Clinical Value of Clip-and-Snare Assisted Endoscopic Submucosal Resection in Treatment of Rectal Neuroendocrine Tumors

Neuroendocrine tumors (NETs), originated from neuroendocrine cells, can occur in any part of the body where neuroendocrine cells exist. Rectum is one of the most common primary locations of NETs [1, 2], accounting for about 27% of all gastroenteropancreatic NETs [3]. Although rectal NETs are potentially malignant [4], most of them have no specific clinical manifestations and are detected accidentally during screening colonoscopy [5].

It is reported that about 80% of rectal NETs have a diameter ≤10 mm, about 15% are 11–19 mm, and only about 5% have a diameter ≥20 mm [6, 7]. It is recommended by the 2016 guidelines of the European Neuroendocrine Tumor Society that endoscopic resection is feasible for highly differentiated rectal NETs with a diameter <20 mm, without muscularis propria invasion and lymph node metastasis [8, 9]. Endoscopic resection was recommended for rectal NETs with small size because of its prognosis as effective as surgery [8], minimal invasiveness, soon recovery, low cost, and better life quality after treatment. At present, many endoscopic techniques are widely applied for local resection of rectal NETs, including endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) [10, 11]. However, EMR has risk of incomplete resection, while ESD requires special instruments and complex skills.

In this study, we introduce a new endoscopic technology, clip-and-snare assisted endoscopic submucosal resection (CS-ESMR), for treatment of rectal NETs with diameter ≤10 mm and then to investigate the therapeutic value of CS-ESMR, including pathological R0 resection and adverse events, such as bleeding, perforation, and postoperative infection compared with EMR and ESD.

This retrospective study was performed at the First Affiliated Hospital of Dalian Medical University. A total of 67 patients were diagnosed rectal NETs by endoscopy from March 2017 to December 2021. Tiny rectal NETs or lesions misdiagnosed as sessile polyps were treated by EMR in outpatient department. Patients diagnosed with rectal NET were assigned to Jinpu Branch Hospital and Changchun Road Branch Hospital according to patients’ wishes. Inclusion criteria: patients who had received endoscopic resection for rectal NETs with diameter ≤10 mm and diagnosis of rectal NET had been confirmed by pathology. Exclusion criteria are (1) cases with incomplete data; (2) lesions with identified lymph node or distant metastasis by abdominal CT; (3) lesions with identified invasion of muscularis propria by endoscopic ultrasound; (4) tumor stage was G3; (5) acute anorectal infection, such as anal fissure and perianal abscess; (6) severe coagulation dysfunction; (7) severe cardiac and pulmonary insufficiency; (8) pregnancy; and (9) less than 18 years old.

According to the endoscopic resection methods, the cases were divided into three groups: CS-ESMR group (Jinpu Branch Hospital), ESD group (Changchun Road Branch Hospital), and EMR group (tiny rectal NETs or the lesion like a sessile polyp). The reporting of this study conforms to STROBE guidelines [12]. The study was executed according to the Helsinki Declaration, followed the local legislation, and was approved by the Ethics Committee of the First Affiliated Hospital of Dalian Medical University (Ethics Reference No.: PJ-KS-KY-2021-96X, date of approval: June 16, 2021). All the patients or their relatives presented written informed consent before the procedure. Clinicopathological features including gender, age, tumor size, resection methods (EMR, CS-ESMR, ESD), time required for endoscopic resection and consumptive material, the incidence of adverse events (bleeding and perforation), pathological information (including tumor differentiation, depth of tumor invasion, immunohistochemistry, and R0 resection or not) were all recorded.

Before the procedure, routine blood tests, coagulation function, liver and kidney function, and electrocardiogram were performed. Endoscopic ultrasound was performed to determine the depth of the lesion, and abdominal CT was performed to exclude lymph node metastasis and distant metastasis. All results were documented.

The CS-ESMR procedure was performed using a transparent cap-covered single-channel upper gastrointestinal endoscope (GIF-H260J, Olympus Optical Co.) with a pre-attached snare (Fig. 1a). After finding the rectal NET (Fig. 1b), a reopenable clip (Hangzhou AGS Bio Tech) was inserted through the working channel of the endoscope to grasp the mucosa adjacent to the lesion (Fig. 1c). When the lesion and surrounding tissues were well elevated by the reopenable clip like a pedicled polyp, the snare was released from the transparent cap, and the mucosa, submucosal lesion, and even some intrinsic muscle layers were completely snared. Then the NET was entirely excised with standard polypectomy technique (Fig. 1d), and the surgical wound was observed for signs of perforation, bleeding, and residual lesion (Fig. 1e). The wound was closed by the lifting reopenable clip and further clips (Fig. 1f) to prevent perforation and bleeding [13] (see online suppl. Video; for all online suppl. material, see https://doi.org/10.1159/000533393). Submucosal injection of solution is not required during the procedure. EMR and ESD were performed as previously described [14, 15].

