Redefining the treatment paradigm for esophageal gastrointestinal stromal tumors: The emerging role of endoscopic resection

Abstract

Esophageal gastrointestinal stromal tumors (GISTs) are exceedingly rare, often detected incidentally due to their asymptomatic nature. Historically, esophagectomy or enucleation has been the standard treatment, but these procedures carry significant morbidity. The retrospective study by Xu et al provides compelling evidence that endoscopic resection (ER) is a viable, minimally invasive alternative for low-risk esophageal GISTs, demonstrating a high en bloc resection rate (96.9%) and favorable long-term oncologic outcomes, including a 5-year overall survival rate of 100% and disease-free survival of 90.6%. These results challenge the conventional surgical paradigm and highlight the need for a paradigm shift towards endoscopic approaches in carefully selected patients. However, several critical questions remain unanswered: What are the precise selection criteria for ER candidacy? How does ER compare to traditional surgical methods in terms of recurrence risk and long-term functional outcomes? Could neoadjuvant therapy enhance the feasibility of ER for larger lesions? As endoscopic techniques continue to evolve, interdisciplinary collaboration among gastroenterologists, oncologists, and surgeons will be crucial to refining treatment algorithms and optimizing patient outcomes. Future prospective studies and randomized trials are warranted to solidify the role of ER as the standard of care for esophageal GISTs.

Key Words: Gastrointestinal stromal tumors; Esophageal neoplasms; Endoscopic resection; Minimally invasive surgical procedures; Treatment outcome; Survival

Core Tip: Endoscopic resection (ER) is emerging as a minimally invasive alternative to traditional surgery for esophageal gastrointestinal stromal tumors (GISTs), particularly for tumors ≤ 4 cm with low mitotic activity. The study by Xu et al provides compelling evidence supporting ER’s high en bloc resection rate and favorable long-term outcomes. However, critical questions remain regarding patient selection criteria, the oncologic safety of R1 resections, and the role of adjuvant therapy. Further prospective studies are needed to define ER’s place in the treatment algorithm and optimize management strategies for esophageal GISTs.

TO THE EDITOR

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms, with an incidence of 10-15 cases per million population. The most common primary sites include the stomach (50%) and small intestine (30%), while esophageal GISTs remain extremely rare, comprising less than 1% of all cases[1] (Figure 1). The pathogenesis is predominantly driven by mutations in the c-KIT gene (80%) or platelet-derived growth factor receptor alpha (PDGFRA) (10%), with metastatic progression primarily affecting the liver and peritoneum[2].

Figure 1 Distribution of gastrointestinal stromal tumors by anatomical location. The majority of gastrointestinal stromal tumors originate in the stomach (60%) and small intestine (30%), while the esophagus accounts for less than 1% of cases, highlighting the rarity of this localization. Data based on aggregated findings from retrospective clinical studies.

Since 2020, esophageal GISTs have been staged according to the 8th edition of the tumor-node-metastasis (TNM) classification system. The primary prognostic factors include mitotic index, tumor size, and localization. According to the 2020 World Health Organization classification, all GISTs are considered potentially malignant mesenchymal tumors, with their biological behavior varying depending on location, size, and mitotic activity[3].

Histopathological features, particularly the mitotic index, remain critical in risk stratification. Tumors with a mitotic index of fewer than 5 mitoses per 50 high-power fields (HPFs) are considered low risk, whereas those exceeding this threshold are classified as high risk[1]. The molecular landscape of GISTs continues to evolve, with emerging evidence of succinate dehydrogenase-deficient subtypes exhibiting distinct biological behavior and therapeutic responses[1,3].

