Laparoscopic Partial Gastrectomy for Large Gastric GISTs

Gastrointestinal stromal tumors (GISTs) are considered the most common mesenchymal tumors in the gastrointestinal tract and the stomach is the most frequently site affected (50–60%). The safety and feasibility of laparoscopic surgery for gastric GISTs of sizes larger than 5 cm remains unclear. It depends on the surgical skills, tumor location, and the learning curve of the surgeons. Between December 2013 and January 2021, 30 patients diagnosed with gastric GISTs underwent laparoscopic partial gastrectomy. This is a retrospective study done in Surgical Oncology unit, Oncology Center, Mansoura University, Egypt. The most common tumor location was in the greater curvature in (46.7%). The mean tumor size was 9.5 cm (range 5–17 cm). All of the patients underwent laparoscopic partial gastrectomy. Associated splenectomy was done for only one patient. The mean operative time was 152.67 min and the estimated blood loss (EBL) was 139.33 ml. The mean hospital stay was 3.53 days. The mean follow-up period was 32.4 months. Laparoscopic resection for gastric GISTs has become a feasible method. Patients with large tumors have the same favorable outcomes as small tumors. Large-sized GISTs may receive neoadjuvant therapy to downstage the disease and make it amenable for laparoscopic resection.


Introduction
Gastrointestinal stromal tumors (GISTs) are considered the most common mesenchymal tumors in the gastrointestinal tract [1] and the stomach is the most frequently site affected (50-60%), followed by the small intestines (20-30%) and rectum (10%) [2]. GISTs originates from interstitial cells of Cajal, which are implicated in the regulation of gut peristalsis [3]. Active mutations of KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene are leading to uncontrolled cell proliferation by continuous tyrosine kinase activity [4]. They are ranged clinically, from small, localized, slowly-growing lesions to very aggressive tumors with high metastatic potentials [5]. Treatment of early tumors includes surgical removal with safety margins from the surrounding healthy tissue [6]. Removal of the regional lymphatic tissue is not indicated, as lymph node metastasis is rarely observed [7].
In the last three decades, laparoscopy use in surgical oncology has gained much popularity in the treatment of both benign and malignant tumors. Laparoscopic resection of a gastric GIST was first done in 1992 [8]. Several studies and meta-analyses have shown that laparoscopic treatment for gastric GISTs is a safe and effective method with less blood loss, less morbidity, and early recovery [9]. The main obstacles to perform minimally invasive resection of gastric GISTs include tumor size larger than 5 cm, invasion into adjacent vital organs, and certain locations such as gastroesophageal junction [10]. Most cohort studies focused on laparoscopic surgery for smaller gastric GISTs; few have been designed for large-sized GISTs (> 5 cm) [11].
The safety and feasibility of laparoscopic surgery for gastric GISTs sized > 5 cm remains unclear. It depends on the surgical skills, tumor location, and the learning curve of the surgeons [12]. Few Asian studies reported that laparoscopic resection is superior to open surgery for gastric GIST. However, most of these studies were conducted in patients with lower BMI, compared to the Western population. Our study aims to assess the feasibility and efficacy of laparoscopic surgery in patients with gastric GISTs and its application for large-sized tumors.

Study Design
This is a retrospective study done in the Surgical Oncology Unit, Oncology Center, Mansoura University, Egypt. After obtaining approval from the Institutional Review Board (IRB) of Faculty of Medicine, Mansoura University code (R.21.03.1266), 30 patients with gastric GISTs were enrolled in this study between December 2013 and January 2021. Patients were diagnosed by Computerized Tomography (CT) of the chest and abdomen, endoluminal ultrasound (EUS) with fine needle aspiration biopsy. Patient with sizable GISTs not amenable to laparoscopic resection received neoadjuvant tyrosine kinase inhibitors to downsize the tumor. Patients with metastatic GISTs were excluded from this study. Informed consent was obtained from all patients before inclusion in this study. Laparoscopic partial gastrectomy was performed without lymphadenectomy. The resected specimens were sent for pathological examination and assessment of the free surgical margins. High-risk tumors with aggressive criteria of recurrence received adjuvant imatinib according to the NCCN Guidelines.

