Endoscopic Submucosal Dissection for Gastric Tube Carcinoma After Esophagectomy Contributes to Long-Term Outcomes: A Retrospective Case Series

Background: Gastric tube carcinoma (GTC) after esophagectomy has been observed increasingly in recent years after advanced treatment of esophageal carcinoma. Surgical removal of the reconstructed gastric tube is not usually preferred; however, endoscopic submucosal dissection (ESD) is greatly anticipated to be a promising option. This study investigated the ecacy and safety of ESD for GTC. Methods: This study was designed based on a retrospective survey performed at our single center between 2003 and 2018. Patients with GTC were treated with ESD and followed-up according to the policy of our institution. The curability of ESD was evaluated histologically according to the Japanese gastric cancer treatment guidelines. Patient characteristics, outcomes of ESD procedures, and long-term outcomes were analyzed. Results: A total of 31 patients (2 females; median age, 73 years) with 45 GTC cases were treated with ESD. The mean period from esophagectomy to the diagnosis of GTC was 10.6 years. The only adverse event due to ESD was bleeding (2 patients: 4.4%). No fatal events, such as perforation, occurred. The rates of complete resections and curative resections were 86.7% and 60.0%, respectively. The 3-year and 5-year overall survival rates were 67.6% and 47.7%, respectively. The 3-year and 5-year disease-specic survival rates were 100% and 92.9%, respectively. One patient died of GTC and 14 patients died of other diseases, including ve primary carcinomas. Conclusions: ESD for GTC can be a safe treatment and contribute to positive long-term outcomes. Long-term regular gastroscopy is required for early detection. Screening should be performed before ESD and follow-up should be performed after ESD to prolong overall survival.

attempted to identify the clinical outcomes of ESD for GTC by analyzing our clinical experience with these cases.

Patients
All patients who underwent ESD for GTC after esophagectomy between 2003 and 2018 at the Niigata University Medical and Dental Hospital were recruited. Atrophic gastritis in the gastric tube was diagnosed endoscopically according to the Kimura-Takemoto classi cation [13]. The present study was designed based on a retrospective survey performed at our single center and was conducted as part of a clinical study approved by our Institutional Review Board. This study was also performed in accordance with the Declaration of Helsinki.
ESD procedure ESD was performed by several experts with more than 6 years of experience with the procedure. Patients were sedated by an intravenous injection of propofol or midazolam; their blood pressure, electrocardiography results, oxygen saturation, and bispectral index were monitored during the ESD procedure. All ESD procedures were performed with an upper gastrointestinal endoscope (GIF-Q260J; Olympus Medical Systems, Tokyo, Japan), a standard electrosurgical generator (VIO300D or ICC200; ERBE, Tübingen, Germany), and a Hook knife (KD-260LR; Olympus Medical Systems). Carbon dioxide insu ation was used during the procedure. Mucosal marking around the tumor margin was performed circumferentially with the Hook knife. Glycerol (10% glycerin and 5% fructose) was injected into the submucosa (SM) to elevate the lesion. Bleeding vessels were coagulated using monopolar Coagrasper Hemostatic Forceps (ED-410LR; Olympus Medical Systems). When the tumor was localized on the suture line, the submucosal dissection was performed, starting from the peripheral area and continuing to the suture line connecting the brotic submucosal layer, while paying careful attention to avoiding damage to the muscle layer because the clear submucosal layer is lost in the area of the suture line (Fig. 2). Figure 3 shows a representative case of GTC on the suture line. For severe brosis on the suture line, attaching an ST hood short-type (DH-28GR; Fuji lm, Tokyo, Japan) or clipping using the line method was performed to create effective countertraction and obtain good visualization [14].

Histopathological assessment
The resected specimens were fastened on boards using pins and xed in 10% formalin. Serial-step sections at 2-mm intervals were made after 24 hours, stained with hematoxylin and eosin, and evaluated by pathologists. The tumor size, depth of invasion, lymphovascular invasion, presence of ulceration, horizontal margin involvement, and vertical margin involvement were evaluated.
At our institution, the curability of ESD for GTC was evaluated based on the 2010 Japanese gastric cancer treatment guidelines [15]. Complete resection was de ned as when en bloc resection with tumorfree horizontal and vertical margins was achieved. Next, the curability of the specimens removed with complete resection was evaluated. Curative resection was de ned as when the complete resection specimens were without lymphovascular invasion and t into one of the following categories: a) histologically differentiated-type pT1a, ulceration-negative; tumor size ≤ 3 cm, b) histologically differentiated-type pT1a, ulceration-positive; tumor size ≤ 2 cm, c) histologically undifferentiated-type pT1a, ulceration-negative; or tumor size ≤ 3 cm, d) histologically differentiated-type pT1b (SM1, < 500 µm from the muscularis mucosa). A tumor consisting of components of both differentiated-type and undifferentiated-type carcinomas was classi ed according to the quantitative predominance. Noncurative resection was de ned as when the specimen could not be diagnosed as a curative resection.

