Expanding the role of endoscopic resection in esophageal gastrointestinal stromal tumors: Insights and challenges

Abstract

While rare, esophageal gastrointestinal stromal tumors (GISTs) have higher malignant potential and are typically diagnosed at larger sizes compared to gastric GISTs. However, well-defined guidelines for their optimal management remain lacking. Most esophageal GISTs are surgically managed with enucleation, while esophagectomy is reserved for larger tumors. Recent advances in endoscopic techniques, such as endoscopic submucosal dissection and submucosal tunneling endoscopic resection (ER), have allowed for endoscopic removal of submucosal esophageal lesions, including GISTs. Xu et al reported on the clinical and oncological outcomes of 32 patients with esophageal GISTs treated with ER. The study demonstrated high en bloc resection rates and favorable 5-year overall survival and disease-free survival. However, it primarily focused on small, incidentally detected GISTs, with 75% of cases classified as very low or low risk according to the National Institutes of Health criteria. The authors favored the submucosal tunneling ER technique despite its procedural challenges in the upper esophagus. In this editorial, we briefly discuss the advantages and limitations of endoscopic techniques compared to surgical approaches. We also emphasize the need to establish specific management criteria for submucosal esophageal lesions to guide clinical practice.

Key Words: Gastrointestinal stromal tumors; Esophageal gastrointestinal stromal tumors; Endoscopic resection; Submucosal tunneling endoscopic resection; Endoscopic submucosal dissection; Esophagectomy; Treatment outcome

Core Tip: Esophageal gastrointestinal stromal tumors are exceedingly rare and tend to be diagnosed at larger sizes with higher malignant potential than their gastric counterparts. Although definitive management guidelines remain lacking, surgical resection has traditionally been the primary treatment. However, recent advancements in endoscopic techniques now offer promising minimally invasive alternatives that can help patients who are not candidates for esophagectomy.

INTRODUCTION

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, accounting for 1%-2% of all gastrointestinal malignancies. The majority originate in the stomach (60%-70%) and small intestine (20%-30%) and typically present in older adults, with a comparable sex distribution[1,2]. Esophageal GISTs are exceedingly rare, comprising only 0.7% of all GISTs[3]. A study analyzing incidence trends and survival outcomes using data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program estimated that the age-standardized incidence rate of esophageal GISTs was 0.005 per 100000 persons in 2000, rising to 0.014 per 100000 persons by 2019[4]. Although the fundamental pathophysiology of esophageal and gastric GISTs is similar, esophageal GISTs have been reported to follow a more aggressive course[5,6]. Compared to gastric GISTs, they have lower overall survival rates, likely due to their higher mitotic rate and larger average tumor size at diagnosis (7 cm)[7]. Additionally, the rarity of esophageal GISTs has hindered the development of well-defined guidelines for their optimal management. The standard approach for non-metastatic GISTs remains complete resection, with enucleation and esophagectomy the primary surgical methods. Yet, in the era of continuously evolving endoscopic resection (ER) techniques, the invasiveness of these surgical approaches raises concerns, particularly for small esophageal GISTs. Recent published case series have demonstrated the feasibility and safety of ER techniques in the management of upper gastrointestinal subepithelial lesions[8,9].

However, studies specifically evaluating ER for esophageal GISTs remain scarce, with most of the available literature comprising case reports or small case series. Motivated by a recent publication by Xu et al[10], which presents the largest series of esophageal GIST patients treated with ER to date, we review the literature, summarize previously reported ER case series of esophageal GISTs, and briefly discuss the advantages and limitations of endoscopic techniques compared to standard surgical approaches. Table 1 presents the key characteristics and outcomes of recently published patient series undergoing ER for esophageal GISTs.

Table 1 Summary of endoscopic resection outcomes in published series of esophageal gastrointestinal stromal tumors.

