With the development of less invasive treatments using a flexible endoscope, indications for therapeutic endoscopy have expanded. Endoscopic submucosal dissection (ESD), introduced around 2000, was a groundbreaking technique that expanded the scope of intraluminal endoscopic surgery.^1-3 Because of its flexibility and dependability, ESD has overcome the limitations of endoscopic mucosal resection (EMR), thereby allowing various gastrointestinal lesions, including subepithelial tumors (SETs), to be treated endoscopically.

The prevalence of gastric SETs is less than 2%.^4,5 The most common gastric SET with malignant potential is gastrointestinal stromal tumor (GIST), the occurrence rate of which is estimated to be approximately 10 per million individuals per year.⁶ In general, SETs that are suspected or diagnosed as GIST and have no metastases to other organs are typical candidates for surgery.^7,8 Lesions larger than 5 cm in size should be removed with open surgery, whereas small ones can be removed laparoscopically. Recently, endoscopy-related procedures have become available for small lesions. SETs, unlike epithelial neoplasms, can be treated with local resection without lymphadenectomy. Therefore, endoscopic intervention using the ESD technique, which is commonly used for minimally invasive treatment, improves the patient’s quality of life in these lesions.

Previously, we summarized various diagnostic techniques for SETs.⁹ A comprehensive review article on systematic diagnostic approaches in gastric SETs using conventional endoscopy has also been published.¹⁰ In this review, we have introduced current therapeutic techniques using endoscopy for SETs that are indicated for removal according to tumor size: EMR/ESD, endoscopic enucleation, endoscopic full-thickness resection (EFTR), and laparoscopic and endoscopic cooperative surgery (LECS). This study serves as “the second arc” following the previous review of SET diagnosis.

This is a narrative review based on systematic evidence gathered about endoscopy-mediated local resection techniques for gastric SETs using PubMed (http://www.ncbi.nlm.nih.gov/pubmed). Gastric SETs include typical mesenchymal tumors (GIST, leiomyoma, and schwannoma), lipoma, malignant lymphoma, neuroendocrine tumor (NET), and SET-like gastric cancer. Some of these lesions are benign and do not require treatment, whereas others with malignant potential have specific treatment strategies/guidelines. In this review, we focused on endoscopic treatments mainly for gastric GISTs. Although treatment guidelines have been published for GISTs,^7,8 they only recommend local resection and do not describe detailed surgical approaches for small GISTs. Therefore, we have herein described endoscopic involvement in local resection precisely by stratifying lesions based on their size.

The following keywords were used to collect evidence: “submucosal tumor” or “SET” or “submucosal lesion” or “subepithelial lesion” and “gastric” or “stomach” for identifying targets and organs, respectively. The following keywords were added for each topic: “EMR” or “ESD,” “endoscopic submucosal excavation (ESE),” “submucosal tunneling endoscopic resection” or “peroral endoscopic tumor resection,” “EFTR,” and “LECS.” After excluding non-English manuscripts, relevant articles were chosen. Other important papers that had slipped through the search were added.

1. Lesions of less than 1 cm

Because minute SETs less than 1 cm in size cause no symptoms, most of them are discovered by chance during an endoscopy performed for another reason.¹¹ In general, the progression rate of incidentally detected small SETs is extremely slow,^12-14 so regular follow-up using conventional endoscopy is acceptable without lesion removal. Indeed, these lesions are difficult to sample endoscopically due to their small size, especially those located in the deeper layer. Consequently, histological diagnosis is rarely obtained and surgical intervention is avoided. In contrast, conventional biopsy can aid in the diagnosis of superficial layer SETs, such as NETs, fundic gland-type cancer, and malignant lymphoma.