Follow-up after ESD
For patients that had a curative resection, an upper endoscopy at annual intervals was performed.
However, for patients that had an incomplete or non-curative resection, an additional repeat ESD or surgical resection was discussed. If it was di cult because of its high invasiveness, then upper endoscopy and computed tomography were carefully performed every 6 months.

Statistics
Patient characteristics, histological results of ESD specimens, and clinical outcomes, including procedurerelated outcomes, clinical course, and long-term outcomes, were analyzed. Regarding patients' demographics and histological ndings, continuous variables are expressed as median and range; noncontinuous data are expressed as a percentage. Kaplan-Meier analyses were used to estimate the cumulative survival of patients. Statistical analyses were performed using Statistical Package for Social Science (SPSS) version 24 (IBM SPSS Inc., Chicago, IL, USA).

Results
Patient characteristics and ESD procedure-related outcomes Patient characteristics and procedure-related outcomes are shown in Table 1. A total of 31 consecutive patients (29 men and 2 women) with 45 GTC cases were treated using ESD. The median age of the patients was 73 years (range, 58-84 years) at the time of ESD. Six patients had multiple lesions with synchronous occurrence, and nine patients had multiple lesions with metachronous occurrence. The median period from esophagectomy to ESD after the initial GTC was 10.6 years (range, 0.8-18.2 years).
The route of reconstruction was retrosternal for 16 cases and the posterior mediastinum for 15 cases. In our series, all patients with GTC had Helicobacter pylori-related atrophic gastritis.

Clinical and histopathological ndings
Histopathological ndings are shown in Table 2. In terms of tumor location, there were 26 lesions in the lower gastric tube, 17 lesions in the middle gastric tube, and 2 lesions in the upper gastric tube. Four lesions were on the suture line. Macroscopically, 34 lesions were diagnosed as 0-IIc (slightly depressed type), 10 lesions were diagnosed as 0-IIa (slightly elevated type), and one lesion was diagnosed as 0-I (elevated type). The median tumor size was 17.5 mm (range, 5-53 mm), with 33 differentiated, 2 undifferentiated, and 10 mixed-type adenocarcinomas. The depth of tumor invasion was pT1a (mucosa [M]) in 29 lesions, pT1b (SM1: <500 µm below the muscularis mucosa in the SM) in 3 lesions, pT1b (SM2: 500 µm or deeper invasion from the SM) in 12 lesions, and pT2 (muscularis propria [MP]) in one lesion. Lymphovascular invasion was observed with seven lesions. The horizontal margin was positive in one lesion and the vertical margin was positive in ve lesions. The positive horizontal margin was misdiagnosed when there was a poorly differentiated lesion. The positive vertical margin was diagnosed because of its invasion deeper than SM2. Of the 15 patients with non-curative resection, one had an undifferentiated mucosal lesion, ve had positive vertical margins, one had only a positive horizontal margin, and eight had negative tumor margins with lymphovascular invasion or invasion more than SM2. All were followed-up without additional surgery. The patient with an undifferentiated mucosal lesion larger than 20 mm was alive. The ve patients with positive vertical margins were divided into four patients with SM2 invasion and one patient with MP invasion. Two patients with SM2 invasion were alive, including one patient who had local recurrence and underwent additional radiation. The other two patients with SM2 invasion died of intrahepatic cholangiocarcinoma and heart failure, respectively. The patient with MP invasion died of local recurrence, despite chemotherapy (5-uorouracil and cisplatin) after ESD. The one patient with only a positive horizontal margin died of pancreatic cancer. Three patients among the eight patients who had negative tumor margins with lymphovascular invasion or invasion more than SM2 were alive, including one patient who was treated with curative ESD for metachronous lesions after non-curative ESD. The other ve patients died of another disease (pneumonia, 2; hypopharyngeal cancer, 1; malignant lymphoma, 1; heart failure, 1). The 3-year and 5-year overall survival rates were 67.6% and 47.7%, respectively. The 3-year and 5-year disease-speci c survival rates were 100% and 92.9%, respectively (Fig. 5). Only one patient died of GTC resected with non-curative ESD. Of the 14 deaths due to other causes, 5 were other primary carcinomas (hypopharyngeal cancer, 2; cervical esophageal cancer, 1; pancreatic cancer, 1; malignant lymphoma, 1).

