Submucosal endoscopy or third-space endoscopy utilizes the potential space between the mucosal and muscularis layers of the gastrointestinal tract to execute therapeutic interventions for various diseases. Over the last decade, endoscopic access to the submucosal space has revolutionized the field of therapeutic endoscopy. Submucosal endoscopy was originally used to perform endoscopic myotomy in patients with achalasia cardia, and its use has grown exponentially since. Currently, submucosal endoscopy is widely used to resect subepithelial tumors and to manage refractory gastroparesis and Zenker’s diverticulum. While the utility of submucosal endoscopy has stood the test of time in esophageal motility disorders and subepithelial tumors, its durability remains to be established in conditions such as Zenker’s diverticulum and refractory gastroparesis. Other emerging indications for submucosal endoscopy include esophageal epiphrenic diverticulum, Hirschsprung’s disease, and esophageal strictures not amenable to conventional endoscopic treatment. The potential of submucosal endoscopy to provide easy and safe access to the mediastinum and peritoneal spaces may open doors to novel indications and rejuvenate the interest of endoscopists in natural orifice transluminal endoscopic surgery in the future. This review focuses on the current spectrum, recent updates, and future direction of submucosal endoscopy in the gastrointestinal tract.
The submucosal or third space is a virtual space between the mucosa and muscularis layer that can be expanded using various injectable solutions and accessed endoscopically. The submucosal space provides the opportunity to manage various pathological conditions involving the submucosal and muscular layers and beyond. The concept of submucosal endoscopy originated approximately one and a half decades ago when Sumiyama et al.,
This review focuses on the current spectrum, recent updates, and future directions of submucosal endoscopy in the GI tract.
In the GI tract, submucosal endoscopy is most widely used in the esophagus. The major indications of submucosal endoscopy in the esophagus include POEM for esophageal motility disorders, submucosal tunneling endoscopic resection (STER) for SETs, submucosal tunneling with endoscopic division of septum in cases of Zenker’s diverticulum (Z-POEM) and epiphrenic diverticulum (diverticular [D]-POEM), and tunneling technique for restoration of the esophagus.
POEM has emerged as a safe and effective modality for the palliation of symptoms in cases of achalasia and other non-achalasia esophageal motility disorders such as diffuse esophageal spasm, jackhammer esophagus, and esophagogastric junction outflow obstruction. The POEM technique is based on the principles of SEMF and involves submucosal lifting, mucosal incision, submucosal tunneling, myotomy, and closure of the mucosal incision (
Emerging data indicate that the response to POEM is durable at long-term follow-ups. The long-term clinical success of POEM in recent studies has ranged from 72% to 96% at follow-up durations of 36 to 120 months (
The management options for Zenker’s diverticulum include surgery, rigid endoscopic diverticulotomy, and flexible endoscopic septotomy (FES). Among these, FES has gained widespread acceptance owing to its excellent safety and efficacy. However, symptoms recur in up to a third of patients after FES and are mainly attributed to incomplete division of the cricopharyngeal septum.
The proposed advantage of Z-POEM is its ability to completely divide the cricopharyngeal septum, which may reduce recurrence in the future. Moreover, preservation of the mucosa reduces the risk of intraprocedural perforations. Several studies have evaluated the safety and efficacy of Z-POEM in patients with Zenker’s diverticulum.
Esophageal epiphrenic diverticulum (EED) is a type of diverticulum that develops in the distal part of the esophagus and is typically associated with motility disorders. Surgery is the mainstay of EED management. While surgical options (thoracotomy or laparoscopy) provide symptom relief in most cases, high morbidity, especially leaks, remains an important concern. Submucosal endoscopy has emerged as a minimally invasive treatment option for patients. Broadly speaking, the technique of D-POEM is similar to that described for Zenker’s diverticulum. A key difference is that myotomy of the lower esophageal sphincter is also performed in addition to dividing the septum in selected cases with evidence of high integrated relaxation pressure. Several studies have described the results of D-POEM for EED.
