As a minimally invasive technique, endoscopic resection may benefit patients diagnosed with early stage gastrointestinal neuroendocrine tumors (NETs). However, no studies have yet been published in which endoscopic submucosal dissection (ESD) has been applied for gastric NETs. For the first time a research group in China applied ESD to remove gastric NETs, and indicated that ESD should be considered for treatment of eligible gastric NETs because the technique shows a high histologically complete resection rate, provides accurate histopathological evaluation, has a low complication rate, and can be performed within a reasonable timeframe.
Gastric NETs have been previously thought to be extremely rare lesions. However, over the last 50 years, the incidence of gastric neuroendocrine tumors (NETs) has been increasing in most countries because of better awareness and an increased widespread use of upper gastrointestinal endoscopy [
Various endoscopic resection procedures such as endoscopic polypectomy, strip biopsy, aspiration resection, and band-snare resection have been described as potential treatment procedures for gastric NETs [
Endoscopic submucosal dissection (ESD) is a method of endoscopic resection and has the advantage of a high probability of en bloc and histologically complete resection even in submucosal tumors because the technique involves dissection of the submucosal tissue beneath the lesion [
With the approval of the institutional review board, from January 2008 to January 2012, 25 patients with confirmed histological diagnosis of gastric neuroendocrine neoplasms were treated with ESD. None had regional lymph node enlargement and distant metastases to the liver or lung on computerized tomography (CT) scanning or endoscopic ultrasonography (EUS) before ESD. Tumor characteristics, complete resection rate, complications, local recurrences, and distant metastases were evaluated in all patients. Informed patient’s consent was obtained prior to the procedures.
Preoperative EUS (high-frequency miniprobe, UM-2R, 12 MHz; UM-3R, 20 MHz, Olympus) was performed to evaluate the depth of tumor invasion and the involvement of regional lymph nodes. The existence of lymph node and distant metastasis was surveyed by contrast-enhanced CT, abdomen ultrasound, and chest X-ray.
To dissect the tumor, endoscopic submucosal dissection was attempted with a single-channel gastroscope (GIF-H260, Olympus) and an insulated-tip electrosurgical knife (KD-611L, Olympus) or hook knife (KD-620LR, Olympus). A transparent cap (D-201-11304, Olympus) was attached to the tip of the gastroscope to provide direct views of the submucosal layer. Other equipment included injection needle (NM-4L-1, Olympus), grasping forceps (FG-8U-1, Olympus), snare (SD-230U-20, Olympus), hot biopsy forceps (FD-410LR, Olympus), clips (HX-610-90, HX-600-135, Olympus), high-frequency generator (ICC-200, ERBE), and argon plasma coagulation unit (APC300, ERBE).
Patients were treated under general anesthesia. After making several marking dots with argon plasma coagulation around the lesion, a mixture solution (including 100 mL of normal saline, 1 mL of indigo carmine, and 1 mL of epinephrine) was injected into the submucosa. The mucosa was incised outside the marking dots. Direct dissection of the submucosal layer beneath the tumor was then performed under direct vision to achieve complete en bloc resection of the specimen. The tumor was dissected along the capsule, and saline solution was injected repeatedly during the dissection when necessary. The resultant artificial ulcer was managed routinely with argon plasma coagulation to prevent delayed bleeding, and hemoclips were used to close the deeply dissected areas as needed (Figure
The procedure of endoscopic submucosal dissection for a gastric neuroendocrine tumor. (a, b) A sessile polyp with a reddened surface of the gastric body. (c) Making. (d) Injection. (e, f) Dissection. (g) Resultant artificial ulcer. (h) Closure of the defect with metallic clips. (i) Completely resected specimen.
There is a clinicopathological categorization of the gastric NETs which distinguishes four types of neuroendocrine neoplasms of the stomach [
The WHO 2010 classification of tumours of the digestive system was used for histopathologic evaluation [
En bloc resection refers to a resection in one piece. A resection with a tumor-free margin in which both the lateral and basal margins were free of tumor cells was considered as a complete resection. A resection in which the tumor extended into the lateral or basal margin, or the margins were indeterminate because of artificial burn effects, was considered as an incomplete resection.