Intraoperative bleeding refers to active bleeding during a procedure requiring electrocoagulation, while post-procedure bleeding is defined as rectal bleeding requiring transfusion and/or endoscopic therapy within 14 days after the resection; endoscopic perforation is defined as a transmural wall defect of the rectum related to the procedure [2]. The procedure time which is referring to the resection process only was recorded.

Pathological evaluation: according to WHO classification standard in 2010, NETs were graded as G1, G2, and G3 according to cell proliferation ability. G1: the number of mitoses is <2/high power field, and the positive index of Ki-67 is ≤2%; G2: the number of mitoses is 2–20/high power field, and the positive index of Ki-67 is 2–20%; G3: the number of mitoses is >20/high power field, and the positive index of Ki-67 is >20% [16, 17]. The depth of invasion, whether combined with other pathological components, surgical margin, vascular or nerve invasion, and so on, were all evaluated.

Pathological complete resection (R0) refers to an en bloc resection of the lesion, with no tumor cells identified at lateral and deep margins, while R1 resection was defined as an en bloc resection of the lesion with margins involved with tumor cells, which implied potential residual tumor on the resection bed [2, 15].

Data analysis was performed using the SPSS 23.0 software (Chicago, IL, USA). All measurement data were expressed by mean ± standard deviation. χ² test was used for counting data, t test was used for measurement data, and Bonferroni correction was used for comparative analysis. p < 0.05 was considered statistically significant.

According to the exclusion criteria above, a total of 67 patients with rectal NETs were enrolled in this study. All the cases were single lesions and underwent endoscopic resection for the first time. Among them were 32 males (47.8%) and 35 females (52.2%), whose ages ranged from 21 to 76 years, with an average age of 50.4 ± 13.2 years. The distance from the tumor to the anus was 3–14 cm. The tumor diameter is 3–10 mm, with an average diameter of 6.3 ± 2.0 mm.

There were 27 cases in CS-ESMR group, 31 cases in the ESD group, and 9 cases in the EMR group. According to the WHO classification, G1 was found in 64 (95.5%) patients and G2 in 3 (4.5%) patients. The tumors were resected en bloc in all 67 cases. There were 55 cases of pathological R0 resection and 12 cases of R1 resection (7 cases in the ESD group and 5 cases in the EMR group). The patients with R1 resection of rectal NETs had a follow-up period of 20–53 months, and there was no case of local recurrence or distal metastasis. The clinical characteristics and follow-up outcomes of 12 cases with R1 resection are shown in Table 1.

There were 12 cases of active bleeding (stopped after electrocoagulation) and 2 cases of perforation (stitched with clips) during the procedures; all these cases were in the ESD groups. There was no post-procedure bleeding and perforation case. There was no significant difference in tumor diameter among the three groups. There was a significant difference about pathological R0 resection between CS-ESMR group and EMR group (p < 0.05) and between the CS-ESMR group and the ESD group (p < 0.05). There was a significant difference about intraoperative bleeding between the CS-ESMR group and the ESD group (p < 0.05), but no significant difference in intraoperative perforation between the two groups (p > 0.05). The procedure time of CS-ESMR group is significantly less than that of ESD group (p < 0.001). Moreover, the cost of CS-ESMR group was significantly less than that of ESD group (p < 0.001) (Table 2).

Rectal NETs are uncommon in clinic and account for only about 1.8% of all rectal tumors [15, 18]. However, with the development of endoscopy, the incidence of rectal NETs has increased worldwide in recent years [19], from 0.1/100 thousand in 1973 to 1.15/100 thousand, increased by 10 times in 40 years [20]. Endoscopically, rectal NETs are generally located in the middle and lower part of the rectum as a slight protrusion with smooth surface and yellow color, usually small in size (<10 mm), and seldom present as multiple, hyperemic surfaces, ulcers, or pedicles [2].

Since about 80% of rectal NETs are less than 10 mm in diameter [21], the risk of metastasis is very low for small rectal NETs [22], and endoscopic local resection is widely recommended [10]. Polypectomy and EMR are simple and safe but have risk of incomplete resection. It is reported that pathological R0 resection of EMR for rectal NETs ranges from 30% to 70% [23‒25]. Nakamura et al. [24] reported in 2016 that the pathological R0 resection of EMR is only 27.3%, and patients with incomplete resection need to be treated again because of tumor residue. In our study, the pathological R0 resection was 44.4% (4/9) in EMR group. The results are consistent with the previous reports and indicate that conventional EMR is not a suitable method for local resection of rectal NETs because of the presence of submucosal layer involvement [14].