Diagnostic approaches

The primary diagnostic approach for GIST involves endoscopic examination. Tumor size serves as a key criterion for determining treatment strategy; thus, tumor diameter measurement is routinely performed[4]. Submucosal tumors smaller than 2 cm, exhibiting a hemispherical shape, smooth contours, and the absence of ulceration or depression, should be monitored once or twice per year. By contrast, lesions exceeding 2 cm in diameter and displaying irregular margins, ulceration, or depression require further evaluation. The second-line diagnostic approach consists of radiological imaging. Computed tomography (CT) is performed using a continuous slice thickness of ≤ 5 mm, preferably with triphase multidetector CT at a slice thickness and interval of ≤ 2 mm. The scanning range should extend from the upper abdomen to the pelvis for staging purposes, particularly to detect intraperitoneal dissemination or ascites. Portal-phase CT is recommended for single-phase scanning, whereas multiphase CT, including precontrast, arterial, portal, and delayed-phase imaging, is preferred for a more accurate assessment of liver metastases. If contrast-enhanced CT is contraindicated due to allergy or other factors, magnetic resonance imaging should be performed. In cases where standard imaging modalities fail to provide a definitive diagnosis, positron emission tomography (PET/CT) with 18F-2-fluoro-2-deoxy-D-glucose is recommended. PET/CT is particularly useful for detecting peritoneal dissemination and distant metastases. According to Gayed et al[5], CT demonstrated a sensitivity of 93% and a specificity of 100%, while PET/CT showed a sensitivity of 86% and a specificity of 98%, with no statistically significant difference between the two modalities for GIST staging. Pathological diagnosis, utilizing forceps biopsy, mucosal incision biopsy, or core biopsy, plays a crucial role in confirming GIST diagnosis.

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) provides sufficient tissue samples for diagnosis with minimal complications[6,7]. Thus, a definitive diagnosis of GIST can almost always be established through EUS-FNA combined with immunohistochemical staining. Immunohistochemical staining for cluster of differentiation 117 (KIT) and Discovered on GIST 1 (DOG1) remains the gold standard for diagnosis, with molecular genetic testing further aiding in cases of KIT and PDGFRA-negative tumors[1,8,9].

Treatment approaches

The primary treatment modality for localized and locally advanced forms of GISTs is surgical resection, whereas targeted therapy is the standard approach for recurrent or metastatic disease.

For small tumors (< 1-2 cm), active surveillance may be considered based on the clinical presentation. However, the potential risk of progression should be carefully evaluated, taking into account morphological findings and risk factors, particularly in cases where surgical intervention is not pursued. A study conducted by Polkowski et al[7] reported that subepithelial tumors exhibit a malignant potential of approximately 13%. For tumors larger than 2 cm, surgical resection is indicated. Limited (organ-preserving) resections with a 1-2 cm margin from the tumor edge are considered appropriate. Lymphadenectomy is only recommended in cases of succinate dehydrogenase-deficient GISTs; in other cases, lymph node dissection is generally not indicated[8]. For tumors located in the esophagus, gastroesophageal junction, duodenum, or rectum, preoperative therapy is recommended to reduce tumor size, thereby increasing the feasibility of organ-preserving surgery.

For tumors with uncertain resectability, neoadjuvant therapy with imatinib is recommended for 6-12 months. Prior to initiating treatment, molecular genetic testing should be performed to exclude the presence of the D842V mutation[9]. Adjuvant therapy with imatinib (400 mg/day for 3 years) is the standard treatment for patients at high risk of recurrence. In cases of KIT exon 9 mutations, higher-dose adjuvant imatinib (800 mg/day for 3 years) may be considered. Conversely, GISTs with the PDGFRA exon 18 D842V mutation should not be treated with adjuvant therapy[8,9]. Patients at very high risk of recurrence due to tumor rupture during surgery should be considered for adjuvant imatinib therapy[8].