Ref.	Number of patients	Tumor size1 (mm)	Tumor location (%)	Technique, n (%)	En bloc resection	Complications	Comments
Zhou et al[17], 2020	16	12 (6-21)	Upper 25, middle 31, lower 44	ESD 8 (50), STER 8 (50)	Not specified	Perforation: 3 (19%), Bleeding: 1 (6%)	No recurrence of malignant gastrointestinal stromal tumor during the 28 months of follow-up
Mohammadi et al[9], 2021	11	33 (22-60)	Upper 9, middle 36, lower 18, not specified 36	Enucleation - not further specified	Not specified	No 91%, not specified 9%	Tumor rupture was observed in 1 patient, who had undergone enucleation, of a 6.0 cm tumor
Lian et al[12], 2024	23	23 (10-40)	Upper 13, middle 52, lower 35	STER: 23 (100)	23 (100%)	One patient with a 3 cm tumor experienced significant intraoperative bleeding	No signs of disease progression during a median follow-up of 31 months (range 13-47 months)
Zhu et al[13], 2024	15	30 (10-75)	Not mentioned but the majority in lower oesophagus	ESD 4 (27), STER 9 (60), EMBL 2 (13)	Not mentioned	Minimal	Single-center study -compared endoscopic and surgical treatment
Xu et al[10], 2025	32	21 (8-27)	Upper 6, middle 31, lower 63	STER and EFTR	31/32 (97%)	Hydrothorax 4/32; post-ESD electrocoagulation syndrome 5/32	The largest published series to date, but with significantly small tumor sizes

¹Mean value (range).

ESD: Endoscopic submucosal dissection; STER: Submucosal tunneling endoscopic resection; EMBL: Endoscopic muscularis-basal layer dissection; EFTR: Endoscopic full-thickness resection.

ER TECHNIQUES: OPTIMAL CLINICAL OUTCOMES WITH MINIMAL INVASIVENESS

Regarding the selection of the appropriate ER technique, there are no clearly defined guidelines for the management of subepithelial lesions of the esophagus, particularly esophageal GISTs. The choice of technique is determined by experienced endoscopists at high-expertise centers and depends on multiple factors, including individual proficiency with each method, lesion size, and the potential for an exophytic growth pattern.

Relatively small esophageal GISTs (1-3 cm) are considered the most suitable candidates for local resection[11]. Histological confirmation is typically straightforward using endoscopic ultrasound-guided fine-needle aspiration/biopsy or mucosal incision-assisted biopsy. In the case of smaller, superficial GISTs that protrude into the lumen that can be completely resected with a snare, conventional endoscopic mucosal resection using a ligation device is very simple and effective[11]. For less superficial lesions, endoscopic muscularis-basal layer dissection—a modified technique derived from endoscopic submucosal dissection (ESD) and endoscopic full-thickness resection—allows for dissection up to the muscularis-basal layer while preserving the integrity of deeper muscle layers and minimizing procedural risks[11].

ESD begins with lesion marking, followed by submucosal injection to lift the mucosa, which is then incised to expose the tumor. Careful dissection is then performed along the tumor capsule to achieve complete en bloc resection. Any resultant wound is closed using endoscopic clips or other advanced closure techniques to reduce the risk of complications[12]. Meanwhile, endoscopic submucosal excavation involves removing the overlying mucosa and enucleating the lesion. However, when the lesion is located in the deeper muscle layer, transluminal perforation is common[11].

For deeper or larger lesions (2-4 cm), ER techniques that preserve mucosal integrity and utilize it as a protective flap are generally preferred, as they have been associated with fewer serious long-term complications, such as stricture formation[13,14]. Given that the esophagus is particularly well-suited for submucosal tunneling, submucosal tunneling ER (STER) has become an established and increasingly adopted ER technique[15]. It begins by creating a fluid cushion, followed by the formation of a submucosal tunnel between the mucosal and muscularis propria layers, typically starting 3-5 cm proximal to the lesion and extending approximately 1 cm distal to it. This method facilitates complete lesion removal while preserving the overlying mucosa, thereby reducing the risk of postoperative gastrointestinal leaks, strictures and gas-related complications[13,14]. Due to the intrinsic size constraints of the tunnel, STER is most appropriate for GISTs smaller than 4 cm and is widely applied to subepithelial lesions of the upper gastrointestinal tract arising from the muscularis propria. However, when the tumor is located in the proximal esophagus, tunnel creation becomes technically challenging, limiting the feasibility of the procedure.

ER is currently a viable treatment option for smaller esophageal GISTs provided that the tumor demonstrates features indicative of low mitotic activity, such as a regular shape, solid consistency, and a uniformly hypoechoic appearance on endoscopic ultrasound. One of the key advantages of ER in this context is its favorable safety profile. In most published patient series, the reported rate of serious adverse events was below 10%, and no study to date has documented a fatal complication[9,10,15-17]. The mean tumor size in these series was approximately 24 mm, further supporting the suitability of ER for smaller lesions.

