Indications and limits of minimally invasive treatment of esophageal gastrointestinal stromal tumor: a narrative review

Introduction

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract with an annual incidence of 7 to 11 per million (1,2). Esophageal GIST, on the other hand, is an exceedingly rare tumor that comprises less than 1% of all GISTs (3). Esophageal GIST arises from the interstitial pacemaker cells of Cajal, are positive for c-KIT (CD117) or CD34, and the majority originate at the esophagogastric junction (3,4). Given its rarity, clinicopathological and outcomes data are limited to case reports and case series (5).

While standard treatment of localized GIST consists of surgical resection with negative margins without routine regional lymphadenectomy, surgical management of esophageal GIST remains a challenge due to esophageal anatomy with lack of tumor confinement by a serosal layer and the tenuous esophageal blood supply. Unlike gastric or intestinal GIST which is amendable to segmental or resection without need for intestinal anastomosis, esophageal GIST resection is limited to esophagectomy or tumor enucleation. Given the rarity of esophageal GISTs, there are currently no clear consensus recommendations or guidelines concerning optimal surgical management (4).

Given the morbidity of a laparotomy and/or thoracotomy, a minimally invasive surgical (MIS) approach is an attractive option in the surgical management of esophageal GIST. MIS approaches include endoscopic, laparoscopic, and robotic approaches and can be utilized for enucleation, esophagectomy, and submucosal tunneling endoscopic resection (STER). This paper reviews the current literature regarding the work-up and management of esophageal GIST in the context of an MIS approach. The literature search using PubMed included retrospective, prospective, and randomized controlled studies published in the English language between 2000 and 2020. We present the following article in accordance with the Narrative Review reporting checklist (available at http://dx.doi.org/10.21037/ls-20-121).

Clinical work-up

GISTs account for 25% of stromal esophageal tumors according to a study by Miettinen et al. that included a cohort of patients with mesenchymal tumors of the esophagus (6). The median age at presentation for esophageal GIST is 61 years old, and esophageal GIST appears to be more common in males with a two-fold predominance (3). Patients most commonly present with symptoms at the time of diagnosis, and a quarter are diagnosed incidentally (3). The most common symptoms include dysphagia (39–53%), weight loss (20%), bleeding (8–12%), chest or abdominal pain (8–15%), and nausea (6%) (3,7). Secondary to the relative abundance of interstitial cells of Cajal along the esophagus, the most common distribution for esophageal GIST is the lower esophagus (81%), middle esophagus (16%), and proximal esophagus (3%), respectively (8). In one large series including 91 patients, the average tumor size on CT imaging was 7.9±5.4 cm (8). Compared to gastric GIST, esophageal GIST has a significantly larger mean tumor size (8.0 vs. 5.1 cm, P<0.001), a higher mean mitotic rate per 50 high power field (HPF) (13.4 vs. 8.0, P=0.005), higher odds of high-risk classification [odds ratio (OR) =4.53, 95% CI, 2.41–8.52], worse disease-specific survival [hazard ratio (HR) =0.158, 95% confidence interval (CI), 0.087–0.288], worse disease-free survival (HR =0.466, 95% CI, 0.241–0.901), and worse overall survival (HR =0.481, 95% CI, 0.294–0.785) (3).

Esophageal GIST appears as a submucosal lesion on imaging. When an esophageal submucosal mass is identified, the differential includes both benign and malignant tumors including leiomyoma, lipoma, hemangioma, schwannoma, leiomyosarcoma, and papillary epithelioma (9,10). Imaging, with options including computed tomography (CT), magnetic resonance imaging (MRI), ¹⁸F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET), endoscopic ultrasound (EUS), and contrast-enhanced EUS, can aid in making a diagnosis, measuring the tumor, and determining if there is local invasion or distant metastasis present (4,10). However, it can be difficult to distinguish leiomyoma from GIST prior to resection due to a similar appearance on CT, MRI, and EUS. In these cases, contrast-enhanced EUS or EUS-fine needle aspiration (EUS-FNA) can be performed to help differentiate between leiomyoma and GIST prior to surgical resection.

CT

As with GISTs in other portions of the gastrointestinal tract, small GISTs are most commonly intramural, and larger tumors may have an exophytic appearance with areas of necrosis (6,11). CT, which should be contrast-enhanced, may show an intraluminal, intramural, or exophytic mass that is hypodense with varying density and patchy enhancement on contrast-enhanced images (12). The mass may be homogenous or heterogeneous secondary to necrosis or calcification (Figure 1). CT allows for measurement of the mass, determination if there is local invasion into adjacent structures, and evaluation of distant metastatic disease to the liver or peritoneum, all necessary information in determining resectability and the appropriate operative approach. Metastatic lesions have a similar appearance to the primary tumor and can be heterogeneous due to necrosis, hemorrhage, or cystic degeneration (13,14). CT is also most often used for surveillance following neoadjuvant systemic therapy to assess tumor response or after surgical resection to detect disease recurrence.

