Upper gastrointestinal submucosal tumors (SMTs) are typically covered by normal mucosa, and precise histological diagnosis is difficult. Periodical endoscopic surveillance of SMTs smaller than 2.0 cm, or surgical intervention for large lesions, is the preferred treatment approach.1 However, the best treatment for upper SMTs sized 2.0 to 5.0 cm is currently under debate. Some SMTs do have malignant potential.2 Furthermore, when the tumor grows, patients may lose the opportunity to receive minimally invasive treatment. Therefore, proper and safe resection of these SMTs is crucial for confirmation of the histological diagnosis, and for clinical treatment.
We previously described a new technique, submucosal tunneling endoscopic resection (STER), for the resection of upper gastrointestinal SMTs originating from the muscularis propria (MP) layer.3 This new endoscopic technique has advantages over endoscopic submucosal dissection (ESD) in terms of maintaining mucosal integrity and reducing the risk of postoperative gastrointestinal tract leaks. Recently, the feasibility and short-term safety of STER has been demonstrated in several preliminary studies with a small number of patients;4–8 however, a large scale study with long-term follow-up is necessary for the clinical application and promotion of this innovative technique. The aim of this study is to evaluate the efficacy and safety of STER for upper gastrointestinal SMTs in a large series of patients, with a long-term follow-up. We hope the data and conclusions provided in this study can become a useful reference tool for doctors and researchers in this field.
After describing the STER technique in early 2011, between June 2011 and May 2013, a total of 180 patients with upper gastrointestinal SMTs originating from the MP layer were included in this study. All patients were from the Zhongshan Hospital of Fudan University.
Lesions were defined by endoscopic ultrasonography (EUS) and/or computed tomography (CT).4 Patients were considered eligible for STER if they met the following inclusion criteria: (i) the tumor originated predominantly from the MP layer without restriction of extraluminal growth; (ii) the long diameter of the tumor was 2.0 to 5.0 cm; (iii) the SMT was predicted to be potentially malignant by EUS; (iv) any SMT that could not be diagnosed conclusively by EUS/EUS-fine needle aspiration, and required histopathological examination; (v) patients who complained about upper gastrointestinal symptoms; and (vi) patients who became stressed when recommended periodic follow-ups and were specifically requested endoscopic resection or aggressive treatment. Exclusion criteria included: (i) in agreement regarding withdrawal; (ii) the transverse diameter of the tumor was >3.5 cm; and (iii) coagulation disorders.
The study and procedures were conducted in accordance with the ethical standards of the Helsinki Declaration of 1975. The study was approved by the Institutional Review Board of Zhongshan Hospital (NO.2009135), and informed consent was obtained from patients for all procedures and interventions described.
STERs were performed with patients under general anesthesia and endotracheal intubation. Prophylactic intravenous antibiotics were administered 30 minutes before the procedure. During the procedure, a standard single accessory-channel gastroscope (GIF-Q260J, Olympus) was used. A CO2 insufflator (Olympus) was employed for carbon dioxide gas insufflations, and in the majority of cases a low CO2 flow rate was used. A mixed solution of normal saline containing 0.4% indigo carmine and 0.025 mg/mL epinephrine was used for submucosal injection. The procedure began with creation of a fluid cushion by injecting the mixed solution 3 to 5 cm orally to the proximal margin of the SMT, according to the tumor location. A 1.5 to 2 cm longitudinal mucosal incision was made using a hook knife or hybrid knife at the top of the fluid cushion to provide mucosal entry to the submucosal space (Fig. 1). The submucosal tunnel was created between the mucosal and muscular layers, ending about 1 cm distal to the tumor to ensure a satisfactory endoscopic view of the SMT and sufficient working space for resection, as described previously.3 Endoscopic resection of the SMT was performed using an insulated-tip knife, hook knife, or hybrid knife. Extraction of the mobilized SMT was achieved by suctioning the tumor into the cap device, or use of a snare or basket to grasp the tumor, and subsequent removal via the mucosal entry. After tumor resection, a Coagrasper was used for hemostasis in the tunnel. In cases where the size of the tumor resected exceeded that of the mucosotomy, the entrance to the submucosal tunnel was enlarged. Finally, hemostatic clips were used to close the mucosal entry (Fig. 1).
