Efficacy and safety of endoscopic submucosal dissection for large gastric stromal tumors

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Clinics and Research in Hepatology and Gastroenterology (2019) xxx, xxx—xxx

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ORIGINAL ARTICLE

Efficacy and safety of endoscopic submucosal dissection for large gastric stromal tumors Qiaofeng Chen †, Mingju Yu †, Yupeng Lei †, Chang Zhong , Zhijian Liu , Xiaojiang Zhou , Guohua Li , Xiaodong Zhou ∗, Youxiang Chen ∗ Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng street, 330006 Nanchang, Jiangxi Province, PR China

KEYWORDS Complications; Efficacy; Endoscopic submucosal dissection; Large gastric stromal tumor

∗ †

Summary Background and aim: Endoscopic submucosal dissection (ESD) of gastric stromal tumors is becoming increasingly common. However, there have been few studies analyzing the therapeutic efficacy and safety of this technique on large (≥ 3 cm) gastric stromal tumors (LGSTs). The aim of this study was to determine the feasibility of ESD for the removal of LGSTs and to investigate the clinical safety and efficacy of ESD for this indication. Methods: A retrospective analysis was carried out on 82 patients with LGSTs who underwent an ESD. Data on therapeutic outcomes and follow-up were collected for an analysis of the rates of en block resection and complete resection. A logistic regression model was used to identify potential risk factors for ESD-related complications, and a receiver operating characteristic (ROC) curve was generated for qualifying independent risk factors. Results: En bloc resection was achieved in 81 lesions (98.8%), and complete resection was achieved in 80 lesions (97.6%). The rates of intraoperative and postoperative bleeding were 6.1% and 3.7%, respectively. The accidental perforation rate was 12.2%, the postoperative perforation rate was 3.7%, the intentional perforation rate was 28.0%, and the postoperative infection rate was 12.2%. There was no postoperative mortality. LGSTs originating from the deep muscularis propria (MP) layer (OR = 4.905, 95% CI: 1.362—17.658, P = 0.015), located at the gastric fundus (OR = 4.927, 95% CI:1.308—18.558, P = 0.018) and with an irregular shape (OR = 4.842, 95% CI: 1.242—18.870, P = 0.023) increased the rate of complications. The prediction model that incorporated these factors demonstrated an area under the ROC curve of 0.77 (95% CI: 0.66—0.89). No tumor recurrence or distant metastasis was observed during the follow-up period, which ranged from 6—36 months.

Corresponding author. E-mail addresses: [email protected] (X. Zhou), [email protected] (Y. Chen). These authors contributed equally to this work.

https://doi.org/10.1016/j.clinre.2019.03.004 2210-7401/© 2019 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Chen Q, et al. Efficacy and safety of endoscopic submucosal dissection for large gastric stromal tumors. Clin Res Hepatol Gastroenterol (2019), https://doi.org/10.1016/j.clinre.2019.03.004

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Q. Chen et al. Conclusions: ESD is a feasible, safe, effective and minimally invasive approach for the resection of LGSTs. Tumors originating from the deep MP layer, located at the fundus and with an irregular shape were identified as risk factors for the development of complications. © 2019 Elsevier Masson SAS. All rights reserved.

Introduction Gastrointestinal stromal tumors (GISTs) represent the most common type of mesenchymal tumor of the gastrointestinal tract, and these tumors originate from the intestinal cells of Cajal or their precursors. Commonly, the malignancy potential of GISTs varies from small benign lesions to aggressive carcinomas, and approximately 40% of GISTs are shown to exhibit clinically local metastasis [1]. According to the National Comprehensive Cancer Network (NCCN) guidelines, the management of GISTs includes two options: complete resection for all non-metastatic GISTs ≥ 2 cm or watchful follow-up every 6—12 months for GISTs < 2 cm that lack high-risk characteristics upon endoscopic ultrasound (EUS) [2]. Surgical resection, including open or laparoscopy surgery, is considered to be the gold standard therapy, as it yields the best long-term outcomes [3,4]. However, in the case of certain lesions for which surgery is not feasible, or when metastatic phenomena are present, targeted therapy should be recommended. However, these surgical styles have led to unsatisfactory results, as they are more invasive and associated with higher total costs and complication rates. Endoscopic submucosal dissection (ESD) was gradually developed as a minimally invasive method for the removal of GISTs with a high en block resection rate, high efficiency and relatively lower adverse events. Numerous studies have confirmed that the resection of small GSTs by ESD is an effective method that can achieve fast recovery and favorable outcomes [5]. However, the complete en block resection (R0) of LGSTs remains a challenge. Additionally, the narrow operation space may result in poor endoscopic visualization, thereby making ESD a technically challenging procedure. Controversy remains regarding the safety, efficacy and long-term outcomes of ESD in the treatment of LGSTs. Accordingly, we conducted this retrospective study to evaluate the safety and efficacy of ESD in the treatment of LGSTs.

