Juergen Hochberger1, Edris Wedi2, Peter Koehler3, SongSa Dammer4, and Thomas Brunk1 1 Vivantes Klinikum im Friedrichshain, Berlin, Germany 2 Sana Klinikum Offenbach, Offenbach, Germany 3 Federal Research Institute for Animal Health (FLI) Mariensee, Neustadt, Germany 4 St. Bernward-Hospital, Hildesheim, Germany Endoscopic resection (ER) started with the introduction of snare polypectomy in the colon, esophagus, cardia, and stomach in Germany and in Japan at the end of the 1960s and beginning of 1970s [1]. Polypectomy as the name says is useful for the removal of polypoid lesions. The technique frequently fails when a soft standard snare is applied to remove an only slightly elevated lesion. With the introduction of saline‐assisted polypectomy in 1973 by Deyhle et al., the removal of flat lesions was facilitated [1]. This technique is nowadays the classic “endoscopic mucosal resection” (EMR) [2–5]. Mechanical alternatives include the use of a stiff monofilament snare to be pressed into the mucosa or the aspiration of mucosa into a plastic cap mounted onto the distal end of the endoscope [6, 7]. The cap is preloaded with a special fine asymmetrical snare placed into a narrow inner rim at the distal end of the cylinder and closed once the mucosal “mushroom” has been aspirated [7]. A common practice in the esophagus and cardia is today the aspiration of the mucosa into a transparent cylinder with externally deployable rubber bands, ligate a pseudo‐mushroom after mucosal aspiration, and to consecutively snare it off underneath the rubber band [8, 9]. Recently, “Underwater EMR” has gained increasing interest [10, 11]. The bowel is filled with water during EMR and conventional snare resection carried out. A recent metanalysis showed an improved “en bloc” resection rate as well as a lower recurrence rate [12–14]. The search for techniques to resect even large mucosal areas with early gastric cancer and to get a thorough histopathologic diagnosis led to the development of “endoscopic submucosal dissection” (ESD) in Japan at the end of the 1990s [15–20]. The concept is based on a freehand needle‐knife technique as applied in needle‐knife sphincterotomy for difficult access to the biliary or pancreatic duct in ERCP. A large submucosal fluid cushion serves as protective layer when the lesion is first isolated by means of a circular cut outside a safety zone marked beforehand by fine coagulation dots placed around the margins of the lesion. After this circumferential incision, the lesion is separated from the muscolaris propria at the level of the submucosa. This gives the technique the name of “submucosal dissection.” Various knives and special tools have been developed for this scope. The latest development in the field of endoscopic resection is “Endoscopic Full Thickness Resection” using an over‐the‐scope clip (OTSC)‐based system (eFTRD; Ovesco Corp; Tuebingen Germany) [18–21]. An area up to 2 cm in the extra‐papillary duodenum and 3 cm in the lower gastrointestinal (GI) tract can be resected including the entire gastrointestinal wall. In the stomach, the situation is not clear yet as the gastric wall is thick. The system includes the principle of over‐the‐scope clip (OTSC) plus endoscopic cap resection of 90% of the tissue inside the macroclip using a flexible braided snare. After marking the area to be removed by fine coagulation dots including a safety zone of 2–3 mm around the lesion, the resection area is drawn into the transparent cylinder of the device by means of a grasping forceps and then kept in place by suction. A nitinol OTSC macroclip is then fired in order to form a tissue mushroom. Third, a snare fitted within the tip of the OTSC cylinder is closed via the external snare handle and current is applied to resect the tissue inside the OTSC about 2 mm over the base of the tissue mushroom. The technique is especially helpful for the treatment of circumscript recurrent adenoma on a scar in the colon. In the following section, the key steps for proper acquisition of EMR, ESD, and endoscopic full thickness resection device (eFTRD) techniques as well as the prerequisites are explained. There is no doubt that a theoretical explanation of the techniques even when illustrated by images, schemes, and video sequences does not replace a one‐to‐one supervised preclinical and clinical teaching situation. However, we hope you will find some helpful tips for your daily practice. Colon: Esophagus: Stomach: Small intestine: EMR is carried out in the entire gastrointestinal tract according to the same principle. Preferred localizations are colo‐rectum, stomach, esophagus, and small intestine. It can be part of any primarily diagnostic intervention in these organs, for example, within preventive colonoscopy. Accordingly, it can also be part of gastroscopy, enteroscopy, and endoscopic retrograde cholangiopancreatography (ERCP) procedures. As described above, EMR can be carried our as standard or as “Underwater EMR” after previous filling of the bowel segment with water, e.g., for the resection of colon polyps [12–14]. There is a large variety in the level of expertise needed for EMR depending on the lesion itself as well as the resection technique applied. As important as the mechanical act itself is today a daily training concerning the proper evaluation and classification of lesions according to endoscopic criteria for dysplasia and malignancy. Prerequisite training must also include submucosal injection using saline and marking of lesions that should be resected. Supervised training in EMR mostly starts start in the second year of fellowship and should be taught together with injection and clip hemostasis after trainees have gathered sufficient experience in unsupervised gastroscopy and colonoscopy [22, 24] (Figure 19.1). An exact number is not known, but 50 unsupervised colonoscopies plus 100 unsupervised gastroscopies could be a good starting point for the first supervised steps in EMR. The learner should begin with uncomplicated colo‐rectal polyps of less than 2 cm and easy to reach, as for example, in the rectum. More sophisticated techniques and EMRs of lesions found in more difficult locations such as the duodenum, the esophagus, or the stomach do require a far higher level of expertise and a prerequisite competence in complication management (defect closure and bleeding control) [22]. The necessary skills for EMR are best obtained in an initial “hands‐on” training course and subsequent clinical guidance by an experienced endoscopist. It is a prerequisite that the trainee is familiar with indications for EMR. The trainee must know contraindications for endoscopic procedures in general and in particular for EMR. Specifically, the trainee has to be able to anticipate and to act upon procedure‐related complications during and after EMR. EMR as well as all other endoscopic resection techniques discussed here require sufficient mastery of the following cognitive skills: Length, stiffness, and width of the instrumentation channel of the endoscope used play an important role for the success, ease, and potential complication management of the procedure. For delineation of the lesion and possible marking of the resection area with coagulation dots, the endoscope with the best optical quality and features such as digital chromoendoscopy and if available Zoom function should be used. In the upper GI tract, this is often a slim, high‐resolution standard gastroscope (e.g., Olympus 190 series; Olympus Japan; Fuji 760 Z or R; Fujifilm Japan) whereas in the colon standard colonoscopes often provide the best optical quality available. For the resection/therapeutic intervention itself, the change to a therapeutic high‐resolution gastroscope with a channel of 3.8 mm is advisable. It allows rapid clearance of the resection bed in case of bleeding by rinsing and effective suction and may be crucial for the successful outcome of the intervention. For the duodenum, including the papilla a duodenoscope is often helpful or the appropriate instrument. At the level of the lower duodenal knee and in the third part of the duodenum, a standard or pediatric colonoscope may be advisable. In the rectum, a therapeutic gastroscope may prove favorable as it is easier to maneuver than a long routine colonoscope. Especially for resections over the hemorrhoidal plexus in the distal rectum, the short instrument proves helpful. EMR in the jejunum is possible by means of a pediatric colonoscope up to 30–50 cm distal to the ligament of Treitz. In principle, EMR can be carried out in the entire small intestine, for example, in familiar adenomatous polyposis (FAP) patients by means of a therapeutic double‐balloon or motor‐driven spiral enteroscope (e.g., EN580T Fujifilm, Japan; Olympus PowerSpiral PSF‐1, Olympus Tokyo, Japan). EMRs of tumors of the papilla of Vater (Figure 19.2) require advanced skills in ERCP and have to be discussed separately. Special locations of EMRs have been described, such as the pharynx and hypopharynx or in the common bile duct on the percutaneous–transhepatic route [25, 26]. Sedation should be carried out according to national guidelines. In cases of severe comorbidity or extremely complex interventions, general anesthesia should be considered. EMR procedures in large lesions or with technically difficult anatomical access may take considerable time, for example, up to 2–3 hours. CO2 insufflation is today the standard for diagnostic and especially therapeutic endoscopy in the entire GI tract. CO2 is absorbed 300 times faster than room air by the intestine and exhausted in exhaled air. In reduces the risk of an “abdominal compartment syndrome” with the risk of vomiting and aspiration in long therapeutic colonic interventions, the risk of