The role of endoscopic resection in the treatment of gastric gastrointestinal stromal tumors

We commend and thank Tan et al. for their contribution to the gastrointestinal stromal tumor (GIST) literature. This paper addresses the important topic of the non-surgical management of GISTs (1). While surgical resection has historically been the standard of care in non-metastatic GIST (2), advancements in endoscopy have created the opportunity for ultra-minimally invasive resections of gastric tumors. Over the last 10 years, there has been an exponential increase in studies in which gastroenterologists push the boundary of what can and should be resected endoscopically. While this may be appealing for benign lesions of the stomach with low metastatic potential, whether this should be pursued for cancers, such as GIST, that can seed and metastasize to the peritoneum remains a topic of controversy.

Advancements in endoscopic tools and the increasing skillset of endoscopists have generated a number of procedures that have been applied to the endoscopic resection of GISTs. There are currently many new and experimental methods being developed as the technology progresses, but the most common techniques described for GISTs include endoscopic submucosal dissection (ESD), endoscopic submucosal excavation (ESE), endoscopic subserosal dissection (ESSD), endoscopic full-thickness resection (EFTR), and submucosal-tunneling endoscopic resection (STER) (Table 1). In ESD, fluid is injected submucosally, the mucosal/ submucosal layers around the lesion are precut, the submucosal layer is then dissected until the tumor is exposed, and it is then dissected from the superficial muscularis propria (MP) layer (3-5). ESE utilizes the same method as ESD but excavates the tumor, allowing for removal from the deep MP layer (6,7). ESSD is a technique that then takes this further by extending beyond the MP layer into the subserosa for deeper tumors and may require closure with clips or endoloops (8). EFTR is accomplished by starting with the standard ESD technique and then extending the incision into the serosal layer around the lesion, and excising the full-thickness gastric wall with its associated tumor via retrieval hook, insulated-tip (IT) cautery, or snare. This procedure creates a planned full-thickness gastric perforation that is then closed with endoscopic clips or other closure device (9). STER is performed by creating a fluid cushion 3–5 cm proximal to the lesion, then making a 1–2 cm longitudinal mucosal incision to create the tunnel entry. A submucosal tunnel is developed between the mucosal and MP layers, dissecting the tumor with an IT, hybrid, or dual-knife cautery. After dissection, the mucosal entry site is closed with standard endoscopic clips or other closure device (10,11).

The literature comparing endoscopic resection of GISTs to surgical resection is promising but severely limited by the quality of these studies. While some are propensity matched, almost all are retrospective and none are randomized, allowing for inherent bias and limitations in applying these results to clinical practice. A true comparison of treatment approaches is made difficult by the fact that patients who are referred for endoscopic resection often have smaller tumors, lower mitotic rates, lower risk assessment, and/or overall more favorable-appearing biology on work-up (10,12). While many studies came to the conclusion that recurrence-free survival (RFS), cancer-specific survival (CSS), and/or overall survival (OS) were comparable between these two modalities (3,5,10,12-14), post-operative follow-up varied immensely between studies and for the vast majority did not exceed 4 years (15). In a sarcoma that recurs 70% of the time within the first 5 years and 90% within the first 10 years post-resection, we may not be capturing the true recurrence rates (16). Additionally, no studies performed mutational testing pre-procedurally or on the tumors post-procedurally which, in the context of the limited and highly targeted therapeutic options for recurrent or metastatic GIST, may underplay true risk.

The National Comprehensive Cancer Network (NCCN) guidelines support active surveillance of GISTs <2 cm that lack high-risk features on endoscopic ultrasound (EUS) or concerning pathology on biopsy (2); however, many patients in this group will opt for resection regardless. In the context of these small, low-risk GISTs, the possibility of endoscopic resection becomes very favorable with the perceived benefits of an ultra-minimally invasive approach outweighing the risks of surgery (17). The trouble arises when this is then expanded to GIST >2 cm or those with high-risk features. The use of endoscopic resection, particularly of larger tumors >5 cm, accepts a certain amount of complications and risk that would otherwise be deemed unacceptable in routine surgical practice. Complications include delayed identification of bleeding, gastric macroperforation, piece-meal removal, and the R1 resection of a sarcoma (9,10,13,14,18). One of the major benefits of surgical resection is that the tumor is retained within the submucosal layer, whereas endoscopic resection exposes the pseudocapsule to surrounding tissue during extraction. While this may have minimal risk in the intra-luminal environment, exposure to the peritoneal cavity in the case of iatrogenic or planned gastric perforation raises concern for seeding if the pseudocapsule ruptures with manipulation or extraction.