Materials and methods Patients A retrospective review was performed on 82 patients who were pathologically diagnosed with GSTs (tumor size ≥ 3 cm and ≤ 6 cm) and underwent ESD in1⁄3an inpatient setting from January 2010 to December 2015. The inclusion criteria were as follows:

• tumor diameter ≥ 3 cm and ≤ 6 cm, based on endoscopic ultrasound (EUS); • preoperative or postoperative pathologic diagnosis as a GST; • application of pure ESD strategy; • without other malignant tumors; • had not undergone preoperative targeted therapy and without rupture of GSTs during the operation; • had not taken anticoagulant or antiplatelet agents that could not be interrupted and • complete blood count and coagulation function were within normal limits. This study was approved by the institutional review board of The First Affiliated Hospital of Nanchang University.

Methods and procedures Prior to the operation, EUS was performed with a radialscanning echo endoscopy unit (UM 240; Olympus Co. Ltd., Tokyo, Japan) or a 12-Fr catheter probe (UM-3R, 12 MHz; Olympus Co. Ltd., Tokyo, Japan) to identify the layer of origin, tumor size (largest diameter), shape (round or oval versus irregular, Fig. 1), internal echogenicity, margin, extent and depth of invasion. The tumor location, growth pattern (intra/extraluminal) and the possibility of lateral growth or distant metastasis were evaluated by abdominal computerized tomography (CT). All patients without surgical contraindication received general anesthesia, and vital signs as well as blood oxygen saturation were monitored during the operation. All ESD procedures were performed by highly experienced endoscopists with more than 10 years of experience using a single-channel endoscope (GIF-Q260 J; Olympus Co. Ltd, Tokyo, Japan) with a transparent distal cap attachment (D-201-11804; Olympus). After the lesions were identified under direct view of the endoscope (Fig. 2A), dots were marked around them by electric coagulation. Several milliliters of mixed solution (including 250 mL of glycerol fructose, 2—3 mL of indigo carmine, and 1 mL of 1:10,000 epinephrine) were multipoint injected into the submucosa layer with an injection needle (NM-4L-1; Olympus) to lift the overlying mucosa (Fig. 2B), followed by circumferential mucosal incision around the marked dots with a hook (KD620LR; Olympus) and an insulation-tip (IT) 2 knife (KD-611 L; Olympus) (with a tip length of 5 mm) either independently or in combination (Fig. 2C). Subsequently, the exposed lesion was gradually separated and completely removed with the hook or IT (Fig. 2D and 2 E), and a snare (SD-230U-20; Olympus) was used to assist with the removal of the lesion if necessary. After the lesion was resected, bleeding during

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Figure 1

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Radial scanning EUS image of LGSTs (arrow). A. Tumor with a round shape. B. Tumor with an irregular shape.

Figure 2 Endoscopic submucosal dissection of an LGST. A. Endoscopic appearance of an LGST in the gastric fundus. B. Submucosal injection around the tumor body. C. Circumferential incision and submucosal dissection. D. Exposing the tumor entirely. E. Complete separation of the tumor from the MP layer. F. Closure of the wound by OTSCs. G. View of the wound after occlusion. H. The resection specimen size was approximately 6.0 × 4.5 cm.

the procedure was coagulated with hot biopsy forceps (FD410LR; Olympus) or by argon plasma coagulation (APC 300, ERBE). If the tumor was located in the deep MP layer or was adhered to the serosa, the entire layer of the tumor was ¨ctive perforation,¨ stripped to cause the a and the perforation was occluded with titanium clips (HX-610-135; Aomori Olympus) or with the over-the-scope clip system (OTSCs, Ovesco Endoscopy AG, Tübingen, Germany) (Fig. 2F and 2 G). If the perforation was too large, a nylon loop pouch suture was performed using a large nylon rope (MAJ-254; Aomori Olympus, Aomori, Japan) and a titanium clip (Fig. 3). All ESDs were performed under carbon dioxide insufflation. All specimens were measured and subsequently fixed with 10% formalin for histopathologic evaluation within 30 min (Fig. 2H).