Procedures
All patients were operated in the supine position with their legs apart (French position). A 12-mm infraumbilical trocar was placed for the camera and 2 additional ports were used (working ports) and one additional 12-mm trocar was used for liver retraction especially in lesser curvature tumors. The tumor location was identified by mobilization and dissection of the stomach away from any adhesion (Fig. 1a). Traction was applied on the omentum surrounding the tumor or the stomach wall to avoid tumor spillage (Fig. 1b). Two intracorporeal stay sutures for traction on the proximal and distal attachments of the tumor were sometimes used (Fig. 1c).
An articulating laparoscopic linear stapler (Echelon® flex 60 mm) was used for gastric resection (Fig. 1d). After Fig. 1 Steps of laparoscopic partial gastrectomy for large gastric GISTs. a Dissection of the tumor from the surrounding tissue. b Traction on the gastric wall for tumor mobilization. c Two intracorporeal stay sutures on the nearby gastric wall for tumor traction. d Laparoscopic resection of the gastric GISTs using linear stapler (Echelon® flex 60 mm) resection intracorporeal seromuscular sutures were placed and the specimen was retrieved by the Endocatch® through extension of the infraumbilical port (Fig. 2).

Study Outcomes
Patient demographics and tumor characteristics, surgical outcomes, postoperative outcomes, and patient's follow-up were collected and assessed.

Statistical Analysis
Analysis of data was performed using Statistical Package for Scientific Studies (SPSS) v.26 for MacOS v11.3. Numerical data was expressed as means ± standard deviation (SD). The Kaplan-Meier method was used to estimate the disease-free survival (DFS).

Study Population
Between December 2013 and January 2021, 30 patients with gastric GISTs underwent laparoscopic partial gastrectomy in the Oncology Center, Mansoura University. The mean age was 53.67 years, and the mean BMI was 32.50 kg/m 2 ( Table 1). Most patients were male (56.7%) and had ASA score I (93.3%). DM, hypertension, and liver disease were the common comorbidities with 10% each. Half of the patients in this study complained from dyspepsia (50%). The mean preoperative tumor size was 9.50 cm (range 5-17 cm). Eleven patients have received neoadjuvant imatinib and the mean tumor size after neoadjuvant treatment was 8.8 cm (range 6-14 cm).

Intraoperative Parameters
The operative details are shown in Table 2. The commonest tumor location was in the greater curvature in 46.7%. All of  the patient underwent laparoscopic partial gastrectomy and associated splenectomy was needed in only one patient with tumor infiltrating the splenic hilum. There was no conversion to laparotomy. The mean operative time was 152.67 min and the estimated blood loss (EBL) was 139.33 ml. Blood transfusion was needed in one patient and there was no intraoperative complication or intrabdominal tumor rupture.

Postoperative Outcome
In total of 30 patients, two patients had grade II postoperative morbidities (according to Clavien and Dindo classification) requiring blood transfusion due to anemia (Table 3).
One patient had grade III morbidity due chest tube insertion for pneumothorax. No patients needed ICU admission, postoperatively. We also reported no postoperative mortality. Most of the patients started oral intake in day 1 postoperatively and the mean duration of the hospital stay was 3.53 days.

Follow-Up
Follow-up data were summarized in Table 5. The mean follow-up period was 32.4 months. Postoperative (adjuvant) therapy with imatinib was administered in 23 (76.7%) patients; ten of them received neoadjuvant treatment. The mean duration of adjuvant treatment was 20.78 months. The disease-free survival (DFS) was 32.13 months (Fig. 3). Local recurrence developed in one patient (3.3%) with hepatic and peritoneal disease after 48 months of the primary diagnosis.

