Stricture prevention after circumferential endoscopic submucosal dissection of the esophagus: Proactive vs reactive strategies

Abstract

In this editorial, we explored currently available strategies for reducing the occurrence of esophageal strictures following circumferential endoscopic submucosal dissection. This manuscript provided a comprehensive overview of the various strategies including recent insights from Wang et al. To this end, stenosis-related symptoms such as dysphagia and vomiting can severely affect a patient’s quality of life. Therefore, we assess the efficacy of both reactive and proactive measures, ranging from traditional approaches like endoscopic balloon dilation and steroid administration to more advanced techniques, including tissue engineering and polyglycolic acid sheet placement. However, no single treatment has shown high efficacy, particularly for resections involving the entire circumference. Despite these shortcomings, the combination of different strategies may improve patient outcomes, although further large-scale studies are needed for validation.

Key Words: Endoscopic submucosal dissection; Esophagus; Circumferential; Stenosis; Stricture

Core Tip: This editorial displayed the current strategies for preventing stenosis formation after circumferential esophageal endoscopic submucosal dissection. Use of a single reactive or proactive strategy has not been found to be highly effective, especially in resections involving the entire esophageal circumference. Combining two or more strategies represents a promising option to optimize patients’ quality of life and reduce symptoms. As a result, there is a pressing need for large prospective studies to further investigate this issue and ultimately determine the most effective strategy.

INTRODUCTION

Over the last decade, the management of esophageal lesions has shifted towards an endoscopic treatment for lesions showing dysplasia or non-invasive carcinoma, aiming for an organ-preserving strategy[1]. Thanks to the advancement of optical diagnosis systems and endoscopic devices, endoscopic submucosal dissection (ESD) has become a standard of care for Barrett’s esophagus-associated and squamous cell lesions with suspected superficial carcinoma[2,3], carrying a 3-year survival rate of up to 92.6% after effective resection[4].

However, alongside the growing effectiveness of ESD, the incidence of both early and delayed complications has also risen. One of the most common post-ESD complications is the development of esophageal strictures, particularly after the excision of circumferential lesions[5,6], which can lead to symptoms such as dysphagia and vomiting. In cases where the excision base is completely involved, the risk of stenosis can approach 100%[7-9]. Conversely, this risk decreases with the amount of residual esophageal mucosa left intact, with a significant reduction observed when less than three-quarters of the circumference is affected[7-9].

Post-ESD chemoradiation therapy and cervical lesions represent additional risk factors of stenosis for squamous cell lesions[10,11]. It is associated with a 5.1-times and 3.8-times increased risk, respectively.

Given that stenosis may manifest within a few weeks following ESD and considering the significant impact on a patient’s quality of life, effective prevention and treatment strategies are eagerly awaited. According to the European Society of Gastrointestinal Endoscopy guidelines, the standard approach to treat post-ESD strictures is represented by endoscopic balloon dilation (EBD), usually performed in multiple sessions[12].

Post-ESD strictures can present greater treatment challenges compared to other benign esophageal strictures, primarily due to the extent of involvement and the anticipated frailty of affected patients. This necessitates a comprehensive approach aimed at alleviating symptoms and improving quality of life[5,6]. To address these challenges, new prevention and therapeutic strategies have been introduced to optimize the management of stenosis. These strategies include steroid injections, systemic administration of medications, and stent placement, along with more advanced interventions. Recently, we read with great interest the findings of Wang et al[13], who reported their experiences with stenosis following the resection of at least three-quarters of the circumferential lumen. Among 120 patients included for analysis, 53 received oral prednisone therapy while 67 received combined oral therapy and submucosal injection of triamcinolone acetonide. The rates of stricture development in these groups were 83.0% and 83.6%, respectively. The study identified the resection of 5/6 of the circumference and the absence of sodium hyaluronate in the injection solution as independent risk factors for stricture formation. These findings underscore the need for more effective strategies, particularly for patients who are difficult to treat. To date, various new tools have been developed and evaluated, especially in animal models, to address this issue.

Based on these considerations, this editorial explored the novel applications in the field of esophageal post-ESD stricture prevention, dividing them into proactive and reactive strategies (Table 1).

Table 1 Summary of reactive and proactive strategies for post-circumferential endoscopic submucosal dissection stenosis prevention.

Reactive	Proactive
Endoscopic balloon dilation; Self-expandable metal stents placement; Self-inflatable balloon placement	Oral prednisolone; Local triamcinolone injection; Polyglycolic acid sheets placement; Autologous oral mucosal epithelial cell sheets
SEMs covered by triamcinolone-soaked PGA sheet
Oral adjuvant prednisolone

SEM: Self-expandable metal; PGA: Polyglycolic acid.