Patients underwent followup endoscopy and/or EUS at 1, 3, 6, and 12 months after ESD and annually thereafter to view the healing of the wound and to check any tumor residual or recurrence. Close followup by abdomen ultrasound, contrast-enhanced CT, and chest radiography were carried out to evaluate distant metastasis every 6 months. A final checkup was performed via telephone questionnaires in August 2012. At that time, followup data for 100.0% of the patients were available for evaluation.
Patient characteristics, lesion features, and clinical outcomes are summarized in Table
Clinicopathological characteristics of 25 patients with gastric neuroendocrine tumors treated by endoscopic submucosal dissection.
Case no. | Age, y | Gender | Location | Macroscopic appearance | Clinicopathological type | Size, mm | En bloc resection | Depth of invasion | WHO classification | Lateral margin | Vertical margin | Vessel invasion | Complication | Additional surgery | Followup, mo |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 36 | F | Gastric body | Submucosal tumor | I | 4, 4, 3 | Yes | Mucosa | NET-G1 | (−) | (−) | Absent | None | None | 55 |
2 | 41 | M | Gastric antrum | Submucosal tumor | III | 10 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | None | None | 52 |
3 | 71 | M | Gastric body | Submucosal tumor | III | 18 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | None | Reject | 45 |
4 | 53 | M | Gastric body | Submucosal tumor | I | 5 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | None | None | 44 |
5 | 55 | F | Gastric body | Submucosal tumor | III | 10 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | None | None | 41 |
6 | 82 | F | Gastric fundus | Submucosal tumor | III | 30 | Yes | Submucosa | NET-G2 | (−) | (−) | Absent | None | Reject | 40 |
7 | 35 | F | Gastric fundus | Polyp | I | 6 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | None | None | 38 |
8 | 40 | F | Gastric body | Polyp | I | 6 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | None | None | 35 |
9 | 47 | F | Gastric body | Submucosal tumor | I | 4 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | None | None | 35 |
10 | 56 | F | Gastric body | Polyp | I | 3, 2 | Yes | Mucosa | NET-G1 | (−) | (−) | Absent | None | None | 31 |
11 | 51 | F | Gastric body | Submucosal tumor | III | 8 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | None | None | 29 |
12 | 55 | M | Gastric body | Polyp | I | 8, 3, 3 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | None | None | 28 |
13 | 55 | M | Gastric body | Polyp | I | 4 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | None | None | 28 |
14 | 57 | M | Gastric body | Submucosal tumor | III | 15 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | Delayed bleeding | Reject | 26 |
15 | 35 | F | Gastric body | Submucosal tumor | III | 25 | Yes | Submucosa | NET-G2 | (−) | (−) | Absent | None | Yes | 25 |
16 | 45 | F | Gastric body | Polyp | I | 6, 3 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | None | None | 22 |
17 | 48 | F | Gastric body | Polyp | I | 5 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | None | None | 21 |
18 | 55 | M | Gastric body | Polyp | I | 5 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | None | None | 20 |
19 | 65 | F | Cardia | Submucosal tumor | III | 20 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | None | Reject | 20 |
20 | 35 | F | Gastric fundus | Erosion | I | 5, 3 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | None | None | 20 |
21 | 47 | M | Gastric fundus | Polyp | I | 4 | Yes | Mucosa | NET-G1 | (−) | (−) | Absent | None | None | 20 |
22 | 57 | F | Gastric body | Polyp | I | 8 | Yes | Mucosa | NET-G1 | (−) | (−) | Absent | None | None | 18 |
23 | 52 | F | Gastric body | Superficial ulcer | III | 15 | Yes | Submucosa | NET-G2 | (−) | (−) | Absent | None | Reject | 12 |
24 | 40 | F | Gastric body | Submucosal tumor | III | 20, 5 | Yes | Submucosa | NET-G1 | (−) | (−) | Absent | None | Reject | 11 |
25 | 70 | F | Gastric body | Erosion | I | 5 | Yes | Mucosa | NET-G1 | (−) | (−) | Absent | None | None | 7 |
NET: neuroendocrine tumor. Reject: the patient rejected the additional surgery.