Figure 1 Esophageal GIST in a 65-year-old man with a several-month history of dysphagia and weight loss. Axial contrast-enhanced CT image shows a large distal esophageal mass (arrows) with central low attenuation secondary to necrosis (*). From Lewis RB et al. “From the radiologic pathology archives: Esophageal neoplasms: Radiologic-pathologic correlation”. Radiographics. 2013;33:1083-108 (11). GIST, gastrointestinal stromal tumor.

MRI

On contrast-enhanced MRI, the solid portions of GISTs have low signal intensity on T1-weighted images and intermediate-to-high signal intensity on T2-weighted images and demonstrate enhancement after gadolinium administration. The marked tissue hypersignal visualized on T2-weighted images are strongly correlated with a diagnosis of a GIST (13,15). Similar to CT, MRI allows for measurement of the tumor, detection of locally advanced GIST, and evaluation of liver metastasis.

FDG-PET

While FDG-PET does not necessarily differentiate leiomyomas from GISTs, the maximum standardized uptake value (SUVmax) appears to correlate with the risk of malignancy for GISTs. In a study of 26 patients who underwent preoperative FDG-PET followed by surgical resection of a gastric GIST, there was a significant correlation between SUVmax and various risk factors for malignancy including Ki-67 index (r=0.854), tumor size (r=0.888), and mitotic count (r=0.791) (16). Using a receiver-operating characteristic (ROC) curve, the authors derived a cut-off SUVmax value of 3.94 to characterize patients as “low-risk” and “high-risk” for malignancy. The sensitivity and specificity for this cut-off value was 85.7% and 94.7%, respectively. FDG-PET may have a role in assessing the response to neoadjuvant therapy (17).

EUS-FNA

Given nearly identical appearances on CT, MRI, and EUS, it can be nearly impossible to distinguish between a benign leiomyoma and a potentially malignant GIST on imaging. However, EUS allows for measurement and characterization of tumor size, shape, and relationship with the layers of the esophageal wall (4,18). In addition, EUS-FNA is the gold standard in obtaining a tissue diagnosis to differentiate the two tumors and can be utilized for mutational analysis if the tissue material is adequate. It is recommended that a 19-gauge needle is used for obtaining a histological sample, the mitotic index, and appropriate immunostaining of CD-117 and CD-34 (10). It appears that the diagnostic rate of an adequate specimen is directly related to the size of the lesion. In a study of 53 patients assessing the proportion of patients with an adequate specimen based on tumor size, 71% had an adequate specimen for a tumor size <20 mm, 86% for a tumor size of 20–40 mm, and 100% for a tumor size of >40 mm (19). Especially for large tumors, a tissue diagnosis is required in order to administer neoadjuvant systemic therapy in order to attempt organ- or function-preserving surgical resection, help avoid tumor rupture, reduce the risk of postoperative morbidity, and increase the likelihood of an MIS approach (20). While historically there has been some concern that preoperative biopsy may seed tumor, compromise oncologic resection, or increase postoperative morbidity, there does not appear to be any evidence of adverse outcomes associated with a preoperative biopsy (21).

Contrast-enhanced EUS

A newer modality that has promise in differentiating between a benign leiomyoma and potentially malignant GIST is contrast-enhanced EUS. In a retrospective study by Pesenti et al. that included 14 patients, the authors used the contrast agent SonoVue^® (Bracco Imaging, Milan, Italy) to evaluate whether contrast-enhanced EUS could differentiate between benign and malignant subepithelial lesions of the stomach or esophagus (10). A final diagnosis was made based upon pathological studies. They observed that all 5 GISTs demonstrated enhancement in the early (after several seconds) and late phases (>30 seconds), whereas none of the other lesions showed enhancement except for one leiomyoma which demonstrated heterogeneous enhancement. While the findings are promising, the authors concluded that future studies with a larger number of patients are required to confirm these findings.

Neoadjuvant therapy

For larger tumors, imatinib, a tyrosine kinase inhibitor, can be utilized in the neoadjuvant setting to downsize the tumor and improve the likelihood of organ preservation and an MIS approach. National Comprehensive Cancer Network (NCCN) guidelines currently recommend consideration of neoadjuvant systemic therapy for locally advanced esophageal GIST or if multi-visceral resection would be required to resect all gross disease (22). Tumor genotyping should be performed for all patients who are considered candidates for neoadjuvant therapy. If an exon 9 KIT mutation is identified, higher daily dosing of 800 mg per day of imatinib should be considered as opposed to the standard 400 mg per day of imatinib. This recommendation is based on a randomized EORTC (European Organization for Research and Treatment of Cancer) phase III trial in which patients who expressed an exon 9 mutant KIT protein and received an initial daily dose of 800 mg of imatinib had significantly improved progression-free survival (HR =0.39, 95% CI, 0.22–0.71) compared to those who expressed an exon 9 KIT mutation and received an initial daily dose of 400 mg of imatinib (23).