over‐extension of the small intestine in upper GI interventions or colonic interventions in the right‐sided colon and finally favors rapid re‐absorption by the peritoneum in case of macro‐ or micro‐perforation. Most manufacturers provide specific insufflation devices for their endoscopes (Figure 19.2). A separate flush pump (e.g., “Endowasher” Griessat Endotechnik, Solingen, Germany) operated by a foot switch and coupled in by means of a separate “jet channel” Y‐adapter at the level of the biopsy valve facilitates the removal of debris, blood, or mucus. This way, the water pump can be operated without taking the instrument out of the accessory channel during irrigation and seems essential for ER techniques (Figure 19.2). The equipment for EMR depends on the individual lesion and anatomical situation and the resection technique planned. Criteria to select specific equipment include size, macroscopic appearance, and location of the target lesion, and may vary considerably. Colon Esophagus Stomach Duodenum [Note: When a side‐viewing duodenoscope is usedrotable (blue), MicroTech endoscopy clips (MicroTech Endoscopy, An Arbor, Mi) are preferred Major and minor papilla Jejunum and deep small intestine Salvage accessories To justify EMR within a procedure, it has to be covered within the informed consent of the patient prior to the intervention. If EMR appears to be indicated during a primarily diagnostic intervention, the physician has to decide if he needs additional information for example, a rectal ultrasound or magnetic resonance imaging (MRI) of the lesser pelvis to exclude invasive growth or if it seems justified to proceed to resection within the same session. Furthermore, it has to be cleared if alternative treatment options have been discussed sufficiently and if the patient would be ready to accept that she/he needs hospitalization after a complex procedure. Especially in the upper GI tract without the necessity of a special preparation and easy and fast access, it is rather recommended to come back in a second session than to proceed to an invasive procedure without having discussed the next steps sufficiently with the patient. EMR in difficult locations or large lesions may require a long‐lasting procedure. Fitness of the patient for prolonged sedation during this intervention and complication management has to be checked early. For special interventions, anesthesia may be required for airway management. Furthermore, the intervention has to be seen in an interdisciplinary context and alternatives be balanced. Is this the best treatment option for the patient also in the eyes of his relatives or of a general surgeon? Often, it is better to postpone an elective intervention if conditions are not optimal or patient and relatives not thoroughly convinced of the procedure. The general preparation is according to the “carrier procedure,” for example, gastroscopy or colonoscopy. Special medication such as anticoagulants should be discontinued according to national guidelines and individual recommendations, for example, of the attending cardiologist [28]. EMR is focused on the removal of epithelial lesions. The first step to an exact evaluation of the lesion is optimal visualization. One should always inspect the entire lesion, including the proximal and lateral margins. Debris or stools should completely be flushed off the lesion and its proximity. Within the last decade, new technical features such as digital chromoendoscopy (NBI, BLI, LCI, I‐scan), zoom and high‐resolution endoscopy (HRE) have added a significant diagnostic yield to standard video endoscopes [29]. Optical contrast such as NBI or BLI can help to better delineate the margins of the lesion and to evaluate the surface structure and the so‐called “pit pattern” [30]. Already by optical appearance, an experienced endoscopist may correctly classify a lesion as suspicious or endoscopically treatable about 80% of the time [31]. However, especially in the upper GI tract and in the rectum, noninvasive imaging such as EUS, CT, or MRI may add significant information on local lymph node status and invasion depth. The value of submucosal (sm) injection as diagnostic tool will be discussed in the next section. In uncertain cases, clip marking 1–2 cm from the lesion, exact determination of the location, biopsies, and a second examination with more information may be a good alternative [32]. In case of suspected or proven early malignant lesions, a prior marking including a safety zone of at least 3 mm from the lesion should be performed using thermocoagulation. The by far easiest tool to use is Argon plasma coagulation (APC) (e.g., 25 W, 0.3 L gas flow “forced coag” in the VIO generator; ERBE Medizintechnik, Tuebingen, Germany). Alternatives are, for example, the tip of a snare at the lowest Wattage possible in order to avoid a thermal injury and secondary