Discussion
Surgical resection of the reconstructed gastric tube for GTC is invasive and is associated with high mortality [5] [16]. ESD, which is a minimally invasive treatment for early gastric cancer, has an important role in the treatment of GTC. Some studies have already reported the long-term outcomes of ESD for GTC [8] [11] [17] [18]. However, all of them were designed based on a retrospective survey at a single center. Although a multicenter prospective study is desirable, it is important to collect clinical data from each institution, because GTC is not frequently encountered. Our clinical data included a comparative number of cases (31 patients and 45 lesions) and comparatively long follow-up (median, 50 months). Therefore, these results can be considered valuable.
Some lesions that were not indicated for ESD according to the Japanese gastric cancer guidelines [15] were included in this study because of their surgical complications. This study found that the rate of complete ESD resections for GTC after esophagectomy was 86.7%. Lesions with incomplete resection included one lesion with a positive lateral margin and ve lesions with positive vertical margins. The reason for the positive lateral margin was misdiagnosis of the tumor margin because of undifferentiated adenocarcinoma. The size of this lesion was larger than 40 mm; therefore, ESD was not indicated. We considered that several negative biopsy samples from outside the lesion should have been con rmed before ESD. This patient died of pancreatic cancer 30 months after ESD without GTC recurrence.
All ve lesions with positive vertical margins had deep invasion to the SM or MP. The patient with invasion to the MP had local recurrence and died despite chemotherapy. One patient with invasion to the SM also had local recurrence and received additional radiation. Because the follow-up term after radiation was short in this case, remnant recurrence is possible. There have been no reports on the e cacy of chemotherapy or radiation for local recurrence of GTC after ESD. Although total reconstruction gastrectomy has been considered the standard treatment for local massive recurrence after ESD, surgery is not usually preferred because of the high risk of complications, such as leakage and pneumonia [5]. Thoracoscopic and endoscopic cooperative surgery have been reported as minimally invasive [19], and the development of other surgical methods with less invasive techniques is expected for advanced GTC.
Only one patient died of GTC during this investigation. The disease-speci c survival rate was more than 92.9%, which was considered a permissible level. However, 14 deaths due to other causes were con rmed, and the 5-year overall survival rate was 47.7%. Because patients were elderly (mean age, 73 years) and already had esophageal and gastric cancer, they were considered at high risk for other primary carcinomas. Moreover, they may have had respiratory and cardiovascular diseases due to smoking, diabetes mellites, or hyperlipidemia. Therefore, we should screen for other diseases before ESD and perform careful follow-up after ESD. ESD is less invasive than surgery for patients with GTC. Therefore, ESD should be considered the rst choice if complete resection is possible.
Although ESD for GTC is safe and effective [8] [11], it is more di cult to resect lesions than early gastric cancer without reconstruction. The gastric tube has limited working space, food retention, and uid pooling due to notable deformity of the stomach and severe brosis on the suture line after surgical reconstruction [12]. Therefore, ESD for GTC should be performed by fully trained endoscopists. When there is a lesion on the suture line, severe brosis of the submucosal layer, and remaining surgical staples, attaching the ST hood short-type and traction methods, such as clipping with the line method, are effective for obtaining good endoscopic visualization [14] [20] [21]. When a lesion is submerged in uid or blood, we should consider positioning the patient in the opposite direction. We consider ESD for GTC a safe treatment, because adverse events (delayed bleeding) occurred in only two cases. However, careful attention to distinctive complications, such as precordial skin burns after ESD in cases involving the retrosternal route, is required [22].
All patients had Helicobacter pylori-related atrophic gastritis. Because they were at high risk for gastric cancer, it is important to detect GTC during the early stage [23]. Furthermore, we must stay aware of metachronous occurrences after curative ESD. Recent remarkable advances in magnifying endoscopy and narrow band imaging systems have allowed the development of early treatments for gastric carcinomas [24] [25] [26]. Careful observation is needed to manage worsening conditions in the gastric tube, such as deformity of the stomach, bleeding, and uid pooling. The period from esophagectomy to GTC was 10.6 years in this study; therefore, regular long-term follow up is necessary.
This study had several limitations. First, our observations are based on an analysis of retrospective data from a single center; therefore, treatments were not based on any clear protocols. Second, the analysis was performed during a long period; therefore, the skill of the endoscopist who performed the diagnosis and ESD procedure for GTC gradually improved, which might have affected the results.

Conclusions
In conclusion, ESD for GTC can be a safe treatment and contribute to long-term outcomes. Because patients with GTC are at high risk for other primary carcinomas or comorbidities, we should perform screening before ESD and follow-up after ESD to prolong the overall survival. The study was approved by the Institutional Review Board at Niigata University.

Consent for publication
Not applicable.

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

Competing interests
The authors declare that they have no competing interests.

Funding
There are no funding sources to declare.
Author's contributions SH, HS, KM, KT, and MT collected data from patient charts and contributed to manuscript writing and analyses. SH, HS, KM, KT, MT, and MK contributed to performing ESD. JY, HI, and ST supervised the study and contributed to revising the manuscript. The authors read and approved the nal manuscript.