To date, there have been three prospective phase II studies performed for neoadjuvant imatinib. Given the rarity of esophageal GIST, neither of the studies included a significant number of patients with primary esophageal GIST. Therefore, application of study findings to patients with esophageal GIST are largely extrapolated from the study of patients with gastric or small bowel GIST. The multicenter Radiation Therapy Oncology Group (RTOG) 0132/American College of Radiology Imaging Network (ACRIN) 6665 trial analyzed 52 patients with KIT-positive GIST with either a primary GIST ≥5 cm or a resectable recurrent or metastatic GIST ≥2 cm. The patients received preoperative imatinib (600 mg per day for 8–12 weeks) followed by adjuvant imatinib for 2 years following surgery. For those with a primary GIST, the response by Response Evaluation Criteria in Solid Tumors (RECIST) was 7% partial, 83% stable, and 10% unknown (24). With a median follow-up of 4.9 years for surviving patients with primary GIST, 5-year progression-free survival was 57%, and 5-year overall survival was 77% (25).

An additional phase II trial was performed in Asia in which 56 patients with gastric GISTs ≥10 cm received 400 mg per day of neoadjuvant imatinib for six to nine months prior to surgical resection (26). The response rate by RECIST was 62% (95% CI, 48–75%), and the R0 resection rate was 91% (95% CI, 79–97%). After a median follow-up of 32 months, the 2-year progression-free survival rate was 89%, and the overall survival rate was 98%. Overall, the treatment was well-tolerated with grade 3–4 neutropenia and rash occurring in 8% and 9% of patients, respectively, and there were no treatment-related deaths.

With respect to evaluation of response to neoadjuvant therapy, NCCN guidelines recommend contrast-enhanced abdominal/pelvic CT, MRI or FDG-PET (22). Irrespective of tumor size and location, a rational interval to re-image patients is 8–12 weeks after initiating neoadjuvant imatinib. A single-institution randomized phase II trial showed that even a short course of neoadjuvant imatinib is associated with evidence of radiographic and histologic response. In this trial, nineteen patients were randomized to receive either 3, 5, or 7 days of neoadjuvant imatinib (27). Approximately 70% of patients had radiographic evidence of response via FDG-PET or contrast-enhanced CT scan. The preoperative duration of imatinib was also associated with the degree of tumor cell apoptosis via terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The best response to neoadjuvant imatinib generally occurs at 28 weeks, and a plateau response is observed at 34 weeks, suggesting that treatment beyond 28–34 weeks may not provide any benefit (28). Collaboration between the medical oncologist and surgeon is recommended to determine the timing of surgical resection following a major response as tumors can develop resistance and progress to the point of unresectability without close follow-up. Imatinib can be stopped immediately before surgery and resumed as soon as the patient is able tolerate oral medications. Other tyrosine kinase inhibitors, such as sunitinib, regorafenib, and avapritinib, should be discontinued at least one week prior to surgery and can be restarted after postoperative recovery (22).

Operative approach and techniques

For esophagectomy and enucleation, operative approaches include open (laparotomy/thoracotomy), laparoscopic and/or thoracoscopic, and robotic approaches. Ivor-Lewis, transhiatal, or three-incision McKeown esophagectomy can be performed for esophageal GIST through an open, video-assisted thoracoscopic surgery (VATS), or robotic-assisted approach. Given the rarity of submucosal tumors requiring esophagectomy, there are currently little outcome data available regarding operative approach for esophageal GISTs, and most studies comparing outcomes by operative approach have been performed for epithelial esophageal cancer. In a retrospective single-institution study by Ahmadi et al. that included 210 patients, the authors observed that those who underwent a combined laparoscopic and thoracoscopic Ivor-Lewis esophagectomy had less median intraoperative blood loss (321 vs. 657 mL, P<0.01), shorter median length of stay (10 vs. 14 days, P<0.01), and lower risk of an adverse event requiring reoperation or admission to the intensive care unit (21% vs. 34%, P<0.01) (29). In comparing a VATS to a robotic approach, Harbison et al. utilized the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) to evaluate short-term outcomes (30). Across 725 minimally invasive cases, there was no significant difference in 30-day morbidity or mortality between VATS and robotic approaches. Given adequate surgeon experience, a minimally invasive VATS or robotic approach appears to be the preferred operative approach when an esophagectomy is required.

Compared to esophagectomy, tumor enucleation is the favored procedure when feasible due to lower postoperative morbidity. Enucleation can also be performed through open, VATS, or robotic-assisted approaches. While there are currently no studies evaluating the association between operative approach and outcomes for enucleation of an esophageal GIST, results can be extrapolated from the literature for esophageal leiomyoma (31). In a study by Khalaileh et al., the authors performed a systematic review comparing outcomes among open thoracotomy, thoracoscopic/laparoscopic, and robotic enucleation of esophageal leiomyoma (32). Across 32 studies and 125 total patients, a minimally invasive approach was associated with longer mean operative time (open: 117.4 minutes, thoracoscopic/laparoscopic: 141.4 minutes, robotic: 151.3 minutes). However, both thoracoscopic/laparoscopic and robotic approaches had a shorter mean hospital length of stay (open: 9.2 days, thoracoscopic/laparoscopic: 6.3 days, robotic: 5.7 days) and a lower rate of mucosal injury (open: 6.1%, thoracoscopic/laparoscopic: 5.6%, robotic: 0%) compared to an open approach.