Resected specimens were fixed in 10% buffered formalin, embedded with paraffin, and sectioned for pathological examination. A tumor having an oval or globular shape was defined as a tumor with regular shape. A complete en bloc resection was defined as a tumor removed in a single piece, with the capsule intact. When the organization of the tumor was difficult to determine, immunohistochemical staining was performed.9
In the present study, pneumothorax and/or hydrothorax requiring therapeutic intervention, major bleeding (> 200 mL), mucosal injury, and esophageal-pleural fistula were the major complications, all of which received therapeutic intervention. Intraoperative minor bleeding was successfully treated by immediate endoscopic coagulation. A small amount of effusion in the thorax, or a small amount of CO2 in the thorax, mediastinum, subcutis, or abdomen can be spontaneously absorbed.10,11 As reported in other studies regarding this tunneling technique,12 these minor adverse technical events had minimal clinical impact or symptoms, did not require therapeutic intervention, and were thus not seen as complications in this study.
All patients were followed up with standard endoscopy and EUS at 3, 6, and 12 months during the first year after the initial procedure to observe the healing of the wound and to check for residual tumor or recurrence. Subsequently, patients were followed yearly. For patients with gastrointestinal stromal tumors (GISTs), a contrast-enhanced CT scan/MRI every 6 to 12 months was recommended.
Data Collection and Statistical Analysis
Clinicopathological, endoscopic, and follow-up data were collected and analyzed. Statistical analysis of independent risks for piecemeal resection, long operative time, and STER-related complications were assessed using univariate and multivariate analyses. Commercial software (IBM SPSS Statistics 18; SPSS Inc, Chicago, IL) was used for statistical analysis, with P < 0.05 taken to be statistically significant.
In this large, consecutive study, 180 patients with upper gastrointestinal SMTs were evaluated (Table 1). The mean age of the patients was 49 ± 10.7 years (median 49 years, range 18–77 years) with a male:female ratio of 2:1 (120/60). The median tumor size was 2.6 cm (range, 2.0–5.0 cm). Among all SMTs, 131 had regular shapes (72.8%) and 49 had irregular shapes (27.2%). Tumors were located in the upper gastrointestinal tract,13 including 7 in the upper esophagus (3.9%), 66 in the middle esophagus (36.7%), 51 in the lower esophagus (28.3%), 43 at the esophagogastric junction (EGJ, 23.9%), and 13 in the stomach (7.2%). All 180 tumors originated from MP layer, among which 58 originated from the superficial MP (32.2%) and 122 originated from the deep MP (67.8%). There were 146 leimyomas (81.1%), 28 GISTs (15.6%), 4 schwannomas (2.2%), and 2 calcifying fibrous tumors (1.1%). On the first postoperative day, patients resumed a liquid diet if they had no complaint of fever, dyspnea, chest pain, or abdominal pain. The median hospitalization time was 3.2 days (range 2–22).
Resection Rate and Procedure Time
In this study, all upper gastrointestinal SMTs were resected, with en bloc resection achieved in 163 of the 180 lesions treated (90.6%). Table 2 shows risk factors for piecemeal resection. In the present study, the size of upper gastrointestinal SMTs had significant impact on the en bloc rate. Furthermore, based on statistical analysis, the piecemeal resection rate in patients with irregular tumors was significantly higher than the rate in those with regular tumors. Other clinicopathological characteristics (eg, age, sex, tumor location, layer, and histopathology) were not associated with piecemeal resection.
In this study, the median time required for the STER procedure was 45 minutes (range 15–200 minutes). According to univariate and multivariate analysis, tumors with greater size and irregular shape were also significant risk factors for long operative times (Table 3). Other clinicopathological characteristics including age, sex, tumor location, layer, and histopathology had no significant impact on the operative time required.