Although ESD and STER are the most commonly employed ER techniques and are generally regarded as safe and effective, they have risks[18]. These potential complications must be carefully weighed during the decision-making process, particularly when selecting candidates for ER of esophageal GISTs. The most frequently reported adverse events include pneumothorax, pneumoperitoneum, bleeding, and perforation, each with varying clinical significance depending on tumor location, size, and operator experience[14,18]. Intraoperative perforations[19] during STER are typically manageable using endoscopic closure techniques, such as through-the-scope clips, over-the-scope clips, or suturing systems. Although rare, delayed perforations and infections represent serious complications of ER that require prompt recognition and, in some cases, systemic antibiotic therapy or even surgical intervention. Gas-related events—such as subcutaneous emphysema, pneumomediastinum, pneumothorax, and pneumoperitoneum—are among the most commonly reported adverse events[18]. Importantly, however, most of these can be conservatively managed without the need for invasive procedures. Thoracentesis may be required in cases of dyspnea or when a pneumothorax causes more than 30% lung collapse.

Postoperative infection is another serious complication, particularly following STER, where hemorrhage or fluid accumulation within the submucosal tunnel increases the risk of secondary infection[18]. To reduce this risk, prophylactic antibiotic administration is recommended, and meticulous hemostasis during the procedure is essential[13,14,18]. In cases of suspected delayed bleeding or pleural effusion, a computed tomography scan is useful for diagnosis. If pleural effusion is confirmed, ultrasound-guided thoracentesis and drainage are necessary to prevent the development of chest infections[18].

Other important parameters in the individualized management of esophageal GISTs include the overall lower cost associated with ER, which is primarily attributed to shorter procedure times, reduced length of hospital stay, and faster patient recovery compared to surgical approaches. This represents a significant consideration for healthcare systems worldwide[9,10,15-17]. Unfortunately, cost-effectiveness analyses specifically evaluating resection methods for esophageal subepithelial tumors are currently lacking. In a published study by Shoji et al[20], the total cost of laparoscopic wedge resection for gastric subepithelial lesions was estimated at 306644 yen (approximately 2045 USD). Compared to laparoscopic surgery, open gastric wedge resection has been shown to incur 1.3 times higher overall costs[21]. Future studies focusing on cost-effectiveness comparisons between endoscopic and surgical management of esophageal subepithelial lesions are clearly warranted. Such data would not only inform clinical decision-making but also support the optimization of healthcare resource allocation in the treatment of these rare tumors.

Despite the growing feasibility of ER for esophageal GISTs, careful patient selection remains essential. Larger tumors, particularly those exceeding 4-5 cm or exhibiting features suggestive of high mitotic activity, may pose significant technical and oncological challenges and are generally considered contraindications for ER. Tumor location also plays a critical role; lesions in the proximal esophagus or those with extraluminal growth are associated with higher procedural complexity and risk. Moreover, the safety and effectiveness of ER are closely linked to the endoscopist’s experience and the availability of advanced closure techniques. These considerations highlight the importance of a tailored, multidisciplinary approach when determining the optimal treatment strategy for each patient.

THE STANDARD SURGICAL APPROACH IN THE ERA OF EVOLVING ENDOSCOPY

In contrast to gastric and intestinal GISTs, which can typically be managed with segmental or wedge resections, surgical options for esophageal GISTs are essentially limited to either enucleation or highly invasive esophagectomy. This limitation stems from the unique anatomical characteristics of the esophagus. The choice of surgical procedure remains unclear and is largely individualized, depending on tumor size, location, and patient-specific factors[22,23].

With regard to postoperative morbidity and mortality, tumor enucleation appears to be the preferable surgical option, particularly in patients with significant comorbidities. Enucleation is generally considered appropriate for smaller esophageal GISTs (up to 5 cm), while esophagectomy is typically recommended for larger tumors, especially those exceeding 9 cm. When appropriate patient selection criteria are applied, the oncological outcomes of these two surgical approaches are comparable[22-24]. Both thoracoscopic enucleation and esophagectomy, including robotic-assisted techniques, have been successfully employed in the management of esophageal GISTs, offering the potential for reduced surgical trauma and improved recovery[22,23]. Additionally, a hybrid technique—thoracoscopic and endoscopic cooperative surgery (TECS)[25]—modeled after laparoscopic and endoscopic cooperative surgery used for gastric subepithelial lesions, combines the advantages of both approaches. TECS may represent a promising future option for intraluminally growing tumors of relatively small size.