In recent years, more and more studies about ESD for rectal NETs have been reported. Compared with EMR, ESD has advantages of higher pathological R0 resection and lower recurrence [26, 27]. In our study, the pathological R0 resection by ESD was lower than in previous studies [27]. The reason is mainly attributable to lack of ESD experience. Our study showed that the pathological R0 resection in ESD group was significantly higher than that in EMR group. However, ESD require advanced skills, it takes more time to learn, procedure time is long, and there is a risk of complications [28] with longer hospital stay and more cost. Therefore, a simple and safe technique with high pathological R0 resection is needed. CS-ESMR meets the above requirements. Since small size rectal NETs are limited to the submucosal layer without lymphovascular invasion [29], CS-ESMR demonstrated a high R0 resection rate and excellent long-term prognosis. During the procedure of CS-ESMR, the lesion and surrounding tissues were grasped and lifted by a reopenable clip, then the mucosa and submucosal lesion were completely resected by a snare, and even partial intrinsic muscle layer was resected in some cases. In our study, CS-ESMR group had higher pathological R0 resection, with lower intraoperative bleeding and perforation, which indicates CS-ESMR is a safe and effective method. CS-ESMR causes small trauma and recovery rapidly, which means shorter hospital stay. Another advantage of CS-ESMR is taking less time. It is reported that the median operation time of ESD is 25 min (10–49 min) [30]. In our study, the procedure time of CS-ESMR is no more than 5 min, significantly less than that of ESD group. Moreover, compared with ESD, CS-ESMR requires less consumptive material, so the cost is significantly reduced.

EMR with a ligating device (EMR-L) has been reported effective for resection of rectal NETs. Previous studies have shown that the rate of R0 resection is similar to that of ESD [31, 32]. Compared with EMR-L, the rectal NET is completely snared more easily using CS-ESMR method, even for the lesions below the endoscopic screen, since the lesion is grasped and lifted by a reopenable clip and separated from muscularis propria. In addition, economic factor is another advantage for CS-ESMR. Furthermore, the procedure is simple and saves time.

Lee et al. [33] reported that EMR using a dual-channel endoscope is a safe and effective technique for resection of small rectal NETs within the submucosa. By lifting the lesion with grasping forceps to separate it from the muscularis propria and strangling the base with a snare through another channel, this method enables satisfied R0 resection rates similar to ESD. However, dual-channel endoscope is not available in most hospitals. Our technique is enlightened by dual-channel endoscopic therapy, which accomplishes the whole procedure, including lifting the lesion by a reopenable clip, strangling the base, resecting the rectal NETs with a snare, and closing the wound with clips through a single-channel endoscope.

It is reported that underwater EMR is a simple and inexpensive new technique for treatment of rectal NETs, with high R0 resection and low adverse events. However, for flat (not so much protruded) lesions, it may be difficult to achieve R0 resection [34, 35].

Endoscopic full-thickness resection, an ultraminimally invasive endoscopic surgery, is mainly used in the treatment of a tumor of the gastrointestinal tract wall [36[36, 38‒40]. By full-wall resection, endoscopic full-thickness resection has advantages of a high R0 resection rate and a relatively low risk of recurrence for submucosal tumors less than 20 mm [37, 38]. However, since it is an active perforation endoscopic technique, wound closure was required by suture instruments (for example, the over-the-scope clip), which increased cost and time of the procedure.

In our study, 12 cases with R1 resection of rectal NETs had a follow-up period of 20–53 months. Theoretically, positive lateral or vertical margin involvement is a potential risk factor for local recurrence. But there was no case of local recurrence or distal metastasis in this study. It may be attributed to the destruction of the neighboring tumor cells by cauterization during EMR and ESD. Park et al. reported that residual tumor cells were found in only 10% of patients considered for R1 resection [11]. So, for R1 resection patients with no signs of poor prognosis, over-treatment should be avoided, especially for elderly patients [2]. Lymphovascular invasion has been regarded as the most important factor for the spread of cancer cells and lymph node metastasis [39]. But Kang et al. [40] point out that endoscopically resected small rectal NETs, even with lymphovascular invasion, are not absolutely necessary for immediate completion of radical surgery. Of course, longer-term follow-up is still necessary.

However, this was a nonrandomized retrospective study conducted in a single center, and all published data on the subject are predominantly retrospective. Small sample was another limitation of the study. In addition, technical differences may present between the endoscopists who performed the procedures. Furthermore, CS-ESMR works well when the lesion is located in the rectum but is likely to have limitations at the proximal colon due to the outward positioning of the snare. A multicenter trial with more cases and long-time follow-up is required to confirm the value of CS-ESMR in treatment of rectal neuroendocrine tumors.

CS-ESMR may be a safe and effective treatment for rectal NETs with a small size (no more than 10 mm), no invasion of the muscularis propria, and no metastasis. It has many advantages: the procedure is easy, simple, less time-consuming with high pathological R0 resection, low risk of adverse events such as bleeding and perforation, low cost, and rapid recovery.

We would like to acknowledge the contribution of the colleagues of the department of endoscopy and pathology at the First Affiliated Hospital of Dalian Medical University.

The study was conducted in compliance with the Helsinki Declaration and in accordance with local legislation, was approved by the Ethics Committee of the First Affiliated Hospital of Dalian Medical University (Ethics Reference No.: PJ-KS-KY-2021-96X). Written informed consent was obtained from all of the patients or their relatives before the procedure.

The authors have no conflicts of interest to declare.

No funding was obtained for this study.

Shi-Bin Guo and Jian Gong designed the study and have equal contribution. Xin-Tong Jiang and Yang Hu collected and analyzed the data, wrote the manuscript, and have equal contribution. Shi-Bin Guo edited the manuscript. All authors have read and approved the manuscript.

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.