perforation of the entire wall. Submucosal injection can help in two senses as diagnostic tool. Adding indigocarmine blue to the injection solution (e.g., Indigo CarminTM, American Regent, Shirley, NY, 1.5–2 mL of a commercial 0.8% solution to a bag of 500 cc of saline) turns the underground to a mid blue after submucosal injection while the lesion remains bright. This leads to a sharp delineation of even shallow lateral margins. Furthermore, the ease to separate layers at the level of the submucosa and the degree of adhesion serve as important diagnostic tools. In case of a clear “lifting” of the entire lesion, resection is almost always possible. A so‐called “non‐lifting sign” of the lesion with central adherence and lateral bulging, in the extreme case similar to a floating tire, always signalizes an increased perforation risk or the risk of incomplete resection. An insufficient or only moderate lifting is not always equivalent to malignant infiltration but may occur due to local scarring and prior inflammation, for example, in flat adenomata in the colon or in case of prior incomplete attempts at resection. However, a “non‐lifting” even after generous fluid injection makes the lesion suspicious and should raise the question whether it is better to continue resection or better to take biopsies and send the patient either to an expert center, or in case of proven malignancy send the patient directly to the surgeon. We favor submucosal injection due to the reasons mentioned. However, for single instruments/techniques, namely the “ligate and snare” technique using rubber bands for tissue ligation prior to resection, it seems that a larger tissue volume of mucosa can be accomplished without prior submucosal injection. Furthermore, some authors prefer to not use submucosal injection in combination with a stiff monofilament snare [33]. The addition of epinephrine to the injection substance is contradictory in the literature [34]. An important practical point in submucosal injection is that in contrast to ulcer hemostasis where the needle is rather pressed into the tissue to avoid leakage of fluid, in case of EMR‐/ESD‐injection, the target layer is the very superficial submucosa. Wall perforation of the needle leading to transmural leakage during further injection and the following resection procedure should be avoided. The needle is first advanced from the catheter and held about 1–2 mm over the mucosal surface. The assistant is asked to start injection. Only when fluid leaves the needle, it is advanced with a sharp “go” to just perforate the mucosa and then immediately pulled back 2–3 mm. This will lead to a typical submucosal blowing up of the mucosa. Trainees must be made aware that if the needle is deeply stuck into the tissue and nothing happens, the fluid is being injected beyond the organ wall. We use a standard 23G shielded universal injection needle (Interject; Boston Scientific, Natick, MA USA) for all EMR and ESD procedures. New injection substances for EMR and ESD show the advantage of a higher viscosity with longer lasting fluid cushion and have been cleared by FDA (e.g., Eleview; Aries Pharmaceuticals, San Diego, CA, USA; ORISE™; Boston Scientific, Natick, MA). In this chapter, we limit our discussion to the description in detail of the three most common EMR techniques applied. Aim of the technique is to enable the resection of flat lesions in which a conventional snare would slip over the pathology (Figure 19.4). The technique is the most popular EMR technique applied especially for the removal of non‐pedunculated colorectal polyps. Technically, submucosal injection of saline or a glycerol solution (e.g., Glycerol 10%, Fresenius Kabi, Germany) provides a soft fluid cushion into which the snare can easily be pressed. A bulging of the mucosa to the interior of the snare provides a higher friction and better grip of the snare filaments when the snare is closed. This increases the tissue volume per cut. Resection proceeds often easier and faster after the first specimen has been removed. A clear step between the muscular resection base and the mucosal surface facilitates subsequent cuts. Following the first resection, the snare is placed, for example, with the left side into the mucosal defect and the right side is placed onto the lesion elevated by submucosal injection. Pressing the snare onto the ground and closing it slowly, the next piece of mucosa to the right is resected. This is repeated until the entire lesion as well as a lateral safety margin has been removed. The technique is therefore often called “piecemeal resection” in case of a larger resection area and multiple particles. It is advisable to start at the lateral margins of the lesion, incorporating a “safety margin” of 2–3 mm in order to reduce the risk for local recurrences (Figure 19.4). The tissue fragments removed are mostly sucked