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DOI: 10.1055/a-1936-9073
An extra 1-cm margin during endoscopic submucosal dissection can control subsquamous tumor extension of esophagogastric junction adenocarcinoma
Introduction
The incidence of esophagogastric junction (EGJ) adenocarcinoma has increased during recent decades, especially in Western countries. This is mainly related to the increasing prevalence of gastroesophageal reflux disease and obesity, and the decreasing prevalence of Helicobacter pylori infection. The incidence of EGJ adenocarcinoma is also increasing in Eastern countries, including Japan, and is expected to continue doing so for similar reasons. Endoscopic submucosal dissection (ESD) is a minimally invasive and curative treatment for superficial gastrointestinal cancer, as it provides a high rate of en bloc resection, regardless of lesion size, and facilitates accurate histopathological diagnosis [1]. Several retrospective studies have recently indicated that ESD is safe and effective for EGJ adenocarcinomas [2] [3] [4] [5] [6].
EGJ adenocarcinomas can extend laterally and invade the neighboring normal esophageal squamous epithelium; this is known as subsquamous tumor extension (STE) [7]. Because STE may not be observable at the esophageal epithelium, it is difficult to accurately define the proximal tumor margin during ESD for EGJ adenocarcinomas; this can lead to postoperative positive lateral margins [3] [5] [6]. In a previous study, we retrospectively showed that an extra 1-cm safety margin achieved 100 % negative lateral margins during ESD for EGJ adenocarcinomas, even when the STE was < 7 mm [4].
In response to the lack of prospectively collected data, the present prospective feasibility study aimed to evaluate whether considering an extra 1-cm safety margin was effective in preventing positive lateral margins during ESD for EGJ adenocarcinomas.
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Patients and methods
Patients
The protocol for this single-center prospective feasibility study was approved by the ethics committee of the Osaka City University Hospital (approval: 3064) and was registered in the University Hospital Medical Network Clinical Trial Registry (UMIN000017120). All patients provided written informed consent before enrollment. The inclusion criteria comprised: (1) an EGJ tumor diagnosed as Siewert’s type II classification; (2) pathological diagnosis of definite or suspected adenocarcinoma; (3) cT1a-M (invasion limited to the muscularis mucosae); (4) no signs of lymph node or distant metastasis; (5) age > 20 years; and (6) provided written informed consent. The exclusion criteria comprised: (1) no informed consent; (2) possibility of pregnancy or lactation; (3) severe mental illness; (4) continuous systemic steroid use; (5) active bacterial or fungal infection; (6) cardiac infarction or unstable angina pectoris within the last 3 months; (7) uncontrollable hypertension or diabetes mellitus; (8) pulmonary disease requiring oxygen; or (9) judged to be ineligible at the discretion of a study investigator. The sample size was, based on our previous experience, calculated as per the number of patients that we could feasibly enroll during the study period.
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Outcome measures
The primary outcome of interest was the rate of complete resection (R0 resection rate), i. e., an en bloc resection with histologically cancer-free margins. The secondary outcomes of interest were the treatment outcomes (curative resection and adverse events [AEs]) and the incidence, extension length, and preoperative diagnostic rate of the STE. Preoperative diagnostic rate was defined as accuracy rate. We determined that STE could be diagnosed if the presence and length of STE were consistent with preoperative endoscopic diagnosis.
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Defining STE and the 1-cm safety margin
Preoperative endoscopy was performed using an Evis Lucera Elite System (Olympus, Tokyo, Japan) with a magnifying upper gastrointestinal endoscope (GIF-H260Z; Olympus). We delineated the lesion’s area via magnifying endoscopy with narrow-band imaging (NBI) ([Fig. 1a]). In all cases, the presence of STE was determined on the basis of the following modalities: 1) white light endoscopy (WLE) for visualizing a slight elevation ([Fig. 1b]) [4]; 2) non-magnifying endoscopy with NBI for visualizing a pale brownish area ([Fig. 1c]) [5]; 3) magnifying endoscopy with NBI for visualizing an irregular microvascular pattern under the normal squamous epithelium ([Fig. 1d]) [7]; and 4) magnifying endoscopy with acetic acid application for visualizing a small white sign ([Fig. 1e]) [8].