Definitions of ESD-related complications Intraoperative bleeding is defined as any bleeding that occurs during the ESD with a dilution of > 2 g/dL in hemoglobin from the pre-procedure level to the level on the next day. Postoperative bleeding after ESD is generally defined as hematemesis or melena, with unstable vital signs or a hemoglobin drop > 2 g/dL, with the need for blood transfusion or emergency endoscopic procedure. Perforation is defined as the visualization of an extra-gastric structure during the procedure, the presence of subcutaneous emphysema, pneumoperitoneum, or free air in the retroperitoneal space [6]. Patients with a post-procedure body temperature ≥ 38 ◦ lasting for longer than 24 h were diagnosed with infection.

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Figure 3 Steps for nylon loop pouch suture using a single-channel endoscope. A. The nylon loop was attached to a clip-fixing device and was simultaneously grasped by grasping or biopsy forceps. B. Placement of the clips and the nylon loop at the proximal edge of the defect site. C. Titanium clips were inserted to anchor the nylon loop around the edge of the defect. D. Tightening the nylon loop slowly until the defect was successfully closed.

Postoperative management and follow-up All patients were told to fast for 2—5 days. Proton pump inhibitors (PPIs), prophylactic antibiotics and fluids were administered intravenously for 2 days, and an oral PPI was given for another eight weeks. Continuous gastrointestinal decompression and the intravenous infusion of PPIs as well as broad-spectrum antibiotics were adopted when either perforation or a large wound occurred during the procedure. Observations, including the vital signs, abdominal pain, abdominal distension and melena, were closely monitored to prevent any delayed bleeding or perforation. Patients without complications were permitted to eat a liquid diet 2 days after the ESD. All patients were followed up and requested to repeat a surveillance EUS and abdominal US/CT in the third, sixth, 12th, and 36th months post-operatively and annually thereafter to observe wound healing and detect any recurrent lesion or distant metastasis.

Pathology evaluation and Risk classification standard Positive reactions for CD117 (c-KIT) or DOG-1 and CD34 were diagnosed as GISTs, and the integrity of the tumor capsule and diagnosis were confirmed by two experienced pathologists (Fig. 4A). En bloc resection was defined as the excision of a GIST in a whole block without fragmentation. Complete resection was defined as the en bloc resection of a GIST with

the pseudocapsule intact. A negative resection margin indicated that the GIST was removed completely (R0 resection). Risk classification criteria were used for the risk assessment of GISTs according to the National Institutes of Health consensus and classification [7]. Risk was categorized into the following groups: extremely low risk, low risk, intermediate risk, and high risk (Fig. 4B and 4 C). High-risk patients and intermediate-risk patients were recommended to take oral imatinib (400 mg per day) for at least 36 months and 12 months, respectively [8].

Statistical analysis All statistical analyses were performed using SPSS version 20.0 (SPSS Inc., Chicago, IL, USA). Continuous data are expressed as the mean ± (standard deviation [SD]) (range) or the median (interquartile range [IQR]). Categorical data are displayed as No. (%) and were analyzed with the Pearson’s chi-square test or the Fisher’s exact test as appropriate. All risk factors for ESD-related complications were assessed by univariate and multivariate logistic regression analyses. A receiver operating characteristic (ROC) curve was constructed to analyze the risk factors for ESD-related complications and to determine the specific threshold value that would optimize its predictive value. Statistical significance was defined as P < 0.05.

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Figure 4 Histopathological evaluation of resected an LGST. The tumor presented as a well-circumscribed fleshy, gray-white and medium-soft fragment of tissue (A). The tumor was composed predominantly of spindle-shaped cells manifesting fascicular growth and mitotic counts of 2-3 per 50 HPF (B ×20 and C ×40).

Results Clinical characteristics and distribution A total of 82 patients who underwent ESD during the period between January 2010 to December 2015 were included. The patient cohort consisted of 43 males and 39 females, with a mean age of 57.6 (±11.6) (range 36-83) years. The male Table 1

to female ratio was 1.1:1 (43:39), and the prevalence of LGSTs has no significant association with sex. A total of 51 patients complained of digestive tract symptoms as the initial manifestation, including bellyache (30.5%), abdominal distension (25.6%), acid reflux/belching/heartburn (7.3%) and melena (3.7%). A total of 31 patients (37.8%) were asymptomatic, and the LGST was detected upon physical examination.