The incidence of complications in this study was 8.3% (Table 1). In detail, pneumothorax and/or hydrothorax with more than 30% lung collapse occurred in 10 patients (5.5%), major bleeding occurred in 2 patients (1.1%), mucosal injury occurred in 2 patients (1.1%), and esophageal-pleural fistula occurred in 1 patient (0.6%). All patients with STER-related complications were treated successfully using conservative treatment, and there were no treatment-related deaths. Based on logistic regression analysis on risk factors for complications, tumors with irregular shape, large tumors, tumors in the deep MP layer, and long operative time were significant contributors to STER-related complications (Table 4). Other clinicopathological characteristics were not associated with STER-related complications.
Among 180 patients with upper gastrointestinal SMTs treated using STER, 1 case was recommended additional surgery, 2 cases were lost to follow-up, and the other 177 cases had a follow-up period of more than 28 months. The overall median follow-up period was 36 months (range, 28–51 months), and all patients were free from local recurrence or distant metastasis during the study period.
With better access to gastroscopy, increasing numbers of upper gastrointestinal SMTs are diagnosed at a small size. Among these SMTs, tumors less than 2.0 cm in size are thought to have a very low risk of malignancy and typically receive recommendation for periodic follow-up.1 However, the management of SMTs sized 2.0 to 5.0 cm is controversial, since the nature and metastatic potential of these tumors remains complicated. Currently, EUS is the primary diagnostic procedure for SMTs. Information regarding size, shape, location, originating layer, echo pattern, and malignant potential of SMTs can be provided using EUS. However, EUS is unable to predict the correct histologic diagnosis in all cases, with results often dependent on the experience of the operator.14,15 Therefore, in controversial cases, minimally invasive endoscopic resection and precise histopathological diagnosis could be beneficial. Compared with other conventional endoscopic techniques, such as EMR and ESD, STER can resect SMTs under direct vision while maintaining mucosal integrity, and consequently, the risk of gastrointestinal tract perforation and leakage is theoretically reduced. Recently, reports evaluating STER for upper gastrointestinal SMTs have become more common,4–8 but few articles provide robust data detailing the long-term outcomes of this technique.
The results of the present study showed that STER is a feasible and effective treatment option. STER was observed to provide a 100% resection rate and a 90.6% en bloc resection rate for upper gastrointestinal SMTs. Meanwhile, a relative short procedural time (median 45 minutes) was also achieved. Inoue et al16 reported that the best application for STER may be in SMTs of the esophagus and cardia that are less than 3.0 cm in diameter. We suggest that implementation of STER for SMTs with a long diameter ≤5.0 cm and a transverse diameter ≤3.5 cm could facilitate a high en bloc resection rate. However, we found it was relatively difficult and time-consuming to resect large tumors, because of limited space in the established submucosal tunnel. Furthermore, based on statistical analysis, irregular tumor shape was another contributor to the likelihood of piecemeal resection of upper gastrointestinal SMTs. Thus, we concluded that for irregular tumors that are large in size it would be difficult for endoscopists to successfully achieve en bloc resection. Preoperative EUS/CT evaluation of the SMT, adequate preparation, and an experienced endoscopist are important for a successful STER in irregularly shaped, large tumors. Symptoms also play a primary role in the resection of small benign esophageal lesions. However, in this study, we found that most complaints were nonspecific symptoms for gastrointestinal SMTs. Generally, larger tumors are significantly more likely to be symptomatic, with tumors less than 5 cm in diameter typically being asymptomatic.17 In the study by Mutrie et al,18 the mean diameter of esophageal leiomyomas among symptomatic patients was 5.3 cm, as compared with 1.5 cm in asymptomatic patients (P < 0.0001).