off via the instrumentation channel and collected in a “polyp trap.” Alternatively, larger fragments can be removed my means of a retrieval net (e.g., “Roth net,” US Endoscopy, Mentor, OH). Care should be taken that the particles are placed in a sufficient quantity of formalin and sufficiently large specimen container. CapEMR uses the principle to suck the lesion into a straight or oblique transparent “distal attachment cap” (Figure 19.5). Caps are provided in different diameters and have an inner rim at their distal end. The cap resection technique implies the use of a special 25 mm asymmetrical multifilament snare in the form of the head of a dolphin to be placed into the distal inner rim of the cylinder. As this maneuver needs training and the application is more complicated nowadays, the equally effective “band and snare” technique is often the preferred method. At first, the endoscope is gently introduced into the upper esophagus. Pressing the rinsing and the suction button of the endoscope at the same time removes mucus from the inner side of the cylinder and leads to a clear vision. At first, a marking of the area to be resected is performed, e.g., using an APC probe (18 W, “forced,” 0.5 seconds pulses forced coag, ERBE VIO prograde probe), including a sufficient safety zone of adjacent inconspicuous tissue (minimum 2–3, recommended 5 mm). In the case of a circumscript Barrett’s cancer, the surrounding Barrett’s epithelium may be resected at the same time or just the prominent part with secondary thermal ablation [35, 36], an initial marking of the resection field is performed, extending at least 3 mm around the lesion. In case of an area exceeding 15 mm, “en bloc” resection using the ESD technique is preferred over EMR (see “Endoscopic submucosal dissection” section). As a second step, the mucosa is generally lifted by submucosal injection using pure saline or recently favoured, a viscous solution such as a 6% glycerol solution (e.g., Glycerosteril; Fresenius‐Kabi, Germany) with an adjunct of indigocarmine blue (0.5 mL of 2% indigocarmine added to 500 cc of the basic solution). One should not be afraid of “overinjection” as passing by with the endoscope from cranially to caudally after a short time the fluid will rapidly disappear. For deposition of the snare within the cylinder, the transparent hood is gently pushed against normal mucosa, for example, in the proximal esophagus, in order to not disturb the lesion itself until the snare is properly seated along the rim of the cylinder. The snare catheter with the snare closed is then advanced until it can be seen within the cylinder. The assistant has then to slowly open the snare the way it is deployed in a clockwise fashion onto the inner rim of the distal cylinder. This just as much that the snare surrounds completely the cylinder but does not protrude over the rim into the lumen. The snare catheter is then fixed with the little finger of the left hand at the endoscope in order to avoid dislocation from the inner rim while the endoscopist is moving. The cylinder tip is then moved to the targeted tissue, suction is applied until a full “red‐out” of the cylinder with tissue. The snare is quickly and completely closed before the suction is released and the snare is slightly advanced as cutting current is applied to resect the lesion. Not to start resection before release of the captured “mushroom” in order to allow the muscularis propria layer to stretch out completely is mandatory in order to avoid local perforation. The popularity of this technique has decreased within the last years due to the simplicity of the “band and snare” technique with premounted kits (see “Band and snare” section) and the increased spread of “ESD” (see “Endoscopic submucosal dissection” section) for larger lesions. Time should not be wasted to take off the specimen at this point but rather to go back to the esophagus again and see if there is any bleeding or wall defect. Both should be fixed immediately in the case that either of this has occurred. Multiple resections can be accomplished this way in the same session. After resection, care should be given to hemostasis of small vessels using coagulation forceps or hemoclips. A technically simple method to resect focal Barrett’s mucosa with a visible lesion up to 10 mm is the so‐called “ligate and cut” technique [16, 34], e.g., using the “Duette” system (Cook Medical Bloomington, Indiana) [17, 37]. A transparent cylinder with six rubber bands similar to the “sixshooter” variceal band ligation device is mounted on the distal end of the endoscope. In contrast to the variceal band ligator set, the EMR set has a different handle and contains a hexagonal snare that can be introduced into the instrumentation channel via an additional access port in the handle (Figure 19.6). The technique is applied without prior injection. The mucosa