An MIS approach has steadily replaced the traditional open thoracotomy for tumor enucleation since 1992 (33). VATS is used for tumors located in the upper and middle thoracic esophagus, and VATS or laparoscopic approaches are utilized for tumors in the lower third of the esophagus. A robotic approach can be used for tumors of any location. For tumors in the upper and middle esophagus, an approach through the right chest is typically preferred unless the tumor “leans” toward the left side of the chest. For tumors in the lower esophagus or esophagogastric junction, a left transthoracic or transabdominal approach is preferred. If a transthoracic approach is utilized, the patient is placed in the lateral decubitus position, and a double-lumen endotracheal tube is placed in order to selectively ventilate the contralateral lung (34). Absolute contraindications to a VATS or transthoracic robotic approach are an inability to achieve adequate working space in the chest or if the patient cannot tolerate single-lung ventilation due to pulmonary disease or previous pulmonary resection, and a relative contraindication is prior thoracic surgery in which severe adhesions are encountered in the chest cavity.

For VATS enucleation, general anesthesia with double lumen intubation is performed. The patient is then placed in a right or left lateral decubitus position with 15° frontal incline. Three or four 10 mm trocar ports are placed into the pleural cavity with location depending on the tumor site. After the tumor is identified thoracoscopically or via transillumination by endoscopy, the mediastinal pleura overlying the tumor is incised longitudinally with hook cautery. The esophagus is then mobilized circumferentially, and the muscle overlying the tumor is split longitudinally. A retracting suture may be placed over the mass to facilitate dissection between the mass and the submucosal layer. After successful resection of the mass and removal of the tumor from the chest, the esophagus is submerged under water, and the esophagus is insufflated via an endoscope or nasogastric tube to confirm that the mucosa is intact. The muscle layer is then re-approximated with an absorbable suture, and a thoracostomy tube is placed through one of the ports (33). A video of a VATS enucleation of an esophageal GIST is provided on the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) website (https://www.sages.org/video/thoracoscopic-enucleation-of-an-esophageal-gastrointestinal-stromal-tumor/) (35).

For robotic-assisted enucleation, a double lumen endotracheal tube is placed, the patient is placed in the lateral decubitus position with a roll positioned under the axilla, and single-lung ventilation is performed. Three or four 8-mm ports are placed, and the chest is insufflated with carbon dioxide. A 12-mm assistant port is typically placed anteriorly above the diaphragmatic insertion. The robot is docked, and the lung is retracted anteriorly to expose the esophagus. Similar to a VATS approach, the mediastinal pleura is divided longitudinally overlying the esophagus, and a myotomy is performed longitudinally over the mass with division of the longitudinal and inner circular muscle fibers with hook cautery or a bipolar dissector. The tumor is then dissected away while ensuring that the tumor pseudocapsule and esophageal mucosa remain intact. Care should be taken not to directly grasp the tumor as it may result in tumor rupture. In addition, blunt dissection should be performed near the mucosa to avoid injury. Once dissected free, the tumor is placed in an endoscopic retrieval bag and removed from the chest cavity through the assistant port site. The esophagus is submerged under water and insufflated with an endoscope to evaluate for a mucosal injury. The myotomy is then closed using a 4-0 absorbable horizontal mattress suture. The robot is then undocked, a thoracostomy tube is placed, and the lung is re-inflated (31). A video of a robotic-assisted enucleation of an esophageal leiomyoma is provided on the SAGES website (https://www.sages.org/video/robotic-enucleation-of-giant-esophageal-leiomyoma/) (36).

STER is a newer minimally invasive technique that was first described by Xu et al. in 2012 for resection of submucosal tumors originating from the muscularis propria layer of the upper gastrointestinal tract (37,38). The mucosa flap that is created acts as a safety valve to prevent luminal content extravasation into the chest or abdomen. Absolute contraindications for STER include severe comorbidity and tumor involvement or direct proximity to extraluminal vessels, and relative contraindications include tumors greater than 3 to 4 cm in the shortest diameter due to an inability to retract the tumor from the mouth or greater than 5 cm in the longest diameter due to a higher risk of aggressive tumor behavior (39). After endotracheal intubation, using a standard gastroscope, a fluid cushion is created with an injection needle 5 cm proximal to the tumor. A longitudinal 2 cm mucosal incision is then made using a hook knife at the esophageal mucosa. A tunnel is then created between the submucosal and muscular layers using a hook or hybrid knife 1 to 2 cm beyond the tumor. Resection of the tumor is then performed using an insulated-tip, hook, or hybrid knife. Special care to safely resect the tumor completely and without violation of the tumor pseudocapsule or unnecessary injury to the esophageal adventitia must be utilized. Occasionally a dual-channel gastroscope is necessary for the use of a grasping forceps to retrieve the specimen into the submucosal tunnel. After tumor resection, the submucosal tunnel is lavaged with normal saline if the adventitia remains intact. Argon plasma coagulation or hot biopsy forceps are used for hemostasis in the submucosal tunnel, and the mucosal incision site is closed with 4 to 6 hemostatic clips (37). A video of a STER of an esophageal leiomyoma is provided on the SAGES website (https://www.sages.org/video/submucosal-tunneling-endoscopic-resection-of-an-esophageal-leiomyoma/) (40).

