeutic colonoscopy. Scand J Gastroenterol.
46.
RI PT
2013;48(7):862-867. doi:10.3109/00365521.2013.793737. Weiland T, Fehlker M, Gottwald T, Schurr MO. Performance of the OTSC System in the endoscopic closure of iatrogenic gastrointestinal perforations: a systematic review. Surg Endosc. 2013;27(7):2258-2274. doi:10.1007/s00464-012-2754-x.
Singhal S, Changela K, Papafragkakis H, Anand S, Krishnaiah M, Duddempudi S. Over the
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47.
Scope Clip. J Clin Gastroenterol. 2013;47(9):749-756. doi:10.1097/MCG.0b013e318296ecb9.
Kantsevoy S V., Bitner M, Mitrakov AA, Thuluvath PJ. Endoscopic suturing closure of large
M AN U
48.
mucosal defects after endoscopic submucosal dissection is technically feasible, fast, and eliminates the need for hospitalization (with videos). Gastrointest Endosc. 2014;79(3):503507. doi:10.1016/j.gie.2013.10.051. 49.
Kantsevoy S V., Bitner M, Hajiyeva G, et al. Endoscopic management of colonic
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perforations: clips versus suturing closure (with videos). Gastrointest Endosc. 2016;84(3):487-493. doi:10.1016/j.gie.2015.08.074. 50.
Terasaki M, Tanaka S, Shigita K, et al. Risk factors for delayed bleeding after endoscopic submucosal dissection for colorectal neoplasms. Int J Colorectal Dis. 2014;29(7):877-882.
51.
EP
doi:10.1007/s00384-014-1901-3.
Yamashina T, Takeuchi Y, Uedo N, et al. Features of electrocoagulation syndrome after endoscopic submucosal dissection for colorectal neoplasm. J Gastroenterol Hepatol.
52.
AC C
2016;31(3):615-620. doi:10.1111/jgh.13052. Hong MJ, Kim JH, Lee S-Y, Sung I-K, Park HS, Shim CS. Prevalence and Clinical Features of Coagulation Syndrome After Endoscopic Submucosal Dissection for Colorectal Neoplasms. Dig Dis Sci. 2015;60(1):211-216. doi:10.1007/s10620-014-3484-9. 53.
Cha J, Lim K, Lee S, et al. Clinical outcomes and risk factors of post-polypectomy coagulation syndrome: a multicenter, retrospective, case-control study. Endoscopy. 2013;45(3):202-207. doi:10.1055/s-0032-1326104.
54.
Jung D, Youn YH, Jahng J, Kim J-H, Park H. Risk of electrocoagulation syndrome after endoscopic submucosal dissection in the colon and rectum. Endoscopy. 2013;45(9):714-717. doi:10.1055/s-0033-1344555. 19
ACCEPTED MANUSCRIPT 55.
Hayashi T, Kudo S-E, Miyachi H, et al. Management and risk factor of stenosis after endoscopic submucosal dissection for colorectal neoplasms. Gastrointest Endosc. December 2016. doi:10.1016/j.gie.2016.11.032.
56.
Shigita K, Oka S, Tanaka S, et al. Long-term outcomes after endoscopic submucosal dissection for superficial colorectal tumors. Gastrointest Endosc. 2017;85(3):546-553.
57.
RI PT
doi:10.1016/j.gie.2016.07.044. Watanabe T, Itabashi M, Shimada Y, et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2014 for treatment of colorectal cancer. Int J Clin Oncol. 2015;20(2):207-239. doi:10.1007/s10147-015-0801-z.
Hassan C, Repici A, Sharma P, et al. Efficacy and safety of endoscopic resection of large
SC
58.
colorectal polyps: a systematic review and meta-analysis. Gut. 2016;65(5):806-820. doi:10.1136/gutjnl-2014-308481.
M AN U
Rex DK, Hassan CC, Dewitt JM. Colorectal endoscopic submucosal dissection in the United States: Why do we hear so much about it and do so little of it? Gastrointest Endosc.
EP
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2017;85(3):554-558. doi:10.1016/j.gie.2016.09.015.
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59.
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ACCEPTED MANUSCRIPT Figure 1 – Pocket-creation method. Laterally spreading tumor, granular type (LST-G), 5 x 4 cm in size, at the recto-sigmoid junction, developed in a patient with long-standing ulcerative colitis [a]. A submucosal pocket was created under the tumor after an initial mucosal incision, approximately 10 mm from the distal side of the tumor, [b]. Once the submucosal pocket had been created [c],
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adenoma with low-grade dysplasia; vertical and lateral margins were free of neoplasia.
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ACCEPTED MANUSCRIPT Table 1 – NBI International Colorectal Endoscopic (NICE) Classification Type 1
Type 2
Type 3
Color
Same or lighter than background
Browner relative to background (verify color arises from vessels)
Brown to dark brown relative to background; sometimes patchy whiter areas
Vessels
None, or isolated lacy vessels across the lesion
Brown vessels surrounding white structures
Area(s) disrupted or lacking vessels
Surface pattern
Dark or white spots of uniform size, or homogeneous absence of pattern
Oval, tubular or branched white structure/s surrounded by brown vessels
Amorphous or absent surface pattern
Most likely pathology
Hyperplastic
Adenoma
Deep submucosal invasive cancer
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ACCEPTED MANUSCRIPT Table 2 – Japanese NBI Expert Team (JNET) Classification Type 2A
Type 2B
Type 3
Vessel pattern
Invisible
Regular caliber Regular distribution (meshed/spiral pattern)
Variable caliber Irregular distribution
Loose vessel areas Interruption of thick vessels
Surface pattern
Regular dark or white spots Similar to surrounding normal mucosa
Regular (tubular/branched/ papillary)
-Irregular or obscure
Amorphous areas
Most likely histology
Hyperplastic polyp/Sessile serrated polyp
Low-grade intramucosal neoplasia
High-grade intramucosal neoplasia/Superfic ial submucosal invasive cancer
Deep submucosal invasive cancer
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ACCEPTED MANUSCRIPT Table 3 – Histology of dissected lesions. Region Europe Asia Asia Asia Asia Asia Asia Europe Europe Asia Asia
Design Prospective Retrospective Prospective Retrospective Retrospective Retrospective Prospective Prospective Retrospective Retrospective Retrospective
Lesions 42 292 1111 250 635 874 816 40 29 816 1259
Adenomas (n) 40 265 875 231 485 736 660 38 24 661 1002
sm1 (n) 1 18 112 7 68 74 88 2 3 88 104
sm2 or deeper (n) 1 9 101 12 71 58 62 0 2 67 153
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Publication year 2007 2009 2010 2010 2012 2012 2013 2013 2013 2014 2017
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Author (Reference) Hurlstone DP et al (14) Isomoto H et al (15) Saito Y et al (10) Yoshida N et al (16) Tamai N et al (11) Lee E-J et al (20) Nakajima T et al (17) Repici A et al (12) Thorlacius H et al (18) Takeuchi Y et al (19) Boda K et al (13)
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