The role of mini-invasive surgery in the treatment of esophageal GISTs

Surgical resection remains the cornerstone of GIST treatment[10]. While traditional open surgery has historically been the standard, minimally invasive techniques, particularly endoscopic and thoracoscopic approaches, are increasingly favored due to their reduced morbidity and faster recovery times. Thoracoscopic and robotic-assisted resections are preferred for tumors larger than 5 cm or those located in challenging anatomical sites[8]. These approaches offer enhanced precision and reduced surgical trauma, making them viable alternatives to open surgery. Nevertheless, the thoracoscopic or robotic approach is not recommended for patients with large tumors due to the risk of tumor rupture, which is strongly associated with a significantly increased risk of recurrence[11]. Additionally, thoracoscopic surgery is not recommended for GISTs larger than 8 cm, as there is insufficient evidence demonstrating its superiority over open surgery for tumors of this size[10]. Nevertheless, there have been reports of successful treatment of large esophageal tumors using a thoracoscopic approach, followed by targeted therapy[12]. Hybrid techniques, such as laparoscopic-endoscopic cooperative surgery (LECS), further expand the feasibility of minimally invasive interventions by integrating the strengths of both modalities[13].

The treatment strategy for esophageal GISTs is determined on a case-by-case basis. Subtotal esophagectomy improves R0 resection rates; however, it involves major surgical intervention, posing risks to organ function and postoperative quality of life. In contrast, local resection is a minimally invasive approach, though concerns exist regarding potential tumor spread into the thoracic cavity[10,14].

Large tumors can cause significant defects in the muscular layer, leading to postoperative esophageal stenosis, dysfunction, and mucosal injury. Notably, successful enucleation using thoracoscopy or robotic-assisted techniques has been reported in cases of small tumors. However, endophytically growing tumors are often challenging to identify from the thoracic cavity and are not suitable for enucleation[15].

Recent studies have compared endoscopic and laparoscopic resections, highlighting the advantages of endoscopic techniques in select cases[16]. Endoscopic resection (ER) techniques, such as submucosal tunneling ER (STER) and endoscopic full-thickness resection (EFTR), have demonstrated promising results in the treatment of small GISTs, particularly in the upper gastrointestinal tract[10]. STER allows for en bloc resection of subepithelial lesions, minimizing the risk of tumor rupture and preserving organ function[17]. EFTR, which involves full-thickness resection with subsequent endoscopic closure, is particularly effective for GISTs confined to the muscularis propria. Both approaches provide oncologically sound resections with reduced postoperative complications compared to traditional surgery. The technical schemes of STER and EFTR are presented in Figure 2[18]. A comparative overview of surgical and ER approaches for esophageal GISTs is provided in Table 1, highlighting differences in invasiveness, organ preservation, complication risks, and clinical indications. Step-by-step execution of the STER technique, as applied in esophageal GIST resection, is illustrated in Figure 3, based on the study by Lian et al[19].

Figure 2 Technique of submucosal tunneling endoscopic resection[18]. A: Technique of submucosal tunneling endoscopic resection: (1) Tumor associated with the muscular membrane of the esophagus; (2) Injection of saline with indigo carmine into the submucosal layer for the safety of initiating slit and forming of submucosal tunnel; (3) Formation of the submucosal tunnel; (4) Enucleation of the tumor; (5) Tumor removal from the submucosal tunnel using a loop; and (6) Closure of the mucosal defect using endoscopic clips; B: Technique of endoscopic full-thickness resection: (1) Tumor associated with the mucous membrane of the esophagus; (2) Injection of saline with indigo carmine into the submucosal layer for safe dissection; (3) Dissection of the tumor; (4) Tumor removal from the esophageal lumen using a loop; and (5) Mucosal defect after tumor dissection. Citation: Smirnov AA, Burakov AN, Blinov EV, Saadulaeva MM, Semenikhin KD, Prudnikov AV, Dvoretskii SI, Kiriltseva MM, Bagnenko SV. The experience of endoscopic resection of benign tumors of the esophagus. Grekov's Bull Surg 2018; 177: 40-44. Copyright ©The Authors 2018. Published by Izdatel'stvo Meditsina Publishers. The authors have obtained the permission (Supplementary material).