1) EMR/ESD

Given the low malignant potential of minute SETs, those in which conventional biopsy fails in histological diagnosis should be monitored and not resected. When histology reveals a possible malignancy in superficial SETs, conventional EMR/ESD is recommended.^15,16 Especially for lesions smaller than 1 cm, EMR with a ligation device is an extremely simple and safe technique (Fig. 1).¹⁷ Following submucosal injection, a rubber band commonly used for ligating esophageal varices is placed under the endoscopically-suctioned lesion, followed by resection with an electrocautery snare placed beneath it. This technique allows for the complete removal of SETs that have invaded the submucosal layer. Because of the thickness of the gastric muscular layer, perforation is uncommon in this procedure. However, these techniques are difficult to apply to SETs located in deeper layers. Close follow-up is beneficial for patients with such tumors, even when the malignancy is suspected histologically. When an increase in tumor size is confirmed, treatment with one of below-mentioned techniques should be considered.

Figure 1. Endoscopic mucosal resection with a ligation device. (A) A subepithelial tumor measuring less than 1 cm was found on the anterior wall of the gastric fornix. The biopsy revealed a fundic gland-type adenocarcinoma. (B) A hyaluronic acid solution diluted five times with normal saline was injected circumferentially into the submucosal layer. (C) After aspiration of the lesion, a rubber band was used to form a pseudopolyp. (D) An electrocautery snare was placed beneath the band. (E) The lesion was removed intact, with no perforations. The histological findings revealed a complete resection with negative surgical margins. (F) The mucosal defect was closed using clips.

2. Lesions of 1 to 3 cm

Small GISTs (1 to 3 cm) are suitable for local resection. Histological examination is relatively simple with endoscopic ultrasound-guided fine needle aspiration/biopsy or mucosal incision-assisted biopsy. Thus, lesions that are successfully histologically diagnosed as GISTs are suitable candidates for surgical intervention. Previously, a removal method of GISTs was limited to pure surgical resection via open or laparoscopic approaches, which occasionally resulted in incomplete tumor resection with positive surgical margins due to poor lesion perception, particularly in intraluminally growing type lesions, or excessive resection, which led to the loss of gastric function. Peroral endoscopy allows us to see tumor margins with great precision. By using intraoperative endoscopy to determine the resection area, the remnant stomach can be preserved to the greatest extent possible.

1) Endoscopic enucleation

Enucleation is the most minimal-sized resection technique. While the tumor margins are clearly visible, surrounding tissues are removed to excavate the lesion. A simple intraluminal technique to SETs is ESE (Fig. 2A), which involves removing the overlying mucosa and enucleating the lesion.^18-21 However, when the lesion is located in the deeper muscle layer, transluminal perforation is common. If the lesion’s location can be accurately determined, lesions on the superficial muscular layer can be treated with planned ESE without perforation. However, it is considered impossible to predict which muscular layers (the inner circular muscle or the outer longitudinal muscle) will be affected by the lesion prior to surgery. Therefore, it is impossible to plan ESE without considering the risk of perforation prior to the procedure.

Figure 2. Endoscopic enucleation and endoscopic full-thickness resection (EFTR). (A) Endoscopic submucosal excavation (ESE): after removal of the overlying mucosa, the lesion is enucleated by dissecting the surrounding tissue. (B) Submucosal tunneling endoscopic resection (STER) or peroral endoscopic tumor resection (POET): a short submucosal tunnel is created, followed by dissection of the surrounding tissue. After tumor removal through the tunnel, the entry site is closed with clips. (C) EFTR: a circumferential mucosal incision and partial submucosal dissection are performed, followed by a circumferential muscular incision with intentional perforation. After retrieval, the full-thickness defect is closed endoscopically. M, mucosa; MP, muscularis propria.

