Full-Thickness Resection (EFTR) and Submucosal Tunneling Endoscopic Resection (STER)

Study

Site

Mean size (mm)

Indication

Success

R₀

Adverse events

Follow-up

Recurrence

Schmidt et al. [36] (2014)

Colon

22 mm

Recurrent non-lifting adenoma

100%

3–6 m

Schmidt et al. [38] (2015)

Colon

24 mm

Non-lifting adenoma

SET

Adenoma in appendix or diverticulum

Coagulopathy

Hirschsprung’s disease

96%

75%

2 Postpolypectomy syndrome (8%)

1 failed due to stenosis (4%)

Schmidt et al. [35] (2015)

Duodenum

28.3 mm

Non-lifting adenoma

100%

75%

2 Minor bleeding (50%)

2 m

Richter-Schrag

et al. [39] (2016)

Colon

50 mm

Non-lifting adenoma

Early adenocarcinoma

80%

4 failed (20%)

1 perforation (5%)

2 m

2 patients (10%)

Andrisani et al. [40](2017)

Colon

26 mm

Non-lifting adenoma

Early adenocarcinoma

100%

1 Postpolypectomy syndrome (5%)

3 m

Vitali et al. [44] (2018)

Colon

17 mm

Non-lifting adenoma

Early adenocarcinoma

NET

100%

83.3%

2 Postpolypectomy syndrome (15%)

12 m

3 patients (23%)

Aepli et al. [47] (2018)

Colon

27 mm

Non-lifting adenoma

NET

Adenoma in appendix or diverticulum

Early adenocarcinoma

93.9%

87.9%

3 bleeding (9%)

1 delayed perforation (3%)

2 failed (6%)

3 m

2 patients needed surgery (6%)

FTRD full-thickness resection device, N number of patients, SET subepithelial tumor, NET neuroendocrine tumor

Indications and Contraindications of EFTR

To date, several major guidelines recommend that subepithelial tumor in particular GIST ≥2 cm or symptomatic tumors should be resected [48–50]. There is currently no consensus of the maximum size of the lesion amenable to EFTR. Sumiyama proposed that EFTR technique can be used to resect large submucosal tumor and laterally spreading tumor (LST) involving the submucosa or muscularis propria [8].

The management of small tumors less than 2 cm is highly debated. Most guidelines recommend periodic endoscopic surveillance [48–50]. However, limitations of endoscopic surveillance include a delayed diagnosis of malignancy, increased patient’s anxiety, and patient’s lost to follow-up and therefore may not be cost-effective in the long term. There is currently no consensus on the association between tumor size and the likelihood of lymph node metastasis [50]. There are several reported cases of small subepithelial tumor <2 cm with malignant potential that presented with early lymph node metastasis [51–53].

We propose the following as indications of EFTR (Fig. 9.1):

../images/442926_1_En_9_Chapter/442926_1_En_9_Fig1_HTML.png — Fig. 9.1

Indications for EFTR

We recommend that only skilled endoscopists with experience in ESD, ESE, and the management of perforation should perform EFTR procedures.

Pre-procedural Assessment

Pre-procedural assessment is a crucial step prior to EFTR. As in any other endoscopic procedures, informed consent is necessary. Patients should be fully informed about the intraoperative and postoperative risks that may occur including the possibility of emergency surgery in the event of a major complication such as torrential bleeding or perforation that failed endoscopic closure. Detailed medical history is vital to ensure there are no contraindications to EFTR as highlighted above. For patients on antithrombotic or antiplatelet medications, it is recommended to stop taking both drugs for at least 1 week prior to EFTR if there is no contraindication to cease these medications temporarily and after discussion with their primary physicians.

Tumor characteristics, size, and location and exclusion of tumor metastasis are also vital information that can be obtained from computed tomography (CT) and endoscopic ultrasound (EUS).