Clinical characteristics of 82 patients with LGISTs.

Patient characteristics Age, mean (± SD) (median, range), year Sex, male/female Clinical symptom, No. (%) Bellyache Abdominal distension Acid reflux/belching/heartburn Melena Asymptomatic Tumor characteristics Location, no. (%) Cardia Fundus Body Angle Antrum Diameter, mean (± SD) (median, range), cm 3 ≤ D < 4, no. (%) 4 ≤ D ≤ 6, no. (%) Shape, no. (%) Round or oval Irregular Growth pattern, no. (%) Intraluminal Extraluminal Intra-extra luminal Origination, no. (%) Muscularis mucosae Superficial MP Deep MP Superficial ulceration, no. (%) Yes No

57.6 (±11.6) (57, 36—83) 43/39 25 (30.5) 21 (25.6) 6 (7.3) 3 (3.7) 31 (37.8)

1 (1.2) 48 (58.5) 27 (32.9) 2 (2.4) 4 (4.9) 3.5 (±0.8) (3, 3-6) 61 (74.4) 21 (25.6) 63 (76.8) 19 (23.2) 64 (78.1) 10 (12.2) 8 (9.7) 2 (2.4) 54 (65.9) 26 (31.7) 19 (23.2) 63 (76.8)

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Q. Chen et al. Table 2

Therapeutic outcomes, postoperative courses and risk classification of patients.

Technique, No. (%) En bloc resection Complete resection Procedure time, median (range), min Resection margin, no. (%) R0 R1 R2 Complications, no. (%) Bleeding Perforation Infection Postoperative fasting time, median (IQR), day Without perforation Perforation Postoperative fasting time, median (IQR), day Hospitalization cost, median (IQR), ×103 yuan Transfer to ICU, No. (%) Postoperative mortality, No. (%) Follow-up time, mean (± SD) (median, range), month Recurrence Metastasis Immunohistochemistry, no. (%) CD117 + CD34 + DOG-1 + NIH risk classification, no. (%) Extremely low risk Low risk Intermediate risk High risk

EUS and abdominal CT were performed for all patients to characterize lesions and to evaluate any evidence of metastasis prior to the procedure. A total of 48 tumors were located in the gastric fundus, 27 were located in the body, 4 were located in the antrum, 2 were located in the angle and 1 was located in the cardia. The mean tumor size was 3.5 cm (±0.8 cm) (range 3-6 cm), and 21 tumors (25.6%) measured ≥ 4.0 cm. Most of the tumors (76.8%) were round- or oval-shaped, while the remaining tumors were irregular (23.2%). A total of 80 tumors (97.6%) originated from the muscularis propria (MP) layer, including 65.9% (54/82) from the superficial MP layer and 31.7% (26/82) from the deep MP layer. A total of 64 tumors (78.1%) exhibited an intraluminal growth pattern, while a small portion exhibited an extra-luminal (12.2%) and intra-/extra-luminal (9.7%) growth pattern. Additionally, only a small portion of the tumors presented superficial ulceration (19/82, 23.2%) (Table 1).

Therapeutic Outcome and complications All patients underwent ESD successfully, with a median procedure duration of 68.0 (range 27—205) min. En bloc resection was achieved in 81 patients (98.8%), complete resection was achieved in 80 patients (97.6%) and tumor

81 (98.8) 80 (97.6) 68.0 (27-205) 80 (97.6) 2 (2.4) 0 (0) 8 (9.8) 13 (15.9) 10 (12.2) 5.0 (4.0—5.8) 3.0 (2.0—3.0) 4.0 (4.0—5.0) 5.0 (4.0—5.8) 16.1 (13.3—20.0) 0 (0) 0 (0) 21.94 (± 6.97) (21, 6—36) 0 (0) 0 (0) 82 (100) 78 (95.1) 80 (97.6) 7 (8.5) 70 (85.4) 5 (6.1) 0 (0)