Figure 3 Submucosal tunneling endoscopic resection for a typical esophageal gastrointestinal stromal tumor[19]. A: Endoscopic view of the tumor; B: The tumor was exposed after establishing the mucosal entry established; C: Removal of the resected tumor after complete resection; D: Endoscopic view of the submucosal tunnel after the tumor was removed; E: Incision site was closed by clips; F: Resected specimen. Citation: Lian JJ, Ji YJ, Chen T, Wang GX, Wang MZ, Li SX, Cao J, Shen L, Lu W, Xu MD. Endoscopic resection for esophageal gastrointestinal stromal tumors: A multi-center feasibility study. Ther Adv Gastroenterol 2024; 17: 17562848241255304. Copyright ©The Authors 2024. Published by SAGE Publications. The authors have obtained the permission (Supplementary material).

Table 1 Comparison of surgical vs endoscopic resection for esophageal gastrointestinal stromal tumor.

Parameter	Surgical resection/esophagectomy	Endoscopic resection (STER/EFTR)
Invasiveness	High	Low
Organ preservation	Not always	Yes
Risk of perforation or rupture	Moderate to high	Low to moderate
R0 resection rate	High (especially with esophagectomy)	Moderate (especially in tumors > 4 cm)
Hospital stay	7-14 days	2-5 days
Tumor size indication	Often > 4 cm	Up to 4 cm (up to 5 cm in selected STER cases)
Possibility of surgical re-treatment	Limited	Feasible

EFTR: Endoscopic full-thickness resection; STER: Submucosal tunneling endoscopic resection.

A study by Kahaleh et al[16] demonstrated comparable oncologic outcomes among STER, EFTR, and LECS, with reduced hospital stays and fewer complications in endoscopically treated patients. Similarly, a retrospective analysis by Lian et al[19] supported the use of STER for esophageal GISTs smaller than 4 cm, emphasizing its safety and efficacy[19]. Chen et al[20] compared ER with enucleation and concluded that STER is a less invasive approach, offering a shorter procedure time and reduced hospital stay compared to thoracic enucleation[20].

For metastatic or recurrent GIST, the National Comprehensive Cancer Network clinical guidelines recommend resection for gastric GISTs smaller than 2 cm if they exhibit high-risk features[20]. All clinical guidelines advocate for surgical intervention in non-gastric GISTs, even if their size is less than 2 cm[3,8,21-23]. Regarding the feasibility of laparoscopic surgery for tumors ≥ 5 cm, the authors provide a positive recommendation. Simple local resection is consistent with minimally invasive surgical principles, and careful handling to prevent tumor rupture is crucial for both open and laparoscopic approaches. However, there is no clear evidence defining a tumor size threshold for safe laparoscopic resection without compromising tumor integrity. Given the lack of evidence supporting systematic lymphadenectomy, local resection of the primary organ without lymph node dissection is the standard surgical approach for primary GISTs.

Highly invasive procedures, such as esophagectomy, may negatively impact postoperative quality of life and should be avoided whenever possible. The neoadjuvant therapy is recommended with imatinib for large GISTs (≥ 10 cm) and in cases where an incomplete resection is suspected. However, the long-term prognosis following adjuvant imatinib therapy in cases of tumor rupture remains unknown[23].

In 2025, Xu et al[24] published a study reporting the outcomes of treating esophageal GISTs using ER. ER techniques have demonstrated promising clinical results in selected patients. In the multicenter study by Xu et al[24], the en bloc resection rate was 96.9%, with an R0 resection rate of 75.0% and an R1 rate of 25.0%, none of which resulted in local recurrence over the follow-up period. The reported complication rate was 12.5%, including minor bleeding and transient perforation, all managed conservatively without conversion to surgery. The median hospital stay was 5.3 days, underscoring the minimally invasive nature of the procedure and its favorable perioperative profile[24]. The reported 5-year overall survival rate of 100% and disease-free survival rate of 90.6% underscore the potential of ER as an alternative to more invasive procedures. These findings align with emerging evidence suggesting that ER may serve as a first-line treatment for small, low-risk esophageal GISTs, particularly those with minimal mitotic activity. The authors also demonstrate that ER preserves esophageal integrity, reducing morbidity associated with extensive surgical resections.