REACTIVE STRATEGIES FOR POST-ESOPHAGEAL ESD STRICTURE PREVENTION AND TREATMENT

Reactive strategies for post-esophageal ESD prevention include managing strictures with a counterforce on the excision base. Those include EBD and self-expandable metal stent (SEM) placement.

Preventive EBD

Endoscopic dilation is utilized as a preventive treatment through EBD, which is usually favored over endoscopic bougie dilatation. Preventive EBD is scheduled within 4 weeks after ESD[14-16], with better outcomes reached if performed within the first 2 weeks. It consists of multiple dilation sessions using an inflatable balloon with a diameter of up to 18 mm (Figure 1). Regarding the prevention of dysphagia, the effectiveness of EBD after three-quarters circumferential ESD ranges from 59.0% to 73.3%[14,15]. A subanalysis of the study conducted by Yamaguchi et al[16] reported that among patients with entirely circumferential lesions, 100% (3 patients) in the EBD group developed strictures, requiring a median of 32.7 dilation sessions and posing an increased risk of complications.

Figure 1 Endoscopic findings following circumferential esophageal endoscopic submucosal dissection. A: Post-endoscopic submucosal dissection base; B: Prophylactic endoscopic dilation performed 2 weeks after resection to mitigate the risk of stricture formation.

Self-inflatable balloon

Recently, Li et al[17] reported the use of a novel inflatable balloon, managed by the patient right after ESD. The device is placed as a nasogastric tube on the fourth day after ESD and filled with air for 15-20 min four times per day for a total period of 2-4 months. Despite the reported sore nose and throat, patients in a recent single-center experience by the same group[18] who adopted this device had a reported risk of stenosis of 20% (5/25). This rate was lower, even if not statistically significant, compared to a control group that underwent a grafted stent placement with a reported a stricture rate of 43.8% (7/16). This device seems promising, especially because of its efficacy in entirely circumferential lesions, although it may impact a patient’s daily life and cause upper airway distress symptoms. Therefore, large multicenter data may clarify its potential role in clinical practice.

Endoscopic stent placement

Stent placement has traditionally been considered for malignant diseases. However, there has been a hypothesis suggesting that the continuous pressure exerted by these devices could promote the dilation of narrowed segments of the esophagus[19]. As a result, the use of fully covered SEMs has shown promising results in a single-center experience by Ye et al[19] on submucosal tunnelling circular endoscopic resection, with 17.4% (4/23) of patients developing stricture and 3 (3/4) patients experiencing stent migration. The latter results are aligned with the only randomized controlled trial conducted on this topic[20]. Interestingly, the cases of stricture development in the SEM group also reported stent migration.

The optimal SEM should have a low risk of ingrowth, typical of fully covered stents, but with anchoring systems that could mitigate the migration risk. Biodegradable stents ideally represented a game changer in this direction. In 2008, Saito et al[21] reported two cases of successful stricture prevention after circumferential esophageal ESD by poly-L-lactic acid monofilaments stent placement on the same day of the resection. However, those experiences remain anecdotal, and no study on adequate sample size has been conducted yet.

PROACTIVE STRATEGIES FOR POST-ESOPHAGEAL ESD STRICTURE PREVENTION AND TREATMENT

Proactive strategies include those emerging techniques that prevent stricture development from the outset without relying on exerting force.

Oral steroids

Oral steroid administration can theoretically prevent stenosis formation through antifibrotic and anti-inflammatory mechanisms of action. It usually consists of 30 mg/day of prednisolone during the first few days and then a slow taper[19].

Steroid prophylactic therapy is widely adopted in the prevention of post-ESD esophageal strictures. Oral prednisolone administration represents an option that has not been demonstrated to add substantial advantages when nearly the whole circumference is involved. In the study by Wang et al[13], the group that received both local injection and systemic steroid administration did not get substantial benefit compared to the group that received only local triamcinolone injection. The latter results are aligned with recent literature data of oral steroids preventing esophageal stricture[10], which is in contrast to earlier reports[7]. Moreover, the rate of adverse events cannot be neglected, given the reported incidence of opportunistic infections and side effects[22,23].