residue occurred in merely two case (since the risk of recurrence is low, routine surveillance with no additional therapy was recommended). The median postoperative fasting time for patients with or without perforation was 4.0 (IQR 4.0—5.0) and 3.0 (IQR 2.0—3.0) days, respectively, and the median postoperative duration of hospital stay was 5.0 (IQR 4.0—5.8) days (Table 2). In present study, there were 8 patients (9.8%) with bleeding, including 3 cases (3.7%) of postoperative bleeding who underwent endoscopic intervention after the ESD. There were 10 (12.2%) cases of accidental perforation and 23 (28.0%) cases of ‘‘active perforation’’ (not included in the complications) during the procedure. There were only 3 (3.7%) patients with post-operative perforation who underwent a re-intervention, and 10 (12.2%) patients with post-ESD infection who were administered intravenous antibiotics and hydration, conservatively, with no appearance of severe abdominal infection or even septicemia. No deaths occurred within 30 days of the procedure (Table 2).

Risk factors for ESD-related complications Based on the univariate and multivariate analyses, we confirmed that the origin, location and shape of tumors were identified as independent risk factors for the occurrence

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Efficacy and safety of ESD for LGSTs Table 3

Comparisons of ESD-related complications according to the clinical characteristics.

Factors (No.) Age (y) < 60 (43) ≥ 60 (39) Sex Male (43) Female (39) Tumor diameter (D, cm) 3 ≤ D < 4 (61) 4 ≤ D ≤ 6 (21) Tumor shape Round or oval (63) Irregular (19) Tumor growth pattern Intraluminal (64) Extraluminal (10) Intra-extra luminal (8) Tumor origination Deep MP (26) a Other layers (56) Tumor location Fundus (48) b Other sites (34) Superficial ulceration Yes (19) No (63) a b c

7

Complications, No. (%)

P-value

Yes

No

9 (20.9) 13 (33.3)

34 (79.1) 26 (66.7)

11 (25.6) 11 (28.2)

32 (74.4) 28 (71.8)

13 (21.3) 9 (42.9)

48 (78.7) 12(57.1)

13 (20.6) 9 (47.4)

50 (79.4) 10 (52.6)

18 (28.1) 2 (20.0) 2 (25.0)

46 (71.9) 8 (80.0) 6 (75.0)

0.206

0.789

0.055

0.021c

0.858

0.007c 12 (44.0) 10 (19.3)

14 (56.0) 46 (80.7) 0.010c

18 (36.7) 4 (0)

30 (63.3) 30 (1)

6 (31.6) 16 (25.4)

13 (68.4) 47 (74.6)

0.594

Other layers including muscularis mucosae and superficial MP. Other sites including body, antrum and angle of the stomach. Statistically significant.

of ESD-related complications. Tumors originating from the deep MP layer (odds ratio [OR] = 4.905, 95% CI: 1.362-17.658, P = 0.015), distributed in the gastric fundus (OR = 4.927, 95% CI: 1.308-18.558, P = 0.018) and with an irregular shape (OR=4.842, 95% CI: 1.242-18.870, P = 0.023) were significantly associated with the development of complications. The occurrence of complications differed greatly between 3 ≤ D < 4 (21.3%) and D ≥ 4 (42.9%), nevertheless, the difference was not significant (P > 0.05). Multivariate models were built to predict the incidence of complications. According to the ROC of the multivariate model, the area under the curve (AUC) was 0.77 (95% CI: 0.66—0.89) (Fig. 5). Additionally, we determined that age, sex, superficial ulcer and growth pattern were not evidently associated with the occurrence of complications (P > 0.05) (Table 3 and 4).

Histopathologic assessment The pathological and immunohistochemical results of all specimens revealed that positive CDll7 staining was observed in 82 cases (100%), CD34 staining was observed in 78 cases (95.1%), and DOG-l staining was observed in 80 cases (97.6%). A total of 7 tumors (8.5%) were classified as extremely low risk, 70 tumors (85.4%) were low risk and

Figure 5 Receiver operating characteristic curve for the logistic regression model predicting ESD-related complications. These complications included tumors originating from the deep MP layer, located at the gastric fundus and with an irregular shape. AUC = 0.77, 95% CI 0.66—0.89, P < 0.001.

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Q. Chen et al. Table 4

Risk factors for complications of endoscopic submucosal dissection.

Factors (no.)