An essential component of esophageal GIST management is accurate risk stratification. The study utilized the modified National Institutes of Health criteria[25], categorizing patients into very low, low, intermediate, and high-risk groups. Notably, the majority of tumors in this cohort were classified as low or very low risk, reinforcing the viability of ER for carefully selected patients. The low recurrence rate observed suggests that complete resection, even with R1 margins in some cases, does not necessarily compromise long-term outcomes. This challenges conventional surgical dogma, which often prioritizes wide-margin resection.

Authors report that most tumors were detected incidentally (87.5%), indicating that early diagnosis plays a pivotal role in optimizing prognosis. Given that esophageal GISTs may remain asymptomatic until they reach a significant size, routine endoscopic surveillance in high-risk populations could facilitate early intervention. The potential for slow tumor progression and low mitotic activity in many esophageal GISTs suggests that timely ER may obviate the need for radical surgery in select patients[25].

Mai et al[26] reported the first successful case of curative cryoablation for an esophageal GIST, demonstrating the potential of this minimally invasive technique as an alternative to surgery. However, the conclusions were limited to a single observation, and further studies are required to assess its oncologic efficacy and safety.

Current limitations and directions for future research

Despite the promising results of ER for esophageal GISTs, several critical limitations must be addressed before this technique can be universally adopted as a standard treatment. The study by Xu et al[24] provides valuable insights into the feasibility and safety of ER; however, certain unresolved issues remain that warrant further investigation.

One of the primary limitations is the tumor size threshold for ER feasibility. The study suggests that tumors larger than 4 cm have a higher probability of incomplete (R1) resection and an increased recurrence rate. While ER has demonstrated high efficacy for tumors ≤ 4 cm[26,27], there is still insufficient evidence regarding its oncological safety in larger tumors. Future studies should focus on defining the upper size limit for ER and evaluating whether neoadjuvant therapy with tyrosine kinase inhibitors (TKIs) such as imatinib can reduce tumor size preoperatively, thereby facilitating R0 resection.

Although formal guidelines for selecting candidates for ER in esophageal GISTs are lacking, preliminary criteria can be inferred from published cohorts. Based on the study by Xu et al[24], ideal candidates for ER may include patients with tumors < 3 cm in diameter, a low mitotic index (< 5 mitoses per 50 HPF), and growth confined to the muscularis propria without evidence of ulceration or mucosal involvement[24]. Lesions located in the distal or middle third of the esophagus, where endoscopic access is more favorable, may also be preferable for ER. These considerations may help guide clinical decision-making while awaiting prospective validation.

Neoadjuvant TKI therapy, particularly with imatinib, has been shown to reduce tumor size and facilitate organ-preserving surgery in large or borderline resectable GISTs, especially in the stomach and duodenum. Typical treatment duration ranges from 6 to 12 months, guided by radiologic and clinical response. Studies have demonstrated that neoadjuvant imatinib can improve R0 resection rates and reduce the need for extensive surgery without compromising oncologic outcomes[28]. While data on its use in esophageal GISTs are lacking, extrapolation from other locations suggests that preoperative TKI therapy may be a useful strategy in selected patients with large lesions considered borderline candidates for ER.

The long-term oncological outcomes of ER remain uncertain, given the relatively small sample size and the retrospective nature of available studies[29]. At the same time, numerous isolated reports of endoscopic treatment, including the use of adjuvant therapy, continue to appear in the literature[30]. While Xu et al[24] reported a 5-year disease-free survival rate of 90.6%, the follow-up period might not be sufficient to assess late recurrences, which are not uncommon in GISTs. Prospective, multicenter trials with extended follow-up are necessary to confirm whether ER can achieve recurrence-free survival comparable to surgical resection, particularly in intermediate- and high-risk patients.