is sucked into the cylinder and the band is fired. The snare is introduced and resection of the created ligation mushroom underneath the band is carried out. Immediately after the next band is placed adjacent to the previous resection site in order to avoid tissue bridges. Wall perforations using the ligate and cut technique are rare [17, 38]. ESD is composed of a sequence of different steps: In the following section, we will go through the different steps of ESD Procedures to be considered for ESD in the upper and lower GI tract are mucosal cancers, lesions containing high‐grade intraepithelial neoplasia or lesions suspect for early cancer exceeding the size of (10–) 15 mm which cannot be safely resected “en bloc” for complete histopathologic work‐up using snare resection techniques [39]. ESD is currently a technique for the “high‐end” endoscopist requiring a long practice in interventional endoscopy and complication management. ESD originated in Japan and is a relatively new procedure in the Western world. The prerequisites and the learning curve to perform a “safe” and sufficiently fast ESD still have to be defined [35, 39]. ESD is a “freehand” needle‐knife technique similar to needle‐knife sphincterotomy when gaining access to the common bile duct in difficult ERCP situations. In the beginning, ESD is time‐consuming and carries an increased complication risk, especially for perforation [34,36–38, 40]. Initial steps in learning ESD should be accompanied by a training program and expert teaching. Early training steps include a progressive approach to the technique in “ex vivo” pig stomachs. Training in live pigs is a useful next step to acquire ESD hemostasis skills and to train the technique in an environment with natural GI motility, elasticity and bleeding. For clinical practice, a close student–teacher relationship and sufficient phases of watching the procedure seem important before a student goes to unsupervised clinical ESD. At least 20 ESD procedures in animal/ex vivo models are required before the trainee reaches a sufficient speed and safety for limited “en bloc” resections (<30 mm) preferentially in the gastric antrum or rectum. ESGE recommends that at least the first 10 procedures in humans should be done under the supervision of an ESD‐proficient endoscopist [35]. Systematic training programs will help to avoid pitfalls in this undoubtedly fascinating technique. To start ESD, an extensive experience in complication management in the upper and lower GI tract and several years of experience in interventional endoscopy are required including EMR for benign and early malignant lesions. Table 19.1 shows the recommendations of the European Society of Gastrointestinal Endoscopy (ESGE) for Training in ESD [35]. The equipment for ESD depends much on the individual preferences and resection technique used [22, 34, 40]. For lesions located in the lower and upper GI‐tract standard gastroscopes and colonoscopes may be used. However, our personal preference is a slim therapeutic high resolution (HR) gastroscope (Fujinon EG 760 CT; Fujifilm Medical, Tokyo, Japan;) with the advantage of a large suction channel. Especially, in a strongly vascularized environment as in the distal rectum, a large channel for suction is of major advantage. Table 19.1 List of recommendations for training in Endoscopic Submucosal Dissection (ESD) of the European Society of Gastrointestinal Endoscopy (ESGE). From Pimentel Nunez et al. [35]. Upper GI tract, recto‐sigmoid, left‐sided colon
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Endoscopic Mucosal Resection, Submucosal Dissection, and Full Thickness Resection Techniques
Introduction
Endoscopic mucosal resection
EMR techniques to be considered
Common EMR techniques according to organs
Special EMR techniques not considered
Procedures to be considered
Prerequisite level of expertise for endoscopic mucosal resection (EMR)
Special considerations
Specific technical and cognitive skills for endoscopic resection techniques
Equipment for EMR
The proper endoscope
Equipment independent of the procedure
Adequate monitoring and supervision during sedation
CO2 insufflation
Endoscopic flush pump
Organ‐specific equipment
Patient preparation
Focus on informed consent
Patient condition and alternative treatment options
Patient preparation
Key steps for proper technique in EMR (see Video 19.1)
Evaluation of the lesion
Marking
Submucosal injection
Resection techniques for EMR
Classic EMR (lift and cut technique; saline‐assisted snare resection)
CapEMR
“Band and snare” EMR
Endoscopic submucosal dissection
Lesions to be considered for ESD
Skills for ESD and who should do it
Prerequisite level of expertise and skill for learning ESD
Special considerations for ESD
Specific technical and cognitive skills for ESD
Equipment for ESD
General considerations on ESD equipment
Essential equipment for ESD