Complete esophageal obstructions involving a long segment of the esophagus (>3 cm) are difficult to manage using currently available endoscopic techniques. In such cases, Wagh and colleagues reported the utility of submucosal endoscopy to restore the esophagus i.e. per-oral endoscopic tunneling for restoration of the esophagus (POETRE).
The major indications for submucosal endoscopy in the stomach include resection of SETs and management of refractory gastroparesis.
A sizable proportion of patients with gastroparesis do not respond to conservative treatment, such as optimization of glycemic control, dietary modifications, and prokinetics, and are classified as having refractory gastroparesis. The management of refractory gastroparesis is challenging and often unsatisfactory. The frontrunners in the management of refractory gastroparesis include gastric electrical stimulation (GES) and laparoscopic pyloroplasty, which has been shown to be a safe and effective treatment options in recent studies.
The technique of G-POEM is essentially similar to that of esophageal POEM and involves mucosal incision, tunneling, and myotomy of the pyloric sphincter (
Multiple studies with short-term follow-up suggest the safety and efficacy of G-POEM (
No randomized trial has compared G-POEM with other treatment modalities for refractory gastroparesis such as GES and surgical pyloroplasty. Limited data indicate that G-POEM may be superior to GES and equally effective to surgical pyloroplasty with the advantage of fewer AEs.
Endoscopic resection techniques for SETs in the upper GI tract include endoscopic submucosal dissection, endoscopic submucosal excavation (ESE), endoscopic full-thickness resection, and STER. Of these, STER utilizes the principles of SEMF for resection of upper GI SETs (
Several studies have compared STER with other treatment modalities, such as ESE and video-assisted thoracoscopic surgery (VATS). In retrospective comparison studies, STER has been equally effective to ESE and VATS.
In conclusion, an individualized approach is warranted for esophagogastric SETs. ESE may be preferred to STER in tumors located in the distal fundus or lesser curvature, and VATS may be a better option for esophageal SETs with a minor axis diameter >30 mm or tumor mass index (major axis×minor axis) >1,000.
Hirschsprung’s disease (HD) or congenital megacolon results from the failed migration of colonic ganglion cells, resulting in the inability of a colonic segment of varying length to relax, leading to functional colonic obstruction. The aganglionic segment is usually localized in the rectosigmoid region; therefore, an endoscopic approach appears intuitive in HD. Bapaye et al.
The PREM technique is illustrated in
The field of submucosal endoscopy is over a decade old. However, new information and advancements are constantly enriching the wisdom of third-space endoscopists. In this section, we discuss the recent progress in submucosal endoscopy (
While the safety and efficacy of POEM have been established in studies published over the last decade, more recent studies have focused on the efficacy of short esophageal myotomy,
The length of esophageal myotomy during POEM is usually 6 to 8 cm based on the initial description of the procedure by experts. However, the same is not evidence-based, and recent studies have questioned the utility of long esophageal myotomies in achalasia. Several randomized trials and systematic reviews have concluded that short esophageal myotomy (3–5 cm) is equally effective, with the advantage of reduced procedure duration and possibly less esophageal acid exposure as compared to those associated with standard esophageal myotomy.
GERD is the most common long-term AE of POEM. Emerging data suggest that although the incidence of post-POEM GERD is high, most patients respond to anti-secretory medications.
The EndoFLIP system has recently been introduced in clinical practice to predict the clinical outcomes of POEM in achalasia and refractory gastroparesis. It utilizes impedance planimetry to determine the DI and cross-sectional area of the gastroesophageal junction or pyloric sphincter. The current literature is divergent with regard to the utility of DI and cross-sectional area in predicting the outcomes of POEM and G-POEM in esophageal motility disorders and refractory gastroparesis, respectively.