The success of an R0 resection is variable in the endoscopic literature, often with an “en bloc resection” being defined as simply having the pseudocapsule intact (3). The acceptability of a positive margin in GIST is currently a topic of controversy, with a number of studies suggesting that, in the absence of tumor rupture, microscopically positive margins in GIST may not be as detrimental to CSS or OS compared to other sarcomas (19-22). A meta-analysis investigating this found that these results may be attenuated by the administration of post-operative imatinib (23). With GIST mutational subtype emerging as a major component of aggressive tumor biology and response to tyrosine kinase inhibitor (TKI) therapy, this would mean that the 15–20% of GISTs who harbor mutations that exhibit primary resistance to imatinib may particularly benefit from a true R0 resection if possible (24,25). The iatrogenic indication of adjuvant imatinib to compensate for an inadequate oncologic resection in a GIST that would otherwise have been considered cured after margin-negative resection should be considered unacceptable.

Surveillance post-endoscopic resection of GISTs presents an additional dilemma due to the lack of established guidelines and the variability of recommendations internationally. The utility and timing of endoscopic surveillance specifically is an area of ambiguity, with some institutions performing endoscopic review at 6–12 months after endoscopic resection and then again within 2–3 years on top of imaging surveillance (17). The current NCCN guidelines on GIST do not yet address endoscopic resection but the same oncologic principles should be applied. These guidelines define a complete resection as R0 but do not require re-excision for an R1resection and recommend the same follow-up intervals for imaging. This includes a history and physical with computed tomography abdomen/pelvis with contrast (CTAP) and/or magnetic resonance imaging (MRI) abdomen/pelvis with and without contrast every 3–6 months for 5 years with the option for less frequent imaging in low-risk tumors (2). While tumor spillage, violation of the pseudocapsule, or piecemeal removal in the context of a surgical resection is recommended to be treated the same as metastatic disease per NCCN, it is not established whether this same classification should be applied if these complications occur intra-luminally during endoscopic resection. There is insufficient evidence regarding the optimal treatment strategy and post-procedural follow-up for this subset of patients. With this in mind, these patients should have an individualized treatment/follow-up plan discussed by a multi-disciplinary team at a specialized sarcoma center due to need for molecular testing and possible systemic and/or additional surgical interventions. The absence of clinical trials comparing surgical resection and endoscopic resection of GISTs forces the oncology community to rely heavily on the current available literature and interpret it in the appropriate context. Based on the current data and our clinical experience we suggest the following. Small (<2 cm) endophytic gastric tumors, with low-risk features on EUS/biopsy [mitoses <5/50 high-power field (HPF), homogenous appearance on EUS, and depth of invasion limited to the MP layer], and no clinical lymph node involvement or metastases, are likely to be appropriate for endoscopic resection with acceptable risk. GISTs 2–5 cm that meet the same low-risk criteria as previously stated, however, would benefit from multi-disciplinary involvement and molecular testing, since imatinib-resistant subtypes have very limited options for adjuvant therapy. Multi-disciplinary collaboration is of particular importance for low risk GISTs 2–5 cm identified at the gastro-esophageal junction, cardia, or pylorus where the benefits of an endoscopic resection may outweigh the risks of the surgical complications that can occur at these sites. For small endophytic gastric GISTs, combined endoscopic and laparoscopic surgery may be a reasonable option for maximum gastric preservation due to difficulties in seeing these tumors from the peritoneal cavity. At this time, we do not believe intermediate/high-risk GISTs, tumors >5 cm, molecular testing showing wild type or TKI-resistant mutational subtypes, or those with concerning features on EUS/biopsy (mitoses >5/50 HPF, heterogenous appearance on EUS, depth of invasion beyond the MP layer, multifocal disease, or evidence of extra-luminal disease) are appropriate for endoscopic resection as the risks outweigh the benefits of an ultra-minimally invasive approach. As endoscopic and surgical technology advances, further research will be required to best guide patients and clinicians, ideally in the form of clinical trials.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gastrointestinal Stromal Tumor. The article has undergone external peer review.

Peer Review File: Available at https://gist.amegroups.com/article/view/10.21037/gist-2025-9/prf

Funding: This research was supported by the Intramural Research Program of the National Institutes of Health (NIH).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gist.amegroups.com/article/view/10.21037/gist-2025-9/coif). The contributions of the NIH author(s) were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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