Complete en bloc resection is crucial for GISTs due to their potential malignancy, and intraoperative tumor rupture must be strictly avoided[26,27]. The rate of piecemeal resection, which is considered a major oncological concern, was reported in 0%-3% of ER[9,10,15-17] cases in studies that provided this data, while a single case of GIST rupture during endoscopic enucleation was described by Mohammadi et al[9]. The follow-up duration in ER series ranged from 28 to 65 months (mean 45 months), and although tumor recurrence was exceptionally rare, the follow-up period was not sufficient to definitively confirm the absence of recurrence.

A direct comparison between ER and surgical resection for esophageal GISTs is challenging, as such comparative studies are absent from the literature. In a meta-analysis by Cai et al[28] comparing endoscopic and laparoscopic resection for gastric GISTs, which are significantly more common than esophageal GISTs, ER was associated with shorter operative times and reduced hospital stays. No significant differences were observed between the two approaches in terms of intraoperative blood loss, hospitalization costs, complication rates, or tumor recurrence. However, for tumors measuring between 2 and 5 cm, ER carried a higher risk of positive resection margins. This finding is clinically relevant, as positive margins or intraoperative tumor rupture automatically classify patients as high risk for recurrence and typically require additional treatment, either through completion surgery or adjuvant systemic therapy. These consequences may result in several disadvantages, including increased risk of tumor relapse, potential long-term side effects from systemic therapies, psychological stress for the patient, and a greater economic burden.

To date, there have not been any prospective trials that evaluated the long-term oncological outcomes of ER for esophageal GISTs. As such, its long-term safety and efficacy remain to be definitively established. Given the rarity of these tumors, existing evidence is primarily derived from small retrospective series, which limits the generalizability of current findings. Therefore, multicenter prospective studies are urgently needed to validate the role of ER, ensure adequate patient inclusion, and generate high-quality data that can inform evidence-based clinical decision-making.

Subepithelial tumors and GISTs located in extreme regions of the esophagus—either in the upper esophagus near the upper esophageal sphincter or in the lower esophagus adjacent to the gastroesophageal junction—represent a particular clinical challenge[29]. Fortunately, such cases are exceedingly rare. The scarcity of data and the technical limitations associated with ER in these anatomically complex locations often render surgical intervention the preferred, if not necessary, treatment approach. However, even surgical management in these regions presents considerable difficulties. Tumors in the upper esophagus pose significant technical challenges due to limited access and proximity to critical structures, whereas lesions near the gastroesophageal junction may require resection involving the lower esophageal sphincter, a procedure associated with a high incidence of long-term reflux-related complications[29]. Additionally, while treatment strategies are generally more straightforward for very small tumors (≤ 2-3 cm), which favor ER, and for large tumors (> 5 cm), which typically require surgery, the optimal approach for borderline-sized lesions remains less defined and should be carefully individualized based on patient- and tumor-specific factors.

In summary, current literature supports the safety and feasibility of ER for small esophageal GISTs. However, no comparative data exist between endoscopic and surgical resection techniques. Larger future studies with long-term outcome evaluation are necessary to establish evidence-based treatment algorithms and may allow for the development of predictive models to guide individualized therapeutic decisions, taking into account factors such as tumor morphology, anatomical location, and patient comorbidities. As endoscopic technology continues to advance and endoscopist training becomes more specialized, the availability of expert centers will play an increasingly critical role in determining the optimal approach for managing these rare tumors. With the rapid evolution of endoscopic techniques, the publication of ongoing clinical trials and future advancements in ER methods is eagerly anticipated.

CONCLUSION

ER techniques represent a feasible and minimally invasive option for the management of small esophageal GISTs, particularly those located in the mid and lower esophagus. The oncological outcome of ER is primarily determined by the ability to achieve en bloc resection and complete tumor removal with an intact capsule, which, based on published series, appears to be satisfactory in appropriately selected cases. In contrast, surgical resection continues to offer optimal oncological outcomes and remains applicable regardless of tumor size or growth pattern. Given the rarity of esophageal GISTs and the lack of long-term data on the safety and efficacy of ER, comparative studies between endoscopic and surgical approaches are clearly warranted. In the future, predictive models incorporating patient characteristics, tumor morphology and location, as well as individualized recurrence risk stratification, may help refine the therapeutic decision-making process. Such tools could better define the cost-benefit profile of each strategy, ultimately contributing to a more personalized and evidence-based approach to the management of these rare tumors.