EFTR Procedure

EFTR is a complex procedure that requires the collaboration and support of various departments that include the anesthetist, intensive care unit, surgeon, and pathology department. The success of EFTR not only relies on the endoscopist’s technical skill but also experienced trained endoscopic nurses. Both endoscopist and nurses must be familiar with all endoscopic devices and suturing techniques to manage any procedure-related complications. All procedures are performed under general anesthesia with airway intubation. It is recommended to give a single dose of prophylactic intravenous antibiotic at least half an hour prior to EFTR. An infusion of a second- or third-generation cephalosporin tends to be the preferred choice of antibiotic prophylaxis for gastrointestinal tract given the broad-spectrum activity against a wide range of gram-positive and gram-negative bacteria. It is crucial to use carbon dioxide insufflation throughout the EFTR procedure.

Instruments

The instruments used for EFTR were similar to those used for ESD that included a standard single-channel forward-viewing gastroscope (180H Olympus Optical Co., Ltd., Japan) with a transparent cap (D-201-11804, Olympus, Tokyo, Japan) attached to the tip of the endoscope to improve endoscopic visualization, to assist in tissue traction, and to facilitate in hemostasis in the event of bleeding. A dual-channel endoscope (GIF-2T240, Olympus Corporation, Tokyo, Japan) is occasionally used for closure of iatrogenic GI wall defect using a purse-string technique . A grasping forceps (FG-8U-1, Olympus) is also used to prevent inadvertent dislodgment of enucleated tumor into the abdominal cavity.

There are a variety of electrosurgical knives that are available and can be used for EFTR. At our center, an insulated-tip (IT) electrosurgical knife (KD-611L, Olympus), a hook knife (KD-620LR, Olympus), or a needle knife (KD-10Q-1, Olympus) are commonly used to resect the wall layers around the tumor. Other crucial equipment includes injection needles (NM-4L-1, Olympus), snares (SD-230U-20, Olympus), basket (MWB-2 × 4, Cook), hot biopsy forceps (FD-410LR, Olympus), hemostatic clips (HX-610-90, HX-600-135, Olympus), endoloop (MAJ-339, Olympus), over-the-scope-clip (OTSC) (also known as Ovesco device (GmbH, Tubingen, Germany)), argon plasma coagulation unit (APC300, ERBE), and high-frequency electrosurgical generator (VIO200, ERBE).

EFTR Steps

EFTR steps are as follows (Video 9.1, Fig. 9.2):

Step 1: For deep lesions or small lesions (<10 mm), several marking dots around the periphery of the SET are made using either the tip of the electrosurgical knife or argon plasma coagulation catheter because the location may become vague after submucosal injection. Otherwise, marking can be omitted.
Step 2: A submucosal injection of a mixture of 100 ml of normal saline and 1 ml of indigo carmine to create a protective submucosal “cushion” to prevent deep thermal injury during tumor resection.
Step 3: A circumferential mucosal incision is made 1–2 mm outside the marked dots or the contour of the SET. Another option is to perform mucosal excision to unroof the SET.
Step 4: Submucosal and subtumoral dissection is performed surrounding the tumor capsule to ensure a complete en bloc resection of the tumor. Meticulous care must be taken to avoid interruption of the tumor capsule. All visible vessels must be coagulated, and prompt hemostasis must be achieved to avoid accumulation of blood in the GI lumen. To avoid inadvertently losing the specimen into the peritoneal cavity, snare can be used for the final cut of the lesion and immediate specimen retrieval after resection. Another method is to use a double-channel endoscope with a grasping forceps inserted into one channel to grasp the lesion while the electrosurgical knife is inserted into the second channel to excise the lesion.
Step 5: Once the tumor is enucleated, the closure of excisional wall defect can be performed using various available methods as described below depending on the size of the GI wall defect. The diameter of the wall defect can be reduced by air suction to assist in closure of the defect.

../images/442926_1_En_9_Chapter/442926_1_En_9_Fig2a_HTML.png — Fig. 9.2

Steps of EFTR for gastric SET originating from muscularis propria. (a) Endoscopic view of a gastric SET originating from muscularis propria. (b) Circumferential incision was made as deep as muscularis propria around the lesion with IT knife. (c) Incision into serosal layer around the lesion was performed with IT knife to create active perforation. (d) The full-thickness gastric wall defect after tumor resection. The liver could be seen through the gastric wall defect after EFTR. (e) The resected tumor was removed by snare. (f, g) The gastric wound was closed with several metallic clips and endoloop by “purse-string” method (double-channel scope). (h) The resected specimen