Choice of procedure

Surgical options include the highly invasive esophagectomy and the much less invasive tumor enucleation and the newer technique of STER. Given that esophagectomy is associated with a complication rate as high as 68% and a perioperative mortality rate as high as 13%, its use in the management of small esophageal GISTs with low risk features is questionable (41). NCCN guidelines state that surgical resection should be achieved with minimal morbidity, and complex multi-visceral resection should be avoided (22). However, there has been concern that tumor enucleation and STER could compromise oncologic outcomes as a result of incomplete tumor resection or increased risk of disruption of the tumor pseudocapsule (21). As there is clear evidence that tumor rupture is associated with an increased risk of disease recurrence, a more aggressive resection is warranted whenever there is concern for possible rupture of the tumor pseudocapsule (42,43).

Several case reports and case series have been published regarding surgical resection of esophageal GIST (Table 1)(5,21,44-51). In the largest series to date, Robb et al. evaluated outcomes across 16 patients who underwent tumor enucleation or esophagectomy for an esophageal GIST (21). Of the 8 patients who underwent enucleation, 5 were completed thoracoscopically, 1 underwent thoracoscopic-to-open conversion due to the tumor involving a large circumference of the esophageal wall, 1 was performed laparoscopically, and 1 was performed via planned thoracotomy. Of the 8 patients who underwent esophagectomy, 7 had a two-field operation with an open laparotomy and thoracotomy, and 1 underwent 3-field esophagectomy with a cervical anastomosis. Compared to esophagectomy, tumor enucleation was associated with significantly shorter median operative time (110 vs. 400 minutes, P=0.025) and hospital length of stay (5.5 vs. 11.5 days, P=0.013), and the severe postoperative complication rate was lower for enucleation (25% vs. 50%). The largest tumor that was resected via enucleation was 6.5 cm, and the median size of enucleated tumors was 4 cm (range, 1.8–6.5 cm). Esophagectomy was performed for larger tumors (median size =8.5 cm, range, 5.5–25 cm). Of those who underwent tumor enucleation, there were no breaches of the tumor pseudocapsule at resection, disease recurrences, or deaths after a median follow-up of 6.4 years. The authors also observed that mucosal ulceration observed on preoperative endoscopy was associated with larger tumor size and higher mitotic index. Given the association between mucosal ulceration and more aggressive tumors, the authors suggest that enucleation should be performed for tumors that do not exhibit mucosal ulceration and are less than 6.5 cm in diameter, and esophagectomy should be performed for tumors that have mucosal ulceration or are greater than 9 cm in diameter. Robb et al. proposed a management algorithm based on tumor size and ulceration status (21).

In addition to enucleation, another less invasive approach is STER. STER is a newly developed endoscopic approach to resecting submucosal tumors originating from the muscularis propria layer of the esophagus. In a retrospective study that included 180 patients with upper gastrointestinal submucosal tumors of which 167 were of esophageal or esophagogastric origin and 28 were GISTs, Chen et al. analyzed outcomes following STER (52). En bloc resection was successful in 90.6% of cases, and the complication rate was 8.3%. Significant risk factors for piecemeal resection were irregular tumor shape and tumor size ≥3 cm. Though the median procedure time was 45 minutes (range, 15–200 minutes) the median duration of hospitalization was 3.2 days. After a median follow-up 36 months, none of the patients experienced a local recurrence or distant metastasis. The authors concluded that STER is appropriate for submucosal tumors with an axial diameter ≤5 cm and a transverse diameter ≤3.5 cm.

In another large series of patients that included 165 patients, Du et al evaluated the effectiveness and safety of STER for submucosal tumors (38). The primary study outcomes were rates of en bloc resection, complete resection, complications, and recurrence. Of note, only 3 patients had a GIST (1.8%), and most of the tumors were leiomyomas (5.2%). Across the 106 esophageal submucosal tumors, the en bloc resection rate was 81.1%, and the complication rate was 19.8%. Gas-related complications and fever were the most common complications, and mucosal injury occurred in 2.8% of patients. In this series the median procedure time was 46 minutes and the mean hospitalization time was 7 days. There were no disease recurrences during follow-up. However, given the small number of patients with a GIST included in the study cohort, these findings should be interpreted with caution.