To avoid transluminal perforation, submucosal tunneling methods have been developed based on the peroral endoscopic myotomy technique known as submucosal tunneling endoscopic resection or peroral endoscopic tumor resection (Fig. 2B).^20-25 This technique involves cutting the proximal side of the mucosa to form a submucosal tunnel that is bound to the lesion. After detecting the lesion endoscopically in the submucosal tunnel, the surrounding tissue is dissected to isolate it. When the isolation is complete, the tumor is removed transorally via the submucosal tunnel. In this technique, transluminal perforation does not occur because of the presence of the overlying mucosal on the tunnel’s roof. This technique requires skilled expertise in endoscopy and some experience to minimize the burning effect on the tumor surface, which may result in histologically unclear surgical margins. Intraoperative bleeding in the narrow tunnel can be problematic due to limited endoscopic visual field. Furthermore, this technique is only suitable for lesions to which the straight submucosal tunnel can be created. Therefore, SETs near the fundus are good indicators for this technique as they can be easily reached through the straight-shaped esophagus. Size limitations are also unavoidable, particularly on the short axis. The diameter of the submucosal tunnel determines the tumor’s minimal size.

These enucleation techniques are deemed reasonable in terms of minimal invasiveness. However, particularly in GISTs, which are the most preferable SETs for resection, enucleation is generally not indicated, because secure en bloc resection with histologically negative surgical margins is strongly advised.^7,8 Enucleation can be performed on other SETs, but because these lesions are mostly benign, resection may not be necessary. Consequently, the indication of these enucleation techniques remains a topic of discussion.

2) Endoscopic full-thickness resection

To ensure negative surgical margins, EFTR is a useful method. This technique allows for the removal of SETs, including GISTs, while the lesion is sandwiched between the mucosa and serosa (Fig. 2C). This technique was developed as an advanced technique over ESD and has been clinically implemented primarily in China,^26-28 whereas EFTR using a dedicated device with an over-the-scope clip (Ovesco Endoscopy, Tuebingen, Germany) is widely used in Western countries.^29,30 First, the surrounding mucosa is cut circumferentially following a submucosal injection. Second, the exposed muscular layers are cut along with the tumor’s horizontal margins. Finally, the removed lesion is extracted transorally (Fig. 3). During the procedure, pneumoperitoneum may develop, necessitating abdominocentesis. The feasibility and safety of this technique have been reported by several studies, including meta-analyses,^31-34 and a comparison of EFTR to laparoscopic surgery has also been made in some studies (Table 1),^35-40 which shows that the tumor size is smaller, complete resection rate is slightly lower, and adverse events occur less frequently in EFTR compared with laparoscopic surgery.

Figure 3. Endoscopic full-thickness resection. (A) A 25-mm intraluminally growing gastrointestinal stromal tumor (GIST) was located on the stomach’s lesser curvature. (B) A circumferential mucosal incision and submucosal dissection were performed, followed by a muscular incision to confirm the edge of the tumor. (C) A large feeding vessel entered the muscular layer from the serosal side. Precoagulation with hemostatic forceps was needed. (D) A full-thickness defect was formed. Because of the attachment of the lesser omentum, the intragastric space remained intact and did not collapse. (E) The defect was tightly sutured using a double-layer closure technique and endoscopic hand suturing. The muscular layer was initially sutured continuously with an absorbable barbed suture. (F) Finally, the mucosal layer was sutured. (G) Mucosal surface of the removed lesion. (H) Serosal side: The final diagnosis was low-risk GIST. A histologically complete resection was achieved.

Table 1 . Outcomes of Endoscopic Full-Thickness Resection versus Laparoscopic Surgery.

Author (year)	Number	Tumor size (mm)	Operation time (min)	Procedure completeness (%)	Hospitalization period (day)	Complete resection (%)	Adverse events (n)	Observational period (mo)	Recurrence (n)
Dong et al. (2014)35	10/8	17/28	120/85	100/100	10.2/7.5	100/100	1/0	12.3	0/0
Wu et al. (2015)36	50/42	34/38	85/88	100/100	7.0/7.5	NA	0/2	NA	0/0
Wang et al. (2016)37	35/33	13/16	91/155	100/100	6.7/7.8	NA	0/4	1–72	0/0
Abe et al. (2018)38	33/39*	23/33	93/145	91/100	7/7	100/100	2/0	48	0/2
Liu et al. (2020)39	62/62	28/28	NA	100/100	NA	87/100	3/2	24/36	0/0
Zhao et al. (2020)40	85/64	16/31	NA	100/100	5/6	95/100	1/3	29/36	0/0

NA, not available..