../images/442926_1_En_9_Chapter/442926_1_En_9_Fig2b_HTML.png — Fig. 9.2

Steps of EFTR for gastric SET originating from muscularis propria. (a) Endoscopic view of a gastric SET originating from muscularis propria. (b) Circumferential incision was made as deep as muscularis propria around the lesion with IT knife. (c) Incision into serosal layer around the lesion was performed with IT knife to create active perforation. (d) The full-thickness gastric wall defect after tumor resection. The liver could be seen through the gastric wall defect after EFTR. (e) The resected tumor was removed by snare. (f, g) The gastric wound was closed with several metallic clips and endoloop by “purse-string” method (double-channel scope). (h) The resected specimen

In the event of an iatrogenic wall perforation, continuous CO₂ insufflation must be avoided to prevent pneumoperitoneum and regular suction of content within the GI lumen is vital to avoid spillage of fluid and blood into the abdominal cavity. Throughout the procedure, care is taken to constantly monitor the patient’s positive end expiratory pressure (PEEP) and for clinical signs of raised intra-abdominal pressure. When necessary, a 20-gauge needle is inserted under aseptic technique directly into the abdominal cavity to relieve pneumoperitoneum during and after the procedure. Patients are on kept nil by mouth after surgery and nursed in semi-Fowler’s position. A nasogastric tube is routinely placed to deflate the stomach; in addition it also helps detect early post-procedural bleeding.

Closure of Iatrogenic GI Wall Perforation

There are various endoscopic methods to close the iatrogenic GI wall perforation after EFTR. This step can be very challenging depending on the size of the wall defect and the location of wall defect. An adequate and reliable closure of the GI wall defect is the most important factor to determine the success of the EFTR procedure. We will focus on several closure techniques that include traditional metallic clips, purse-string technique, and other newer closure devices available.

(i)

Metallic clips closure (Fig. 9.3)

There are a variety of metallic clips available in clinical practice to close GI wall defects. Endoluminal metallic clips have been widely used in clinical practice for closure of GI wall defects, anastomotic fistulas, and small perforations after endoscopic resection and to achieve hemostasis. The successful application of endoscopic metallic clips to close perforation in the stomach was first reported in 1993 by Binmoeller et al. [54] Minami et al. [55] reported a study of 121 patients, in which 117 patient had successful closure of ESD perforation using metallic clips, achieving success rate of 98.3%. At our center, metallic clips are generally used to close elongated wall defects that are less than 2 cm in cross-sectional diameter.
(ii)

Purse-string closure technique (metallic clips combined with endoloop)

Matsuda first introduced the metallic clips combined with endoloop snare to close EMR defects successfully [56]. This technique can be divided into two ways:

Linear closure : This is applicable for small defects with a single endoloop and two metallic clips anchoring over the proximal and distal edges of the defect to close.

Purse-string closure : This way is suitable for large defects. It uses a single endoloop and about five to six metallic clips gathering mucosa around the defects to the center to close [57] (Video 9.1). This technique has many variations; the commonly used maneuver was performed by a double-channel gastroscope, introducing endoloop through one channel and metallic clips through the other channel. For centers without double-channel gastroscope, single-channel method can be used with a specially designed loop (LeClamp™, LEOMED, Changzhou, China) (Fig. 9.4).

../images/442926_1_En_9_Chapter/442926_1_En_9_Fig3_HTML.png — Fig. 9.3

Metallic clips closure. (a) The full-thickness gastric wall defect after tumor resection. (b) The gastric wound was closed by several metallic clips successfully

../images/442926_1_En_9_Chapter/442926_1_En_9_Fig4_HTML.png — Fig. 9.4

Purse-string suturing technique (single-channel method). (a) Endoscopic view of a gastric wall defect after EFTR. (b) A loop was placed above the wall defect and detached from the loop hook. (c) Several metallic clips were anchoring at the defect edge. (d–f) The loop hook was introduced to tighten the loop to achieve complete closure of the full-thickness defect

(iii)