Tumor rupture is associated with an increased risk of recurrence and decreased overall survival (53-55). In a retrospective review of 242 patients, rupture events occurred in 103 patients. The 5-year recurrence-free survival of patients with macroscopic tumor rupture was 37% versus 96% for patients with no defect. Early reports of the endoscopic series may not be mature enough to provide meaningful data regarding the risk for tumor recurrence with piecemeal resection in cases when the mediastinum is entered. Additionally, there is no data as to whether this scenario should impact recommendations to administer adjuvant therapy. Understanding these outcomes will be dependent on accurate descriptions of the tumor pseudocapsule by the surgeon and the pathologist, and a consensus definition has been recently proposed (56).

Conclusions

Esophageal GIST is an infrequent tumor with a potential for aggressive behavior. Initial work-up should include CT or MRI imaging to characterize the tumor and EUS-FNA to obtain a tissue diagnosis. Patients with larger or locally advanced tumors that may require esophagectomy or multi-visceral resection should undergo neoadjuvant systemic therapy with a tyrosine kinase inhibitor. If possible, esophagectomy should be avoided due to a high risk of postoperative morbidity, and VATS or robotic enucleation or STER are feasible minimally invasive options based on current case series in the literature. In order to better understand the long-term consequences of piecemeal resection, adoption of standardized terminology to describe the status of the tumor pseudocapsule is important.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Ferdinando Carlo Maria Cananzi) for the series “Minimally invasive approach in Gastrointestinal Stromal Tumors (GISTs)” published in Laparoscopic Surgery. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at http://dx.doi.org/10.21037/ls-20-121