*Sixteen cases of laparoscopic and endoscopic cooperative surgery are included..

EFTR includes two important steps: tumor removal and defect closure. During muscular incision, especially when the lesion is located on the anterior wall, the stomach is deflated due to transluminal perforation. When there is poor endoscopic visibility in the collapsed stomach, secure and accurate tumor resection attached with some nontumorous margins becomes difficult. Therefore, a traction technique should be developed to provide ideal tension to the surrounding tissue. Several traction methods have been developed, including the clip-with-line technique,⁴¹ a dedicated traction device,⁴² grasping forceps with a detachable hood,³⁸ and so on. A retrieval net, which is used for lesion retrieval, can also serve as a traction device. By inserting this net alongside the endoscope and grasping a portion of the lesion, the traction can be optimally obtained as desired because of the presence of a hard sheath. Along with traction, defect closure is an important issue in EFTR. Several closure methods have been developed, which are primarily divided into two categories:^43,44 clip-based closure and suturing. Simple clipping with conventional endoclips is the most accessible technique²⁶ when the defect size is small enough to close with clips, but the closure force is low because full-thickness closure is difficult and only mucosal closure is achieved. The over-the-scope clip is regarded as the most reliable clip device due to its ability to grasp full-thickness layers.⁴⁵ The purse-string closure method with clips and a detachable snare⁴⁶ and the reopenable clip over-the-line method⁴⁷ are used for defect closure defect rim collection. However, the closure force of this technique is limited if the closure is only completed on the mucosal layer. Furthermore, as the stomach deflates following intentional perforation, full-thickness closure becomes challenging. Clip-and-cut EFTR may be a smart technique,⁴⁸ in which the full-thickness defect size remains small and the intraluminal space is preserved as much as possible due to step-by-step clip closure of the muscle layer along with a short-step sero-muscular incision. The most reliable full-thickness closure method is thought to be endoscopic suturing as it is similar to surgical suturing. Several suturing devices/techniques, such as OverStitch (Apollo Endosurgery, Austin, TX, USA)⁴⁹ and endoscopic hand suturing with the SutuArt (Olympus Co., Ltd., Tokyo, Japan),^50,51 are available for EFTR; these techniques are expected to be promising with the accumulation of more clinical evidence.

Although EFTR is an ideal approach for treating small SETs, technical skills and some experiences are required for a successful procedure, and the difficulty of this technique varies depending on the endoscopist and institution. In an introductory phase of this technique, EFTR through a single laparoscopic port placement may be an option for security.⁵² In the case of massive bleeding or a large defect that cannot be managed endoscopically, a “semicooperative” situation with surgeons allows for faster laparoscopic recovery. In terms of tumor removal, the rate of histologically complete resection (R0) is not excellent in EFTR, which remains a problem to be addressed, although no histological R0 resection is considered clinically irrelevant in terms of survival.^53-55 However, if the target has malignant potential, close-in dissection may result in tumor collapse and subsequent tumor cell seeding via the full-thickness defect. Therefore, SETs should be removed en bloc without positive surgical margins, and endoscopists should always try avoiding exposing the tumor surface. If complete resection via EFTR is deemed technically difficult, laparoscopic intervention should be considered.

3) Laparoscopic and endoscopic cooperative surgery

The concept of LECS was introduced in 2008,⁵⁶ following the establishment of ESD. This technique involves endoscopists and surgeons working together in a single operating room to perform surgery on a single patient, which is an extremely unique setting (Fig. 4). Under general anesthesia, laparoscopist inserts several ports into the abdominal wall to create a surgical field for lesion removal. Then, an endoscopist inserts a flexible endoscope perorally to confirm the lesion, which is then isolated via submucosal injection and circumferential mucosal incision. Following some degree of submucosal dissection, an intentional muscular incision is made to create perforation. Laparoscopists take over the muscular incision along with the mucosal gutter. Finally, the lesion is removed through the abdominal wall, and the full-thickness defect is securely closed laparoscopically. The procedure is completed by retrieving the ports and closing the skin incisions. Currently, this technique has been called “classical LECS,” after the development of the following related techniques.