Omental patch method

An omental patch method is not commonly used now; because of the advances in closure devices, most of the defect can be successful closed endoscopically. Hashiba et al. reported successful endoscopic repair of gastric perforation with an omental patch [58]. Dray et al. using animal model reported technical feasibility of omentoplasty for gastrotomy closure [59]. This technique is usually reserved for large wall defects (more than 3 cm in size) that has failed closure using the purse-string technique. This technique utilizes the greater omentum or the lesser omentum as a patch. The omentum is suctioned into the GI lumen through the perforation site to seal the wall defect, and the omentum is anchored to the edge of the wall defect using several metallic clips.
(iv)

Endoscopic suturing device

Endoscopic suturing device is an indispensable component of any advanced endoscopic resection. There is a recent rapid expansion of endoscopic suturing devices that are currently available, and we are now able to achieve closure of full-thickness resection defects. However, these endoscopic closure devices are generally not widely available, are costly, and are at early stages of development. In addition, there is only very limited preliminary data in regard to its safety and effectiveness. We hereby focus on several endoscopic closure devices that are available and used in clinical practice.

(a)

Over-the-scope clips (OTSC)

Among all the closure devices available, OTSC has been increasingly used to close various wall defects and bleeding ulcers. The OTSC consists of a nitinol alloy and is installed on an applicator that is mounted onto the tip of the gastroscope. The clip is applied by stretching a wire that is led through the working channel of the endoscope (similar to common endoscopic band ligation systems) [60–62].

In contrast to other mechanical closing devices, the new OTSC clips can grasp much more tissue and offer a strong and long-standing closure of the wound margins in a one-step application technique. The new OTSC system was originally developed and used in humans for hemostasis of ulcer bleeding and for closure of iatrogenic perforations of the GI tract [63–64]. However, one big concern of this device is the device residual in the wound (Fig. 9.5).

../images/442926_1_En_9_Chapter/442926_1_En_9_Fig5_HTML.png — Fig. 9.5

A case of residual OTSC 5 years after initial EFTR. (a) Retained OTSC was found on 5-year follow-up endoscopy after initial EFTR. (b, c) A snare was used to remove the clip by resecting the underlying tissue. (d) Removed OTSC with grasped tissue. (e, f) OTSC

(b)

OverStitch™ suturing system

Apollo OverStitch suturing device has evolved from the previously developed Eagle Claw device. This device was approved in 2011 by the Food and Drug Administration and is used for closure of fistulas and perforations, oversewing ulcers, and bariatric endoscopy in the United States [59]. However, in Asia, the OverStitch is not yet available and many endoscopists used endoloop and clips to close EFTR defects [65–66]. This device is a single-use device that is mounted onto a double-channel gastroscope. This device enables both interrupted and continuous suture application and allows full-thickness suturing as well as tissue approximation or plication in the gastrointestinal tract (Fig. 9.6). This suturing device has been shown to have the ability to attain durable closure of gastric defects ranging from 18 mm to 50 mm in an animal model [66].

../images/442926_1_En_9_Chapter/442926_1_En_9_Fig6_HTML.png — Fig. 9.6

A case of colonic defect after EFTR closed by OverStitch. (a) Endoscopic view of a colonic SET. (b) Mucosal incision after submucosal injection. (c) The SET originated from MP layer. (d) The wound after EFTR. (e, f) Continuous suture of the wound was achieved successfully by Overstitch suturing device

Kantsevoy et al. demonstrated in his study that 12 patients who underwent ESD for both gastric and colonic lesions had successful closure of defect using OverStitch device in all patients, and all patients were discharged home on the same day of the procedure [67].

Rajan et al. demonstrated in a porcine study the feasibility of suturing to seal full-thickness gastric defects with an average size of 11 mm without site ulceration [63].

Since then, there are an increased number of studies that demonstrated the effectiveness of OverStitch in closure of wall defect [68, 69].

Pathologic Evaluation

The specimens are fixed, embedded with paraffin, and then sectioned. Hematoxylin and eosin and immunohistochemical staining (CD34, CD117, actin, S-100, desmin, vimentin, Ki-67, etc.) are carried out. Complete resection is defined as en bloc resection, in which the capsule of the tumor is intact and the basal and lateral margins are free of tumor cells.

Post-procedure Management

Post-procedure care is crucial. All patients are kept strictly nil by mouth after EFTR and nursed in a semi-Fowler’s position. A nasogastric (NG) tube is recommended to decompress the stomach and to detect early post-procedure bleeding, and vital signs and abdominal signs are monitored closely. At our center, a third-generation cephalosporin is used for the first 3 postoperative days. Oral proton pump inhibitors are prescribed for 2 months and used to protect gastric mucosa in patients with upper GI lesions.