Peer Review File: Available at http://dx.doi.org/10.21037/ls-20-121

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/ls-20-121). The series “Minimally invasive approach in Gastrointestinal Stromal Tumors (GISTs)” was commissioned by the editorial office without any funding or sponsorship. 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Ma GL, Murphy JD, Martinez ME, et al. Epidemiology of gastrointestinal stromal tumors in the era of histology codes: results of a population-based study. Cancer Epidemiol Biomarkers Prev 2015;24:298-302. [Crossref] [PubMed]
2. Cassier PA, Ducimetiere F, Lurkin A, et al. A prospective epidemiological study of new incident GISTs during two consecutive years in Rhone Alpes region: incidence and molecular distribution of GIST in a European region. Br J Cancer 2010;103:165-70. [Crossref] [PubMed]
3. Lott S, Schmieder M, Mayer B, et al. Gastrointestinal stromal tumors of the esophagus: evaluation of a pooled case series regarding clinicopathological features and clinical outcome. Am J Cancer Res 2014;5:333-43. [PubMed]
4. Hihara J, Mukaida H, Hirabayashi N. Gastrointestinal stromal tumor of the esophagus: current issues of diagnosis, surgery and drug therapy. Transl Gastroenterol Hepatol 2018;3:6. [Crossref] [PubMed]
5. Duffaud F, Meeus P, Bertucci F, et al. Patterns of care and clinical outcomes in primary oesophageal gastrointestinal stromal tumours (GIST): A retrospective study of the French Sarcoma Group (FSG). Eur J Surg Oncol 2017;43:1110-6. [Crossref] [PubMed]
6. Miettinen M, Sarlomo-Rikala M, Sobin LH, et al. Esophageal stromal tumors: a clinicopathologic, immunohistochemical, and molecular genetic study of 17 cases and comparison with esophageal leiomyomas and leiomyosarcomas. Am J Surg Pathol 2000;24:211-22. [Crossref] [PubMed]
7. Feng F, Tian Y, Liu Z, et al. Clinicopathologic Features and Clinical Outcomes of Esophageal Gastrointestinal Stromal Tumor: Evaluation of a Pooled Case Series. Medicine (Baltimore) 2016;95:e2446 [Crossref] [PubMed]
8. Pence K, Correa AM, Chan E, et al. Management of esophageal gastrointestinal stromal tumor: review of one hundred seven patients. Dis Esophagus 2017;30:1-5. [Crossref] [PubMed]
9. Zhang FB, Shi HC, Shu YS, et al. Diagnosis and surgical treatment of esophageal gastrointestinal stromal tumors. World J Gastroenterol 2015;21:5630-4. [Crossref] [PubMed]
10. Pesenti C, Bories E, Caillol F, et al. Characterization of subepithelial lesions of the stomach and esophagus by contrast-enhanced EUS: A retrospective study. Endosc Ultrasound 2019;8:43-9. [Crossref] [PubMed]
11. Lewis RB, Mehrotra AK, Rodriguez P, et al. From the radiologic pathology archives: esophageal neoplasms: radiologic-pathologic correlation. Radiographics 2013;33:1083-108. [Crossref] [PubMed]
12. Panbude SN, Ankathi SK, Ramaswamy AT, et al. Gastrointestinal Stromal Tumor (GIST) from esophagus to anorectum - diagnosis, response evaluation and surveillance on computed tomography (CT) scan. Indian J Radiol Imaging 2019;29:133-40. [Crossref] [PubMed]
13. Chourmouzi D, Sinakos E, Papalavrentios L, et al. Gastrointestinal stromal tumors: a pictorial review. J Gastrointestin Liver Dis 2009;18:379-83. [PubMed]
14. Hong X, Choi H, Loyer EM, et al. Gastrointestinal stromal tumor: role of CT in diagnosis and in response evaluation and surveillance after treatment with imatinib. Radiographics 2006;26:481-95. [Crossref] [PubMed]
15. Caramella T, Schmidt S, Chevallier P, et al. MR features of gastrointestinal stromal tumors. Clin Imaging 2005;29:251-4. [Crossref] [PubMed]
16. Park JW, Cho CH, Jeong DS, et al. Role of F-fluoro-2-deoxyglucose Positron Emission Tomography in Gastric GIST: Predicting Malignant Potential Pre-operatively. J Gastric Cancer 2011;11:173-9. [Crossref] [PubMed]
17. Schuetze SM, Rubin BP, Vernon C, et al. Use of positron emission tomography in localized extremity soft tissue sarcoma treated with neoadjuvant chemotherapy. Cancer 2005;103:339-48. [Crossref] [PubMed]
18. Saftoiu A. Endoscopic ultrasound-guided fine needle aspiration biopsy for the molecular diagnosis of gastrointestinal stromal tumors: shifting treatment options. J Gastrointestin Liver Dis 2008;17:131-3. [PubMed]
19. Akahoshi K, Sumida Y, Matsui N, et al. Preoperative diagnosis of gastrointestinal stromal tumor by endoscopic ultrasound-guided fine needle aspiration. World J Gastroenterol 2007;13:2077-82. [Crossref] [PubMed]
20. Iwatsuki M, Harada K, Iwagami S, et al. Neoadjuvant and adjuvant therapy for gastrointestinal stromal tumors. Ann Gastroenterol Surg 2018;3:43-9. [Crossref] [PubMed]
21. Robb WB, Bruyere E, Amielh D, et al. Esophageal gastrointestinal stromal tumor: is tumoral enucleation a viable therapeutic option? Ann Surg 2015;261:117-24. [Crossref] [PubMed]
22. NCCN clinical practice guidelines in oncology (NCCN Guidelines): Soft tissue sarcoma. NCCN Guidelines Version 2.2020; 2020.
23. Debiec-Rychter M, Sciot R, Le Cesne A, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 2006;42:1093-103. [Crossref] [PubMed]
24. Eisenberg BL, Harris J, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol 2009;99:42-7. [Crossref] [PubMed]
25. Wang D, Zhang Q, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: long-term follow-up results of Radiation Therapy Oncology Group 0132. Ann Surg Oncol 2012;19:1074-80. [Crossref] [PubMed]
26. Kurokawa Y, Yang HK, Cho H, et al. Phase II study of neoadjuvant imatinib in large gastrointestinal stromal tumours of the stomach. Br J Cancer 2017;117:25-32. [Crossref] [PubMed]
27. McAuliffe JC, Hunt KK, Lazar AJ, et al. A randomized, phase II study of preoperative plus postoperative imatinib in GIST: evidence of rapid radiographic response and temporal induction of tumor cell apoptosis. Ann Surg Oncol 2009;16:910-9. [Crossref] [PubMed]