Over the last decade, submucosal endoscopy has proven useful for a broad spectrum of GI diseases. Of note, submucosal endoscopy is an evolving field, and the certainty of evidence and efficacy varies across different indications in the GI tract. While the safety and efficacy of submucosal endoscopy have been consistent across the indications, the durability of response needs to be established for some indications, such as refractory gastroparesis and Zenker’s diverticulum. Additionally, evidence of its efficacy is limited in HD and esophageal strictures. With continued advancements in the field of submucosal endoscopy, there may be renewed interest in NOTES in the future. This is exemplified by recent reports of endoscopic transcolonic appendicectomy and transgastric cholecystectomy.
Submucosal endoscopy has been one of the most rewarding innovations in the field of therapeutic endoscopy in the recent era. Beginning with achalasia, the submucosal space is now being utilized to manage several GI diseases. While the utility of submucosal endoscopy has stood the test of time in esophageal motility disorders and SETs, its durability remains to be established in other conditions such as Zenker’s diverticulum and refractory gastroparesis. Additionally, novel techniques are required to reduce the incidence of GERD after POEM. Further studies are required to identify the predictors of response to G-POEM in patients with refractory gastroparesis. The potential of submucosal endoscopy to provide easy and safe access to the mediastinal and peritoneal spaces may open doors to novel indications and rejuvenate the interest of endoscopists in NOTES in the future.
The authors have no potential conflicts of interest.
None.
Conceptualization: ZN; Data curation: ZN, DNR; Formal analysis: ZN; Supervision: DNR; Validation: DNR; Visualisation: ZN, DNR; Writing–original draft: ZN; Writing–review & editing: DNR.
Current spectrum of submucosal endoscopy in gastrointestinal tract.
Technique of per-oral endoscopic myotomy in esophageal motility disorders. (A) Submucosal lifting injection using an injection needle. (B) Mucosal incision using a triangular knife. (C) Submucosal tunneling using a triangular knife. (D) Control of intraprocedural bleeding using coagulation forceps. (E) Selective circular (upper part) and full-thickness myotomy. (F) Closure of the mucosal incision with endoclips.
Submucosal tunneling with division of cricopharyngeal septum in a case of Zenker’s diverticulum. (A) Endoscopic image revealing the cricopharyngeal septum. (B) Submucosal lifting injection proximal to the septum. (C) Mucosal incision using an electrosurgical knife. (D) Submucosal tunneling along the diverticulum pouch. (E) Submucosal tunneling along the esophageal side and complete exposure of the septum. (F) Division of the cricopharyngeal septum using an electrosurgical knife. (G) Completion of cricopharyngeal myotomy. (H) Closure of mucosal incision with multiple endoclips.
Gastric per-oral endoscopic myotomy in a case of refractory gastroparesis. (A) Submucosal lifting injection 3 to 4 cm proximal to the pylorus. (B) Submucosal tunneling towards the pylorus. (C) Visualization of the pyloric sphincter. (D) Confirmation of extension of submucosal tunnel beyond the pyloric sphincter. (E) Execution of endoscopic pyloromyotomy. (F) Endoscopic appearance of the pyloric sphincter after pyloromyotomy. Courtesy by Harshal Mandavdhare (Associate Professor, Post Graduate Institute of Medical Education and Research, Chandigarh, India).
Submucosal tunneling endoscopic resection in a case of esophageal subepithelial tumor. (A) Endoscopic appearance of the mid-esophageal subepithelial lesion. (B) Submucosal lifting injection 2 to 3 cm above the subepithelial lesion. (C) Vertical mucosal incision using a triangular knife. (D) Submucosal tunneling along the presumed orientation of the subepithelial lesion. (E) Exposure of the subepithelial tumor. (F) Dissection of the tumor from surrounding attachments. (G) Retrieval of the tumor using a polypectomy snare. (H) Closure of the mucosal incision using endoclips.
Individualized approach to gastric subepithelial. Note the preferred location of gastric submucosal lesions for ESE and STER (from Lu et al. PLoS One 2015;10:e0119870
Per-rectal endoscopic myotomy in a patient with Hirschsprung’s disease. (A) Submucosal lifting injection. (B) Transverse mucosal incision 1 to 2 cm above the anal verge. (C) Submucosal tunneling with arrows indicating the muscle layer. (D) Completion of submucosal tunneling. (E) Full-thickness myotomy. (F) Closure of the mucosal incision using endoclips. Courtesy by Mohan Ramchandani (Consultant Gastroenterologist, Asian Institute of Gastroenterology, Hyderabad, India).