The NG tube is typically removed after 48 hours if there is no sign of bleeding or worsening of abdominal pain. The patients are started on a liquid diet and gradually upgraded to a soft and then finally to a normal diet prior to discharge from hospital.

Clinical Outcomes of EFTR

As shown in Table 9.2, EFTR with closure of the defect has shown promising clinical outcomes, with technical success nearly reaching 100%, with complete en bloc resection in almost all studies. The main indications in these studies were SETs. This may owe to the fact that SETs usually arise from the muscularis propria layer, which requires full-thickness resection. The adverse events are related mainly to the iatrogenic perforation with resultant abdominal pain, distension, fever, and localized peritonitis, all of which had been successfully managed in the mentioned studies. On comparing this to the use of FRTD, inferior results with FTRD as shown in Table 9.1 may be due to the big size of the device that hinders technical success in all cases. FTRD is approved to use only in the colon as it has a wider lumen, and hence most of the studies are on colonic lesions, while EFTR was studied mainly in the stomach and colon. Besides, FTRD is a previously set device with one-step resection technique limiting its use in different locations such as the stomach and in bigger lesions (>3 cm). On the other hand, EFTR, is a free-hand technique, enabling precise full resection of the lesions as well as closure of the defects with variable methods under complete supervision of the endoscopist. Some closure devices such as the suturing device are very expensive and not widely available; however the purse-string technique using the endoloop and metallic clips had offered a convenient substitution. Meanwhile, there are very few studies on the EFTR which are mainly retrospective. So, prospective randomized controlled trials including larger number of patients are required comparing the different closure techniques and comparing FTRD and EFTR to one another.

Table 9.2

Clinical outcomes of EFTR

Study	N	Site	Mean size (mm)	Pathological diagnosis	Closure	Success	R₀	Adverse events	Follow up (m)
Zhou et al. [24] (2011)	26	Gastric	28 mm	GIST (16) Leiomyoma (6) Glomus tumor (1) Schwannoma (1)	Metallic clips	100%	100%	No	8 m
Shi et al. [57] (2013)	20	Gastric	14.7 m	GIST (12) Leiomyoma (4) Schwannoma (2) Granular cell tumor (1) Ectopic pancreas (1)	Purse-string	100%	100%	Abdominal pain and fever (5)	3 m
Feng et al. [27] (2014)	48	Gastric	15.9 mm	GIST (43) Leiomyoma (4) Schwannoma (1)	Metallic clips	100%	100%	Distension (5)	2,6,12& 24 m
Ye et al. [63] (2014)	51	Gastric	24 mm	GIST (30) Leiomyoma (21)	Purse-string	98%	98%	No	22.4 m
Huang et al. [26] (2014)	35	Gastric	28 mm	GIST (25) Leiomyoma (7) Autonomic nerve tumor (2)	Metallic clip ± omental patch	100%	100%	No	6 m
Kantsevoy et al. [67] (2014)	12	Gastric Colon	42.6 mm	Gastric lipoma (2) Ectopic pancreas (1) Intestinal metaplasia (1) Colonic adenoma (6) Intramucosal rectal cancer (2)	Suturing device	100%	100%	No	3 m
Yang et al. [28] (2015)	41	Gastric	16.3 mm	GIST (33) Leiomyoma (4) NET (1) Ectopic pancreas (1) Schwannoma (1) Hyaline degeneration (1)	OTSC or metallic clips	100%	100%	Abdominal pain, fever, dysuria, vomiting (9)	—
Guo et al. [29] (2015)	23	Gastric	12.1 mm	GIST (19) Leiomyoma (4)	OSTC	100%	100%	Localized peritonitis (2) Fever (4)	3 m
Kantsevoy et al. [67] (2016)	16	Colon	5.6 mm	Adenoma	Suturing device	100%	100%	No	3 m

EFTR endoscopic full-thickness resection, N number of patients, GIST gastrointestinal stromal tumor, NET neuroendocrine tumor, OTSC over-the-scope clip, mm millimeter, m months

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