Discussion
This study demonstrates the feasibility of laparoscopic partial gastrectomy for gastric GISTs. The large-sized GISTs that are not feasible for laparoscopic resection or may be associated with multi-organ resection may receive neoadjuvant therapy to be downsized, thus making them suitable for resection and avoid intrabdominal spillage and dissemination. Laparoscopic resection of gastric GISTs has been recently adopted, because the prognosis of GISTs depends mainly on the tumor size and morphological features rather than the wide margins of resection [13].
Laparoscopic surgeries have many advantages over the traditional open surgery. Laparoscopy reduces the intraoperative blood loss, postoperative pain, and allows the early recovery of the patient with the oral intake and shorten the hospital stay [14].
The European Society for Medical Oncology (ESMO) indicated laparoscopic resection of small-sized GISTs. The treatment of large-sized tumors with minimally invasive surgeries is not preferred due to the risk of intra-operative spillage [15], which is considered a significant factor for tumor recurrence.
Recent data from the National Comprehensive Cancer Network (NCCN) have indicated laparoscopic or laparoscopicassisted resection of gastric GISTs larger than 5 cm [16]. Nowadays, there is no cutoff tumor size for safe laparoscopic surgery. It is suggested to be around 4-5 cm for safe laparoscopic resection especially in non-experienced centers. In a study by Melstrom et al. [17], the mean tumor size in 17 patients was 4.3 cm (range 1.5-9.1 cm). In the current study, the mean tumor size was 9.50 cm (range 5-17 cm) and all patients underwent total laparoscopic resection without single intra-operative tumor rupture.
Many authors demonstrated their experience of safe laparoscopic resection of large-sized GISTs > 5 cm without any complications [12]. Large tumor resection requires longer operative times, and may be associated with more significant blood loss. Tumor size is not the only difficulty with laparoscopic resection of gastric GISTs, but also the tumor location as in the gastroesophageal junction, the gastric antrum, or posterior gastric wall. The most common tumor location in our study was in the greater curvature of the stomach (46.7%), which made it easier for laparoscopic resection .
Bischof et al. [18] reported a mean operative time of 157 min which is comparable to that in our study (153 min). Roggin and Posner presented results from five reports on the laparoscopic resection of GISTs and the conversion rates ranged from 0 to 6.5% [19]. However, we reported no intraoperative complications nor conversion into laparotomy in our study.
Oral intake was started in most of the patients in our study in POD 1; thus, the mean hospital stay was 3.53 days. In the study by Chi et al., oral intake was 3.5 days but the mean hospital stay was 6.1 days [20]. In our series, patients had a smooth postoperative course apart from blood transfusion for two cases due to anemia and another had pneumothorax necessitating chest tube insertion. We had no postoperative mortality in our study. Gertsen et al. [21] reported that 6 patients (27%) had postoperative morbidity. One patient was re-operated for anastomotic leakage. Two patients developed pneumonia, one had postoperative cardiac complications, and another had urologic complication. There was no postoperative mortality.
Most of the tumors in our study were pathologically large-sized (5 to 10 cm) and only four patients had a tumor size more than 10 cm. The largest tumor size was 13 cm (2 patients) and the mean tumor size was 7.2 cm. All patients had total laparoscopic resection with delivery of specimens through extension of the infraumbilical port without the need for a mini-laparotomy. Immunohistochemical examination was done for all patients revealing positive CD117, CD34, and DOG1 for 96.7%, 93.3%, and 100% patients, respectively, and most of the tumors were of intermediate risk. In another study, the tumor size was 4 cm and the largest was 5.5 cm and the immunohistochemical examination was CD 117 (97.1%), CD 34 (70.6%), and DOG1 (26.5%). Their National Institute of Health (NIH) tumor risk was low in 50% of the cases [22].
Adjuvant therapy was given to 23 patients, in our study. These patients were with intermediate and high-risk tumor features. Patients were followed up within a mean period of 32.4 months. Clinical and radiological assessment were done. Local recurrence developed in one patient (3.3%) with hepatic and peritoneal disease after 48 months. This patient had a tumor with high-risk features (mitotic index > 5) and received both neoadjuvant and adjuvant therapy. The recurrence rate after laparoscopic resection of gastric GISTs was reported to be ranged from 4.8 to 18% [23].
Another study found no significant difference in terms of disease-free survival and overall survival between the laparoscopic and the open resections for gastric GISTs. In the laparoscopic group, six patients had either local recurrence or distant metastasis and four of these patients died, while, in the open group, ten had either local recurrence or distant metastasis and five of them died. These results indicate that laparoscopic surgery for gastric GISTs has oncologic outcomes similar to that of open surgery [20].

Conclusion
This study demonstrated the feasibility of laparoscopic resection for large gastric GISTs. Patients with large tumors have the same favorable outcomes as small tumors. However, large-sized GISTs may benefit from neoadjuvant therapy making them more amenable to laparoscopic resections.
Author Contribution All authors have made substantial contributions to conceptualization, methodology, validation, formal analysis, investigation, writing original draft, review and editing, visualization, and project administration. All authors have approved the submitted version of the article.

Declarations
Ethics Approval Approval is from the Institutional Review Board (IRB) of Faculty of Medicine, Mansoura University code (R.21.03.1266).

Conflicts of Interest
The authors declare no competing interests.