Univariate analysis OR (95% CI)

Age (y) < 60 (43) ≥ 60 (39) Sex Male (43) Female (39) Tumor diameter (D, cm) 3 ≤ D < 4 (58) 4 ≤ D ≤ 6 (24) Tumor shape Round or oval (64) Irregular (18) Tumor growth pattern Intraluminal (64) Extraluminal (10) Intra-extra luminal (8) Tumor origination a Other layers (56) Deep MP (26) Tumor location b Other sites (34) Fundus (48) Superficial ulceration No (19) Yes (63)

Multivariate analysis P value

OR (95% CI)

0.209 1 (reference) 1.889 (0.701—5.091)

0.111 1 (reference) 2.742 (0.792—9.494)

0.789 1 (reference) 1.143 (0.430—3.038)

0.566 1 (reference) 0.702 (0.210—2.350)

0.060 1 (reference) 2.769 (0.960—7.989)

0.197 1 (reference) 2.344 (0.642—8.556)

0.025c 1 (reference) 3.462 (1.166—10.273)

0.023c 1 (reference) 4.842 (1.242—18.870)

0.860 1 (reference) 0.639 (0.124—3.302) 0.852 (0.157—4.619)

0.593 0.853 0.009c

1 (reference) 3.943 (1.407—11.051)

0.567 1 (reference) 0.430 (0.047—3.978) 0.439 (0.065—2.948)

0.457 0.397 0.015c

1 (reference) 4.905 (1.362—17.658) 0.014c

1 (reference) 4.500 (1.361—14.878)

0.018c 1 (reference) 4.927 (1.308—18.558)

0.595 1 (reference) 1.356 (0.442—4.161)

P-value

0.693 1 (reference) 0.743 (0.171—3.240)

OR = odds ratio; 95% CI = 95% confidence. a Other layers including muscularis mucosae and superficial MP. b Other sites including body, antrum and angle of the stomach. c Statistically significant.

merely 5 tumors (6.1%) were defined as intermediate risk, according to the NCCN guidelines (Table 2).

Follow-up after ESD The mean follow-up period of the 82 patients after ESD was 21.94 (± 6.97) months (range 6-36 months) (Table 2). All patients underwent EUS 3-6 times and abdominal US or CT 2—5 times. During the follow-up period, it was determined that all wounds had completely healed, and no residual, local recurrent or metastatic tumors were detected. The 5 patients of intermediate risk received adjuvant imatinib orally for 6—10 months after the endoscopic resection. Unfortunately, all 5 patients discontinued imatinib for reasons other than intolerable adverse effect or economic difficulty.

Discussion GISTs are the most common mesenchymal tumors of the gastrointestinal tract. GISTs exhibit occult onset [9] and are usually asymptomatic when they appear alone. However, they may present symptoms, including bellyache, abdominal distension, anemia and melena, when complicated with

acute gastritis, gastroduodenal ulcers, or when the tumor is large and superficial ulceration is present [10]. GISTs located at the fundus account for approximately 60% of cases and usually arise in middle to older ages without gender predilection. All GISTs have malignant potential; even small interstitialomas have a risk of metastasis and relapse, and the malignancy of GISTs develops with increasing tumor diameter, thus complete resection is critical. Although endoscopic technologies are well developed, it was recently reported that surgery remains the most frequently selected method for the removal of GISTs ≥ 2 cm in diameter, while endoscopic resection is favored for treating tumors with a diameter of < 2 cm [11]. However, since surgical resection is associated with large wounds, a high complication rate, long postoperative recovery time, high hospitalization expense and relatively poorer quality of life, patients exhibit greater preference for minimally invasive endoscopic resection, especially with the appearance of ESD. ESD was developed initially as a strategy for the endoscopic resection of superficial gastric cancers [12], but ESD has been gradually confirmed to be a feasible and safe treatment for the removal of GSTs (especially D < 2 cm). Zhou et al [5] reported that the mean procedure time of ESD for 19 small GSTs was 87.5 min, and the perforation rate was 15.0%. Shen et al [13] also confirmed that patients