28. Tirumani SH, Shinagare AB, Jagannathan JP, et al. Radiologic assessment of earliest, best, and plateau response of gastrointestinal stromal tumors to neoadjuvant imatinib prior to successful surgical resection. Eur J Surg Oncol 2014;40:420-8. [Crossref] [PubMed]
29. Ahmadi N, Crnic A, Seely AJ, et al. Impact of surgical approach on perioperative and long-term outcomes following esophagectomy for esophageal cancer. Surg Endosc 2018;32:1892-900. [Crossref] [PubMed]
30. Harbison GJ, Vossler JD, Yim NH, et al. Outcomes of robotic versus non-robotic minimally-invasive esophagectomy for esophageal cancer: An American College of Surgeons NSQIP database analysis. Am J Surg 2019;218:1223-8. [Crossref] [PubMed]
31. Herbert B, McGinn JT, Maloney A, et al. Robotic/thoracoscopic approach to esophageal gastro-intestinal stromal tumor. Shanghai Chest 2020;4:31. [Crossref]
32. Khalaileh A, Savetsky I, Adileh M, et al. Robotic-assisted enucleation of a large lower esophageal leiomyoma and review of literature. Int J Med Robot 2013;9:253-7. [Crossref] [PubMed]
33. Luh SP, Hou SM, Fang CC, et al. Video-thoracoscopic enucleation of esophageal leiomyoma. World J Surg Oncol 2012;10:52. [Crossref] [PubMed]
34. Shin S, Choi YS, Shim YM, et al. Enucleation of esophageal submucosal tumors: a single institution's experience. Ann Thorac Surg 2014;97:454-9. [Crossref] [PubMed]
35. Reavis KM. Thoracoscopic enucleation of an esophageal gastrointestinal stromal tumor. Society of American Gastrointestinal and Endoscopic Surgeons. 2010. Available online: https://www.sages.org/video/thoracoscopic-enucleation-of-an-esophageal-gastrointestinal-stromal-tumor/. Accessed August 29, 2020.
36. Gamenthaler A, Meredith K. Robotic enucleation of giant esophageal leiomyoma. Society of American Gastrointestinal and Endoscopic Surgeons. 2013. Available online: https://www.sages.org/video/robotic-enucleation-of-giant-esophageal-leiomyoma/. Accessed August 29, 2020.
37. Xu MD, Cai MY, Zhou PH, et al. Submucosal tunneling endoscopic resection: a new technique for treating upper GI submucosal tumors originating from the muscularis propria layer (with videos). Gastrointest Endosc 2012;75:195-9. [Crossref] [PubMed]
38. Du C, Chai NL, Ling-Hu EQ, et al. Submucosal tunneling endoscopic resection: An effective and safe therapy for upper gastrointestinal submucosal tumors originating from the muscularis propria layer. World J Gastroenterol 2019;25:245-57. [Crossref] [PubMed]
39. Zhang X, Modayil R, Criscitelli T, et al. Endoscopic resection for subepithelial lesions-pure endoscopic full-thickness resection and submucosal tunneling endoscopic resection. Transl Gastroenterol Hepatol 2019;4:39. [Crossref] [PubMed]
40. Chang JH. Submucosal tunneling endoscopic resection of an esophageal leiomyoma. Society of American Gastrointestinal and Endoscopic Surgeons. 2018. Available online: https://www.sages.org/video/submucosal-tunneling-endoscopic-resection-of-an-esophageal-leiomyoma/. Accessed August 29, 2020.
41. Swisher SG, Deford L, Merriman KW, et al. Effect of operative volume on morbidity, mortality, and hospital use after esophagectomy for cancer. J Thorac Cardiovasc Surg 2000;119:1126-32. [Crossref] [PubMed]
42. Takahashi T, Nakajima K, Nishitani A, et al. An enhanced risk-group stratification system for more practical prognostication of clinically malignant gastrointestinal stromal tumors. Int J Clin Oncol 2007;12:369-74. [Crossref] [PubMed]
43. Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 2008;39:1411-9. [Crossref] [PubMed]
44. Jiang P, Jiao Z, Han B, et al. Clinical characteristics and surgical treatment of oesophageal gastrointestinal stromal tumours. Eur J Cardiothorac Surg 2010;38:223-7. [Crossref] [PubMed]
45. Lee HJ, Park SI, Kim DK, et al. Surgical resection of esophageal gastrointestinal stromal tumors. Ann Thorac Surg 2009;87:1569-71. [Crossref] [PubMed]
46. von Rahden BH, Stein HJ, Feussner H, et al. Enucleation of submucosal tumors of the esophagus: minimally invasive versus open approach. Surg Endosc 2004;18:924-30. [Crossref] [PubMed]
47. Blum MG, Bilimoria KY, Wayne JD, et al. Surgical considerations for the management and resection of esophageal gastrointestinal stromal tumors. Ann Thorac Surg 2007;84:1717-23. [Crossref] [PubMed]
48. Koide N, Kishimoto K, Komatsu O, et al. Thoracoscopic enucleation of esophageal stromal tumor. Dis Esophagus 2004;17:104-8. [Crossref] [PubMed]
49. Chang WC, Tzao C, Shen DH, et al. Gastrointestinal stromal tumor (GIST) of the esophagus detected by positron emission tomography/computed tomography. Dig Dis Sci 2005;50:1315-8. [Crossref] [PubMed]
50. Huang CS, Hsu WH, Wu YC, et al. Enucleation of an advanced esophageal gastrointestinal stromal tumor with liver metastasis. J Gastroenterol Hepatol 2006;21:482-3. [Crossref] [PubMed]
51. Yamada H, Shinohara T, Yokoyama K, et al. Thoracoscopic enucleation of esophageal gastrointestinal stromal tumor using prone positioning in a patient with severe chronic obstructive lung disease. J Laparoendosc Adv Surg Tech A 2011;21:635-9. [Crossref] [PubMed]
52. Chen T, Zhou PH, Chu Y, et al. Long-term Outcomes of Submucosal Tunneling Endoscopic Resection for Upper Gastrointestinal Submucosal Tumors. Ann Surg 2017;265:363-9. [Crossref] [PubMed]
53. Nishida T, Cho H, Hirota S, et al. Clinicopathological Features and Prognosis of Primary GISTs with Tumor Rupture in the Real World. Ann Surg Oncol 2018;25:1961-9. [Crossref] [PubMed]
54. Holmebakk T, Hompland I, Bjerkehagen B, et al. Recurrence-Free Survival After Resection of Gastric Gastrointestinal Stromal Tumors Classified According to a Strict Definition of Tumor Rupture: A Population-Based Study. Ann Surg Oncol 2018;25:1133-9. [Crossref] [PubMed]
55. Joensuu H, Vehtari A, Riihimaki J, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol 2012;13:265-74. [Crossref] [PubMed]
56. Nishida T, Holmebakk T, Raut CP, et al. Defining Tumor Rupture in Gastrointestinal Stromal Tumor. Ann Surg Oncol 2019;26:1669-75. [Crossref] [PubMed]