Local steroid injection

At the same time, the effectiveness of local steroid injections is also under investigation. This technique consists of post-ESD local triamcinolone injections with an endoscopic injection needle. However, reports from the literature are not fully aligned. Recently, Okimoto et al[24] demonstrated a low rate of stricture occurrence with two different protocols in > 3/4 circumference esophageal ESD. Among the 27 participants, 7 underwent weekly local triamcinolone injections, while 20 had a single injection post-ESD. The stricture rate was low in both groups (0% and 5%, respectively). The latter results are quite different from those reported by Wang et al[13], who reported a stenosis rate of 83.6% in the combined systemic and local administration group. Interestingly, in this study, nearly half of the lesions involved more than 5/6 of the circumference. The efficacy of local steroid injection, indeed, seems to drop when the resection involves nearly the entire circumference[25].

Polyglycolic acid sheets

At the same time, other treatments have been tested and are currently under investigation to prevent benign post-ESD esophageal stricture. Polyglycolic acid sheets (PGAs) with fibrin gel injection have not been demonstrated to be superior to local triamcinolone injection. In a historical cohort study by Iizuka et al[26], 18.8% of the patients receiving PGAs and 8.3% receiving triamcinolone injections developed a stricture after > 75% circumference esophageal ESD. PGAs are intended as biophysical barriers to reduce inflammation and promote local microbial degradation to prevent stricture development[27].

TISSUE ENGINEERING AND NEW TECHNOLOGIES

Tissue engineering technologies are currently offering new solutions. They are intended to provide structural and functional remodeling and epithelization to prevent stenosis. Creating and transplanting sheets of cells, such as oral mucosal epithelial cells, autologous skin epidermal cells, or adipose-derived stromal cells, to cover mucosal defects can prevent fibrosis. Among those, only autologous oral mucosal epithelial placement has been tested on humans to date. Despite representing a promising solution, its experience remains limited to small sample sizes, as demonstrated in a study conducted by Yamaguchi et al[28]. Oral mucosal autologous epithelial sheets prevented stricture formation in six out of ten ESDs with at least 5/6 of the esophageal circumference; however, the cases with 100% of the circumference still developed stenosis. On the contrary, Ohki et al[29] recently published a long-term follow-up experience, showing no stricture development in all 10 patients who had undergone resection and received oral mucosa autologous esophageal placement.

Adipose-derived stromal cells can be easily isolated and through local immune isolation provide an anti-inflammatory effect. A study on pig models has demonstrated their high effectiveness in preventing stenosis in circumferential esophageal ESDs (16% vs 100% stenosis rate)[30]. Other techniques include using extracellular matrix as scaffolding tissue for regeneration, which has many advantages in terms of biocompatibility. However, problems with patch fixation remain, and a combination with stents is needed to lay the material[31].

COMBINATION TREATMENTS

The literature has investigated the combination of two types of treatments, with EBD serving as an add-on for all strategies. An experience by Li et al[32] included 9 patients who had undergone at least 3/4 circumference ESD and were treated with 4-week SEM covered by a triamcinolone-soaked PGA sheet. Interestingly, 3 patients with 100% circumference excision developed stricture, with a need for endoscopic dilation, while the other 6 (also including 3 more patients with whole excision) did not. Despite the small sample size, the latter strategy seems to cover both aspects of the prevention and represents a promising option, given its effectiveness on whole circumference ESD. Chai et al[33] already reported a solid impact of PGA + SEM placement in 2018. They showed a reduced risk of stenosis (PGA + SEM = 20.5% vs SEM = 46.9%; P = 0.024) with reduced impact on circumferential resections. Moreover, Nagami et al[34] demonstrated that the adjunction of triamcinolone-soaked PGAs could be an easy and effective addition to this multiapproach. On the contrary, the adjuvant role of oral prednisone has not been shown to impact the risk of stenosis significantly, which also emerged in the experience of Wang et al[13].

CONCLUSION

Current data indicate that reactive strategies, such as EBD and SEMs, while effective to some extent, present limitations, including patient discomfort, risk of complications, and the need for repeated interventions. Proactive measures, such as steroid therapy (local and systemic), PGA sheets, and tissue engineering solutions, show promise but remain inconsistent in cases of complete circumferential resection. The variability in outcomes across studies underscores the urgent need for personalized, multimodal approaches that leverage the strengths of different interventions to optimize patient outcomes. In conclusion, preventing esophageal stenosis following circumferential ESD remains a complex challenge and an opportunity for research. Both proactive and reactive strategies offer varying degrees of success, which dramatically decreases when the entire circumference is involved. Combining personalized, patient-specific treatments and ongoing research into innovative preventive techniques may create a more effective approach to reduce post-ESD stricture development and optimize patient’s quality of life.