Figure 4. Laparoscopic and endoscopic cooperative surgery. (A) A 4-cm intraluminally growing lesion was observed on the anterior wall of the gastric angle. (B) After circumferential mucosal incision and partial submucosal dissection, the muscular layer was perforated. (C) Laparoscopically, the tip of electrocautery endoscopic device was visualized through an intentionally created hole (yellow arrow). (D) The circumferential muscular incision was completed laparoscopically. (E) The full-thickness defect was securely closed laparoscopically. The lesion was retrieved through the abdominal wall. (F) The intragastric space was well preserved without deformity.

Favorable surgical outcomes have been reported primarily from Japanese institutions.⁵⁷ The benefits of LECS are as follows: the resection area can be minimally adjusted based on the lesion size, potentially preventing postoperative stomach deformity, especially for intraluminally growing type tumors. Endoscopic demarcation of the lesion by confirming the lesion edges at close range can help avoid unexpected incomplete tumor resection when approaching from the outside of the stomach. However, longer operation times may be required, particularly during the technique’s introductory phase. More staff involvement is required compared with that in standard laparoscopic surgery, resulting in lower cost-effectiveness.

This classical LECS can also aid in iatrogenic tumor cell seeding into the abdominal space in SETs with ulcers and epithelial neoplasms, in which tumor cells are exposed inside the lumen and float in gastric juice.^58,59 Classical LECS requires intentional perforation during the procedure, which increases the risk of intra-abdominal tumor cell seeding in these lesions. To address this issue, several nonexposure approaches have been developed as LECS-related techniques, including the combination of laparoscopic and endoscopic approaches to neoplasia with nonexposure technique (CLEAN-NET),⁶⁰ nonexposed endoscopic wall-inversion surgery (NEWS),⁶¹ and nonexposure simple suturing EFTR (NESS-EFTR)/closed LECS.^62,63 In CLEAN-NET, the lesion’s seromuscular layers are first incised circumferentially after placing serosal markings around the lesion and creating a submucosal fluid cushion using endoscopic navigation. The lesion is then pulled outside, and the stretched mucosal layers are laparoscopically cut with staples. NEWS also offers a circumferential seromuscular incision similar to CLEAN-NET, followed by laparoscopic seromuscular suturing with the lesion inverted toward the inside of the stomach and endoscopic mucosal incisions. In NESS-EFTR/closed LECS, endoscopic mucosal incision is performed first, followed by laparoscopic seromuscular suturing with the lesion inverted in the same way as NEWS and endoscopic seromuscular incision. CLEAN-NET retrieves the removed lesion transabdominally, whereas NEWS and NESS-EFTR/closed LECS retrieve it transorally.

LECS produced positive results in both short- and long-term analyses, although most studies referred to a specific LECS procedure. According to some comparative studies between LECS and conventional surgery, LECS is equivalent to laparoscopic wedge resection in terms of procedure completeness, hospitalization period, curability, and survival; superior in terms of perioperative complications; and inferior in terms of operation time (Table 2).^64-68 A prospective randomized study is needed to provide more robust evidence on LECS.

Table 2 . Outcomes of Laparoscopic and Endoscopic Cooperative Surgery versus Laparoscopic Surgery.

Author (year)	Number	Tumor size (mm)	Operation time (min)	Procedure completeness (%)	Hospitalization period (day)	Complete resection (%)	Adverse events (n)	Observational period (mo)	Recurrence (n)
Komatsu et al. (2016)64	33/15	29/29	220/96	100/100	10/12	100/100	0/3	NA	NA
Yin et al. (2018)65	15/30	30/37	65/82	100/100	6.5/6.3	100/100	2/3	69.5	1/0
Shoji et al. (2018)66	14/31	33/32	210/112	100/100	9.6/8.8	100/100	0/7	NA	0/0
Hajer et al. (2019)67	11/12	27/35	96/62	100/100	6.8/6.5	100/92	2/0	12	0/0
Kanehira et al. (2020)68	50/19	35/30	105/59	100/100	6.1/6.0	100/100	0/0	18	0/0

NA, not available..