The prognostic significance of R1 resection in ER is another unresolved issue. Unlike traditional surgical resection, where R1 status is associated with poor outcomes, the impact of microscopic residual tumor after ER remains unclear. Xu et al[24] reported an R0 resection rate of 75%, leaving 25% of patients with R1 resections. However, the recurrence rate in these cases was not significantly higher than in R0 resections. This raises the question of whether R1 margins in ER should be managed differently than in surgery. Further research should investigate whether adjuvant therapy is necessary for patients with R1 resections or whether close endoscopic surveillance alone is sufficient.

In addition to oncologic outcomes, functional results following ER are an important consideration. Several studies have reported favorable postoperative functional outcomes, including preserved esophageal motility, low rates of dysphagia, and better quality of life compared to surgical resection[19,20]. These aspects further support the use of ER in anatomically and biologically favorable cases.

In gastric GISTs, multiple studies have demonstrated that R1 margins do not significantly impact recurrence or survival, particularly when adjuvant therapy is administered in high-risk cases[31]. Similarly, data from rectal GISTs suggest that a microscopic margin involvement may be acceptable in the context of complete gross resection and favorable tumor biology. Whether these findings are applicable to esophageal tumors is not yet established, highlighting the need for site-specific data and long-term follow-up.

The role of adjuvant therapy after ER is yet to be determined. In the study by Xu et al[24], only two patients received adjuvant imatinib, making it difficult to assess its impact on recurrence prevention. While TKIs are widely used in adjuvant settings following surgical resection of high-risk GISTs[9], their utility after ER remains to be evaluated. Future research should identify specific risk factors that would indicate a benefit from adjuvant therapy in patients undergoing ER.

Technical advancements in ER methods require further exploration. The study highlights that STER is the preferred approach for small esophageal GISTs, as it minimizes mucosal injury and reduces complications such as strictures. However, for tumors originating from the deeper layers, endoscopic full-thickness resection may be a viable alternative[18]. Additional comparative studies are needed to determine which ER techniques yield the best oncological and functional outcomes.

Future research should focus on developing precise criteria for patient selection. While low- and very-low-risk GISTs appear to be ideal candidates for ER, the potential extension of indications to include intermediate-risk tumors remains an open question. Incorporating molecular profiling into the risk stratification of esophageal GISTs may further refine treatment algorithms and improve patient outcomes[1]. Also, future prospective, multicenter randomized controlled trials are warranted to evaluate the long-term oncologic efficacy and safety of ER techniques compared to surgical resection. Study designs comparing patient selection criteria or recurrence rates following R1 vs R0 resection would be particularly informative. In addition, advances in molecular oncology suggest that gene-based therapies targeting TP53 and CDH1 mutations, as explored in gastric cancer, may eventually offer novel therapeutic options for upper gastrointestinal tumors, including esophageal GISTs[32].

In summary, while ER has emerged as a promising minimally invasive approach for esophageal GISTs, its limitations necessitate further research. Large-scale prospective studies, longer follow-up periods, and investigations into the role of neoadjuvant and adjuvant therapies will be crucial in establishing ER as a definitive treatment option for a broader range of patients.

CONCLUSION

ER has emerged as a viable, minimally invasive alternative to surgery for selected patients with esophageal GIST, particularly those ≤ 4 cm with low mitotic activity. It offers advantages such as organ preservation, reduced morbidity, and shorter recovery times. However, long-term oncologic outcomes, the significance of R1 resections, and the role of adjuvant therapy remain uncertain. Further prospective studies are needed to refine patient selection criteria, optimize treatment strategies, and establish ER as a definitive standard for managing esophageal GISTs.