With respect to clinicopathological categorization, 22 lesions in 15 patients were type I gastric NETs arising in chronic atrophic gastritis with hypergastrinemia, while other 11 lesions in 10 patients were type III because of absence of atrophic gastritis in these cases. None showed metastatic disease to lymph nodes or distal organs on preoperative examinations. Before ESD procedures, histological diagnosis of gastric NETs had been confirmed via biopsies in 4 cases.
All the tumors were removed in an en bloc fashion (33/33, 100%). The average maximum diameter of the lesions was 8.2 mm (range 2–30 mm), and the procedure time was 22.5 minutes (range 10–45 minutes). Results of pathological studies determined that 30 lesions were NET-G1 and 3 lesions were NET-G2. Complete resection was achieved in all the tumors (33/33, 100%). All of them were confined to the submucosa in histopathologic assessment, and no lymphovascular invasion was observed in any of the tumors.
Delayed bleeding occurred in one case 3 days after ESD. Successful hemostasis was achieved by coagulating forceps and spraying with thrombin during emergency endoscopy. The procedure-related perforation was not seen in any tumor.
Because type III gastric NETs with diameter larger than 10 mm may have high risks of metastasis, additional surgical intervention should be considered in 7 cases. However, only 1 of them underwent additional surgery, and we could not reveal residual lesions or metastatic lymph nodes in the surgical specimens. Other 6 cases refused additional surgery, citing their age, physical condition, or other personal reasons. Therefore, they were under careful followup.
During a mean of 28.9 months (range 7–55 months) followup periods, local recurrence occurred in two patients after initial ESD (case no. 1 and no. 12). Both of them then underwent repeat ESD successfully. Metastasis to lymph nodes or distal organs was not observed in any patient. No patients died during the study period.
Because most gastrointestinal NETs are not confined to the mucosa but, rather, invade the submucosa [
Gastric neuroendocrine neoplasms are divided into four groups by the clinicopathological classification: type I: NETs associated with type A chronic gastritis; type II: carcinoids with endocrine neoplasia; type III: sporadic carcinoids without hypergastrinemia; type IV: poorly differentiated neuroendocrine carcinomas [
Bleeding and perforation are the two main complications of ESD. In this study, only one case had delayed bleeding 3 days after ESD. Successful hemostasis was achieved by coagulating forceps and spraying with thrombin during emergency endoscopy. No patient had immediate or delayed perforation. The relatively low ESD complication rate most likely reflects the small size of lesions. Furthermore, we always keep our minds upon the prevention and handling of bleeding during procedure. Once bleeding occurs during ESD, hemostasis may take a long time, and the endoscopic view may be affected; blind hemostasis may eventually lead to perforation. In our study, immediate minor bleeding was treated successfully by grasping the bleeding vessels with hot biopsy forceps and coagulating them during ESD. Direct coagulation with the hook knife could be done for small vessels in the submucosa, and metallic clips were often deployed for more brisk bleeding.
In conclusion, the present study indicates that because of complete resection, ESD may reasonably serve as radical treatment for gastric NETs when lesions are within the existing criteria. It also provides enough histological information for tumor grading and staging even when lesions are beyond the selection criteria, which informs decisions regarding subsequent surgery. In addition, endoscopic treatment might be also considered in particular in patients with a high risk of perioperative complications due to old age or advanced comorbidity, for example, or if there are other contraindications to major surgery, even though the lesions are little beyond the existing criteria.
The authors declare that they have no conflict of interests to report with respect to this paper.
This study was supported by Grants from the Medical Leading Project of Shanghai Municipal Science and Technology Committee (no. 10411969600) and the Major Project of Shanghai Municipal Science and Technology Committee (nos. 11411950502 and 11DZ2280400).