Long-term outcomes of per-oral endoscopic myotomy in esophageal motility disorder
Study | Country, study design | Age (yr) | Type of motility disorder | Reflux esophagitis (%) | Clinical success (%) | Follow-up (mo) | |
---|---|---|---|---|---|---|---|
Guo et al. (2017) |
China, R | 67 | 40.7±15.3 | I 13, II 50, III 4 | 13.4 | 88.1 | 40.1±2.8 |
Hernández Mondragón et al. (2017) |
Mexico, R | 65 | 47 (20–81) | I 19, II 34, III 12 | 15.4 | 72 | 48 |
Teitelbaum et al. (2018) |
USA, R | 36 | 54.5 (20–88) | I 10, II 17, | 13 | 79.3 | 65 (60–76) |
DES 2, EGJOO 7 | |||||||
Liu et al. (2020) |
China, R | 1,538 | 40.3±14.5 | I 466, II 964, III 108 | 22.6 | 92.9 | 42 |
Brewer Gutierrez et al. (2020) |
Multicenter, R | 146 | 49.8±16 | I 41, II 70, III 9 | 16.8 | 95.2 | 55 (49.9–60.6) |
Podboy et al. (2021) |
USA, R | 55 | 59.18±2.4 | I 13, II 23, III 15, | 3.6 | 72.7 | 47.3±13.8 |
US 2, EGJOO 1, DES 1 | |||||||
Nabi et al. (2021) |
India, R | 74 | 43.5±16.09 | III 53, DES 11, JHE 10 | 48.6 | 90.5 | 47.5 (2–77) |
Onimaru et al. (2021) |
Japan, R | 15 | 49.7±15.9 | NR | NR | 73.3 | ≥120 |
McKay et al. (2021) |
USA, P | 100 | 57 (20–88) | I 29, II 41, III 5, | NR | 79 | 72 (66–82) |
EGJOO19, DES 6 | |||||||
Campagna et al. (2021) |
USA, R | 100 | 53 | I 27, II 58, III 16 | 33.3 | 88 | 55 |
EGJOO 8, JHE 4, DES 1 |
Values are presented as mean±standard deviation or median (range).
R, retrospective; DES, diffuse esophageal spasm; EGJOO, esophagogastric junction outflow obstruction; NR, not reported; JHE, jackhammer esophagus; P, prospective; US, unspecified.
Outcomes of submucosal tunneling and division of the septum in cases of Zenker’s diverticulum
Study | Size (mm) | Procedure time (min) | Adverse events (%) | Clinical success (%) | Follow-up (mo) | |
---|---|---|---|---|---|---|
Repici et al. (2020) |
20 | 17.5 | 13.8 | 0 | 100 | 12 |
Yang et al. (2020) |
75 | 31.3 | 52.4 | 6.7 | 92.0 | 9.7 |
Budnicka et al. (2021) |
22 | 30 | 48.8 | 13.6 | 90.9 | 3 |
Elkholy et al. (2021) |
24 | 40 | 61 | 0 | 95.8 | 10 |
Sanaei et al. (2021) |
32 | 29.4 | 47.7 | 12.5 | 96.7 | 5.5 |
Mittal et al. (2021) |
24 | 27 | NR | 16.7 | 90.9 | 5.7 |
Al Ghamdi et al. (2022) |
119 | 34.8 | 46.1 | 16.8 | 92.7 | NR |
Kahaleh et al. (2022) |
52 | NR | 42.5 | 9.6 | 92.0 | 3.4 |
NR, not reported.