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Efficacy and safety of ESD for LGSTs with small GSTs (D < 2 cm) who underwent ESD had a significantly shorter procedure time, stomach tube retention time, length of stay and reduced blood volume compared with those who underwent surgery. Although accumulating evidence suggests that all LGSTs (pathologically, commonly defined as D ≥ 3 cm) should be removed due to their relatively high risk, controversy remains regarding the selection of surgical approaches, and few previous studies have provided robust data detailing the outcomes of ESD. The results of this study revealed that ESD is a feasible and effective treatment option for LGSTs, in terms of the high en bloc resection rate (81/82, 98.8%) and complete resection rate (80/82, 97.6%), which were as good as or better than those for surgical resections [14,15]. Moreover, the median procedure time was 68.0 (27—205) min, which was similar to that of that of the abovementioned small GSTs but was significantly shorter than that for laparoscopic [245 (120—380) min] and open resections [228 (150—360) min], as stated in previous reports [16,17]. With regard to the postoperative duration of hospitalization, the overwhelming majority of hospitalizations (76/82, 92.7%) ranged from three to seven days, and they can be prolonged if there are complications with a large wound during the operation or a serious postoperative serious. According to two previous studies, we determined that ESD was significantly superior to both laparoscopic and open resection in terms of the length of postoperative hospital stay and the time to a liquid diet [18—20]. In the present study, the mean diameter of 82 LGSTs was 3.5 (±0.8) cm, with the largest tumor measuring approximately 6.0 cm. It is too technically challenging to smoothly retrieve the tumor (both the longitudinal and transverse diameter ≥ 4 cm) intact through the cardia and pharyngeal sphincter. Therefore, endoscopists in our institution chose to cut the tumor into two or three pieces within the stomach by snare, which causes denaturation and necrosis of the tumor cell proteins, thereby reducing the probability of local tumor implantation with rupture of the tumor. This process may inevitably result in prejudicing the pathological evaluation due to the damage to the integrity of the tumor; therefore, the incisal edges were clearly labeled for the pathologist to decrease the negative influence of resection completeness on the evaluation, which is consistent with previous reports by Bialek et al. [21]. However, no residual lesions, tumor recurrence or metastasis was discovered during the follow-up period, which vigorously confirmed the safety and feasibility of ESD in the treatment of LGSTs. Perforation was the primary complication of ESD in the treatment of LGSTs. The incidence of perforation secondary to ESD ranges from 0% to 20%, according to previous studies [21—23]. In this study, the perforation rate was 15.9%, and perforation primarily occurred in tumors originating from the deep MP layer. A possible explanation may be that giant tumors originating from the deeper MP layer generally adhered closely to the serous layer and protruded into the abdominal cavity. A total of 28.0% cases were all artificially perforated for a complete resection of the tumor body instead of preserving the integrity of the gastric wall. All the intentional perforations were closed under endoscopy without surgical intervention, and they healed in a short time without sequelae when managed with PPIs, antibiotics and gastrointestinal decompression. Therefore, many scholars

9 ¨ ¨ctive perforationduring suggest that a the procedure should not be defined as a complication of ESD for the removal of LGSTs. In our institution, the closing techniques for ESD-related defects were achieved by a variety of methods and devices, including titanium clips, OTSCs and nylon loop pouch suture; the specific methods vary depending on the location and size of the defects. In the case of perforations smaller than 20 mm, endoscopic clipping is generally performed. Sometimes, if the clip placement is difficult because of the location of the perforation, OTSCs can be an alternative. Perforations measuring up to 20—30 mm are closed by OTSCs, with or without the use of grasping devices to place them [24]. If the OTSC technique is unavailable or the perforations are very large (25—40 mm), nylon loop pouch suture through a single-channel endoscope is performed using a large nylon rope plus titanium clips [25]. In the current study, all perforations were successfully closed under endoscopy, and no surgical intervention was required. The postoperative infection rate was 12.2% in this study, and the infections were primarily peritoneal infections caused by large perforations or wounds. Particularly, delayed perforations that were related with an insufficient closure resulted in post-ESD infections. Fortunately, all infections were essentially controlled without serious consequences after conservative treatment, including intravenous antibiotics and fluids. For this reason, we suggest that the fluid in the gastric cavity should be suctioned out as much as possible before active perforation to reduce the likelihood of infection. Moreover, ensuring a safe and effective closure techniques is essential to prevent infection, re-intervention and adverse events. Bleeding occurred in 8 patients (9.8%), with blood loss lower than 100 mL per case; if not staunched immediately, this bleeding would increase the difficulty of manipulation and hamper the operating process due to the disturbed visible field. Ultimately, all bleeding was controlled after endoscopic intervention and active medical treatment, and no patients were transferred to ICU or died. Additionally, we determined that the occurrence of complications was not strongly associated with age, gender, tumor growth pattern or superficial ulceration (P > 0.05). Many studies have shown that large tumor size is considered to be an independent adverse prognostic factor associated with poor outcomes, including recurrence and metastasis [7,26], but the effect of a large tumor size on procedure-related complications remains undefined. Our data showed no significant association between the incidence of ESD-related complications and tumor size (P > 0.05). However, tumors in the gastric fundus lead to an increased risk for developing adverse events, likely due to the thin wall of the fundus and a narrowed space or limited visual field for manipulating upon the fundus, which is consistent with the report by Wang et al. [27]. Hence, ESD for LGSTs located in the fundus should be performed by endoscopists who are experienced and skilled to achieve satisfactory efficacy. Previous studies demonstrated that ESD-related complications developed more frequently in the deep MP layer compared with other layers (P < 0.05), which may be due to a rich vascular supply within the MP layer. This finding was confirmed in our study. Accordingly, we can