3. Lesions of 3 to 5 cm

Moderate-sized SETs are also easily diagnosed histologically using either endoscopic ultrasound-guided fine needle aspiration or mucosal incision-assisted biopsy. These lesions occasionally develop ulceration on the top of the protrusion, allowing conventional endoscopic biopsy to obtain tumor tissue directly. Even if the tissue cannot be sampled, surgical removal should be preferred in terms of potential malignancy, given the tumor size.

Moderate-sized lesions cannot be removed perorally, so a surgical approach is required. Endoscopic intervention can be used as a less invasive treatment because it reduces the resection area as much as possible. However, some LECS techniques, such as NEWS and NESS-EFTR/closed LECS, require the removed lesion to be retrieved transorally; therefore, these cannot be indicated. Classical LECS or CLEAN-NET can be used for treating moderate-sized SETs. For ulcerated lesions, CLEAN-NET is considered the best technique; however, depending on the location, laparoscopists may encounter difficulties performing the procedure because the lesion must be sufficiently pulled toward the outside to place the linear stapler in the optimal position. Intraluminally growing SETs are also difficult to remove using this technique because of their size. For these lesions, an inverted LECS technique was developed;⁶⁹ in this technique, classical LECS is performed with the surrounding wall of the lesion hoisted at several points with strings through the abdominal wall, and the lesion is removed so that the gastric juice does not spill into the abdominal cavity. This technique is also known as the “crown” method due to the shape of the hoisted surrounding wall.

4. Lesions of larger than 5 cm

SETs larger than 5 cm in size should be generally removed via open surgery due to poor visualization in laparoscopy, especially if the tumor is a solitary lesion with no metastases. Laparoscopic resection is used at some tertiary referral institutions,⁷⁰ and it is appropriate for relatively small lesions near 5 cm. Furthermore, classical LECS is being tested for these lesions at leading hospitals. These advanced procedures should be performed with caution, considering the risk-benefit ratio in terms of technical difficulty, invasiveness, procedure time, and curability.

Endoscopic intervention is appropriate for the surgical treatment of SETs because these lesions can be resected locally. Due to the precise and fine control of a flexible endoscope under close visualization, the target can be removed in a required manner depending on tumor size (Fig. 5). Furthermore, minimal resection helps preserve patients’ quality of life. With the advancement in diagnostic techniques, the number of small-but-relevant SETs identified will increase in the future. Endoscopy-based techniques for SET treatment have also been developed. Some endoscopic resection methods discussed in this review are difficult and potentially dangerous, both technically and pathologically. Hopefully, leading institutions in the field of therapeutic endoscopy will overcome the various barriers to endoscopic intervention for SETs. Endoscopic devices specifically designed for SET resection may also be developed in the future. However, evidence must be accumulated before endoscopy-based techniques for SET treatment are established and generalized as standard techniques in the near future.

Figure 5. Treatment selection of endoscopic intervention for subepithelial tumors according to their size. For small and superficial lesions, EMR or ESD is appropriate. In small lesions that can be removed transorally, endoscopic enucleation, endoscopic full-thickness resection (EFTR), and laparoscopic and endoscopic cooperative surgery (LECS) can be used. LECS is also useful for lesions larger than 3 cm as minimally invasive treatment. EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection; ESE, endoscopic submucosal excavation; STER, submucosal tunneling endoscopic resection; POET, peroral endoscopic tumor resection.

No potential conflict of interest relevant to this article was reported.

Study concept and design: O.G. Data acquisition: K.H., E.K. Drafting of the manuscript: O.G. Administrative, technical, or material support; study supervision: K.I. Approval of final manuscript: all authors.