Outcomes of gastric per-oral endoscopic myotomy in refractory gastroparesis
Study | Study design | Age (yr) | Etiology (%) | Clinical success (%) | Adverse events (%) | Predictors of success or failure | |
---|---|---|---|---|---|---|---|
Mekaroonkamol et al. (2019) |
Retrospective, single center | 40 | 47.7±15.5 | DG: 62.5 | 80.0 at 1 mo | 7.5 | Success: predominant nausea/vomiting and shorter duration of disease |
NDG: 37.5 | 57.1 at 1 yr | ||||||
70.0 at 1.5 yr | |||||||
Gregor et al. (2021) |
Prospective, single center | 52 | 48 (25–80) | DG: 40.5 | 58.0 at 6 mo | 5.8 | Failure: longer duration of symptoms |
NDG: 59.5 | 48.0 at 1 yr | ||||||
Abdelfatah et al. (2021) |
Retrospective, single center | 90 | 42.4±12.6 | DG: 42.2 | 81.0 at 3–6 mo | 4.4 | Failure: high BMI and use of psychiatric medications |
NDG: 57.8 | 69.1 at 1 yr | ||||||
Ragi et al. (2021) |
Retrospective, multicenter | 76 | 56 (43–64) | DG: 34.2 | 65.8 at 1 yr | 6 | Success: high preoperative GCSI satiety subscale score |
NDG: 65.8 | Failure: high rate of gastric retention at 4 hours | ||||||
Vosoughi et al. (2022) |
Prospective, multicenter | 80 | 49.3±14.9 | DG: 23.8 | 57.5 at 1 mo | 6.2 | Success: baseline GCSI Score >2.6 and baseline gastric retention >20% at 4 hours |
NDG: 76.2 | 56.0 at 1 yr | ||||||
Labonde et al. (2022) |
Prospective, multicenter | 46 | 54±15.9 | DG: 32.6 | 65.2 at 3 yr | NR | Success: cases with predictive score ≥2 |
NDG: 67.4 |
Values are presented as mean±standard deviation or median (range). DG, diabetic gastroparesis; NDG, non-diabetic gastroparesis; BMI, body mass index; GCSI, gastric cardinal symptom index; NR, not reported.
Recent updates and future directions on submucosal endoscopy in the gastrointestinal tract
Disease | Procedure | Update | Future directions |
---|---|---|---|
Achalasia cardia | POEM | Short and long esophageal myotomy are equally effective in type I/II achalasia | Long-term outcomes of POEM especially with reference to gastroesophageal reflux; modified techniques for prevention of GERD |
Single dose of antibiotic prophylaxis may be sufficient before POEM | |||
POEM is superior to PD and equivalent to HM at 2-years follow-up | |||
Subepithelial tumors | STER/POET | Transesophageal resection of mediastinal cysts and extraluminal tumors is feasible | Randomized comparison with endoscopic submucosal excavation, predictors of |
Gastroparesis | G-POEM | Outcomes of G-POEM are modest in refractory gastroparesis | Long-term outcomes, utility of EndoFLIP and predictors of outcomes, randomized comparison with surgical pyloroplasty |
Zenker’s diverticulum | Z-POEM | Variation in techniques (over the septum, Z-POEM+mucosotmy and hybrid Z-POEM) may improve technical and clinical outcomes | Long-term outcomes of Z-POEM and comparative trials with flexible endoscopic myotomy |
Others (Hirschsprung’s disease, esophageal strictures) | PREM, POETRE | Submucosal endoscopy may be a potential alternative to surgery in Hirschsprung’s disease and complete esophageal obstruction | Long-term outcomes, comparison with surgery |
POEM, per-oral endoscopic myotomy; PD, pneumatic dilatation; HM, Heller’s myotomy; GERD, gastroesophageal reflux disease; STER, submucosal tunneling endoscopic resection; POET, per-oral endoscopic tumor resection; G-POEM, gastric POEM; EndoFLIP, endoluminal functional lumen imaging probe; PREM, per-rectal endoscopic myotomy; POETRE, per-oral endoscopic tunneling for restoration of the esophagus.