Please cite this article in press as: Chen Q, et al. Efficacy and safety of endoscopic submucosal dissection for large gastric stromal tumors. Clin Res Hepatol Gastroenterol (2019), https://doi.org/10.1016/j.clinre.2019.03.004

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10 identify the origin of the lesions via carefully performing EUS to reduce the complications during the procedure. In addition, several studies reported that GSTs with irregular shape may not increase the possibility of complication rates, whereas in our study, we found that irregular tumors were significantly correlated with the overall complication rate (P = 0.023). A possible explanation for this phenomenon may be that tumors with an irregular shape can increase the difficulty and duration time of the procedure. In future research, we will assess the origin and characteristics of LGSTs through EUS and hypotonic or contrast-enhanced CT to make a better treatment decision and further reduce the complications of ESD in the therapy of LGSTs. In recent years, a novel endoscopic intervention has been developed from the ESD technique, namely, submucosal tunneling endoscopic resection (STER), which has been demonstrated to be safe and effective for the treatment of GISTs. In this technique, a longitudinal mucosal incision is made to create the tunnel entry, and a submucosal tunnel is made between the submucosal and the MP layers. Then complete resection of the tumor is performed in the tunnel, and the mucosal entry is closed using endoscopic clips after removing the tumor. STER possesses multiple advantages compared to ESD in the removal of GISTs, such as the maintenance of mucosal integrity, rapid wound healing and reduced risks of complications, such as stenosis, perforation, and extraluminal infection [28]. However, STER is primarily performed to treat GISTs with a relatively small size. LGSTs (≥ 3 cm) are difficult to resect by STER due to confined tunneling space, which may lead to poor endoscopic visualization and insufficient en bloc resection. Further large-scale studies of the comparison between ESD and STER in treating LGSTs are warranted. The study has several limitations. First, it is a retrospective study with selective bias and a single-center study with a limited sample size. A prospective, multicenter randomized trial is warranted. Additionally, we did not compare ESD with other conventional treatments. Finally, most cases had occurred in the last 5 years, and we cannot evaluate the long-term outcomes with such a limited follow-up time; a longer follow-up period is required to support our findings. In conclusion, ESD is a safe and effective method for the resection of LGSTs; moreover, the strength of technical proficiency and tumor location influence the En bloc resection rate and the occurrence of adverse events. Cautious manipulation under endoscopy and a timely response to adverse events can contribute greatly to the patient outcomes. ESD is feasible for tumors with an irregular shape and tumors in the deep MP layer, but both of these conditions are associated with a relatively high risk for the development of complications.

Funding None to declare.

Authorship statement Xiaodong Zhou and Youxiang Chen is the Guarantor of the article.

Q. Chen et al. Qiaofeng Chen, Mingju Yu and Yupeng Lei brought the concept; Qiaofeng Chen, Chang Zhong and Yupeng Lei Collected the data; Qiaofeng Chen and Mingju Yu made the statistical analysis and wrote the paper; Zhijian Liu, Xiaojiang Zhou and Guohua Li were involved in patient care and inclusion; Xiaodong Zhou and Youxiang Chen revised the manuscript for important intellectual content. All co-authors approved the final version of the paper.

Disclosure of interest The authors declare that they have no competing interest.

Acknowledgments We are grateful to all the participants and colleagues for their contribution.

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Please cite this article in press as: Chen Q, et al. Efficacy and safety of endoscopic submucosal dissection for large gastric stromal tumors. Clin Res Hepatol Gastroenterol (2019), https://doi.org/10.1016/j.clinre.2019.03.004