Irregular shape and large size were also risk factors for procedures requiring a long operative time (≥ 60 min). In this study, the percentage of procedures requiring a long operative time in tumors with size <3.0 cm and 3.0–5.0 cm was 20.0% and 64.4%, respectively. This result has been confirmed by 2 other preliminary studies on STER for large upper gastrointestinal SMTs, in which the mean operative times were 76.7 and 77 minutes, respectively.19,20 Our data has shown that tumor location had no impact on en bloc resection and procedure time; however, we found it was more difficult to establish a submucosal tunnel for tumors in the upper esophagus, than for tumors in the middle and lower esophagus, because of the relatively small lumen. For resection of tumors in the EGJ, it is crucial to repeatedly confirm the location of the tumor and tunnel, because it is easy to lose orientation when the submucosal tunnel is being established. Our experience is that a small dose of indigo carmine or methylene blue can be injected into the submucosa around the tumor location to aid in orientating the submucosal tunnel, subsequently decreasing the procedure time. With respect to STER for gastric SMTs, there are several differences required in the technique used with esophageal SMTs. First, unlike the submucosal tunnel established in the esophagus, effective tunneling can only be performed on the greater curvature of the gastric antrum or the lesser curvature of gastric corpus. It is very difficult to establish the tunnel in the gastric fundus, lesser curvature of the gastric antrum, or the greater curvature of gastric corpus, successfully. For SMTs in these gastric locations, ESD may be a better option. Second, the entry of the submucosal tunnel should be located 3 cm orally to the proximal margin of the SMT, because of gastric flexibility (Fig. 2). In this study, due to limitations apparent in establishing the tunnel in the stomach, tumors resected by STER in the stomach were located on either the greater curvature of gastric antrum, or the lesser curvature of gastric corpus, thus accounting for the relatively low occurrence of gastric SMTs observed.
Like other endoscopic surgeries, STER can exhibit complications. In the present study, the overall rate of STER-related complications was 8.3% (15 of 180 cases). Tumors with irregular shape, large tumors, long operative times, and tumors in the deep MP layer were risk factors for development of complications. In the study by Ye et al,6 it was reported that the rate of complications was significantly higher for lesions originating in the deeper MP layer (7/10 cases, 70%) than in the superficial MP layer (1/75, 1.3%). This may be because of anatomical characteristics related to the esophagus; the esophageal muscular layer lacks the protection of covered serosa. To reduce gas complications, the most prevalent type of complication encountered, CO2 insufflation was used during the STER procedure.4 In our center, we have used CO2 for gas insufflations regularly since early 2011. In the present study, starting from the middle of 2011, we found that small amounts of CO2 in the thorax, mediastinum, and subcutis could be absorbed rapidly without any intervention. Observation alone was recommended for patients without clinical symptoms.21
Upper gastrointestinal SMTs are composed primarily of leiomyomas and GISTs.15 In this study, we found that piecemeal resection of leiomyomas did not influence long-term outcomes. However, GISTs have greater potential malignancy, and should be resected completely en bloc. The NCCN and ESMO guidelines recommend that GISTs 2.0 cm or larger should be resected.22,23 In this study, all GISTs were regular and were en bloc resected. Among these cases, the capsule of 1 GIST with a size of 4.5 cm was compromised when the tumor was being removed from the submucosal tunnel, and this patient was recommended additional surgery. The long-term outcomes of STER for both leiomyomas and GISTs in the present study were excellent; neither local recurrence nor distant metastasis has been observed during a median follow-up of 36 months (range, 28–51 months).
This study had some limitations. One limitation is that the study design used was retrospective. Another limitation was that this new technique was not compared with other conventional treatments. Thus, a prospective, randomized controlled study must be performed in the future to validate the results observed.
STER is an effective and safe methodology for the resection of upper gastrointestinal SMTs. Tumor size and shape impact the piecemeal resection rate and procedural difficulty. Besides tumor size and shape, tumor in the deep MP layer and long operative time are also risk factors for STER-related complications. STER for large tumors with irregular shape in the deep MP layer is feasible, but associated with relatively high risks of piecemeal resection and complications.
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