The marking dots were generally positioned at least 2 mm outside the tumor margin. However, these dots were placed 1cm away from the oral side of any suspected STE or 1 cm away from the squamous-columnar junction in cases without endoscopic signs of STE. The 1-cm safety margin was measured using a 1-cm marking on the tip of the device’s sheath ([Fig. 1f], [Fig. 1g], [Fig. 1h]). ESD was performed as previously reported [4]. A flush knife (Flush knife, DK2620JN; Fujifilm Medical, Tokyo, Japan) was used as the main electrosurgical knife.
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Pathological examination
The fresh and post-formalin fixation specimens were photographed with a scale. The resected specimens were cut into 2-mm slices from the oral side to the anal side, and each slice was evaluated to determine the histological type, size, depth of invasion, lateral and vertical margins, and lymphovascular invasion status of the EGJ tumor. In cases with STE, the length of the extension was determined with a scale using microscopy, and the lesion was then mapped on the photographs of the fresh specimen. The length of the STE was based on the photograph of the fresh specimen. In the same case as described in [Fig. 1], an EGJ adenocarcinoma arising from the Barrett’s esophagus was defined as a Barrett’s adenocarcinoma and was identified from the presence of esophageal glands at the anal side of the carcinoma ([Fig. 2]).
Gastroesophageal reflux disease or proton pump inhibitor (PPI) use sometimes makes it difficult to assume that double muscularis mucosa and columnar epithelial island. Thus, in this study, esophageal glands on the anal side of the lesion were considered as an accurate definition of Barrett’s adenocarcinoma. All adenocarcinomas that were not considered as Barrett’s adenocarcinomas were classified as non-Barrett’s adenocarcinomas.
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Definitions
PPI intake was defined as taking PPI before endoscopy. It was defined as Helicobacter pylori infection, if any following test was positive, the urea breath test, serum anti-Helicobacter pylori body titer, and stool antigen test. The presence of circular Barrett mucosa extending longitudinally for 3 cm or more was defined as long-segment Barrett’s esophagus (LSBE), and the others were defined as short-segment Barrett’s esophagus (SSBE) [9]. Gastric atrophy was definition based on Kimura-Takemoto Classification. Mild atrophy was defined as C-1 and C-2, moderate was as C-3 and O-1, severe was O-2 and O-3, and no was as C0.
An en bloc resection was defined as the resection of a single specimen that included all the marking dots. Complete resection was defined as an en bloc resection with histologically cancer-free margins. Curative resection of a Barrett’s adenocarcinoma was defined as the complete resection of a differentiated adenocarcinoma with an invasion depth of T1a-DMM (deep muscularis mucosa) and no lymphovascular invasion, as these patients have a very low risk of metastasis [10]. Curative resection of a non-Barrett’s adenocarcinoma was defined as the complete resection of an adenocarcinoma with an invasion depth of < 500 µm from the muscularis mucosa, no lymphovascular invasion, and a poorly differentiated component [11].
Perforation was defined as an endoscopically visible hole in the esophageal or gastric wall that exposed the mediastinal or peritoneal cavity. Delayed bleeding was defined as bleeding with hematemesis or melena that required endoscopic reintervention or transfusion after the ESD procedure. Esophageal stricture was defined as diameter reduction that prevented the passage of a standard 9.2-mm endoscope at the follow-up endoscopic examination (1 to 2 months after ESD).
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Statistical analyses
Continuous variables were reported as median (range) and analyzed using the Mann-Whitney U test, categorical variables were reported as number (percentage) and analyzed using Fisher’s exact test. Differences were considered statistically significant at P < 0.05. All statistical analyses were performed using EZR software (version 1.35; Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R software (The R Foundation for Statistical Computing, Vienna, Austria).
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Results
Clinical characteristics
Fourteen patients presented with a suspected EGJ adenocarcinoma between September 2015 and December 2018. One patient with histologically no cancer and another in whom an evaluation for STE was impossible, because the specimen was not cut from the oral side to the anal side, were excluded. Thus, 12 patients ([Table 1]), five of whom were histologically diagnosed with a Barrett’s adenocarcinoma, were enrolled in this study.
|
Total |
Barrett's adenocarcinoma |
Non-Barrett’s adenocarcinoma |
|
|
n = 12 |
n = 5 |
n = 7 |
|
|
Age, years, median (range) |
64 (50 – 80) |
63 (50 – 76) |
64 (60 – 80) |
|
Sex, male/ female, n |
9/3 |
5/0 |
4/3 |
|
ASA PS, 1/2/3, n |
2/8/2 |
5/0/0 |
2/3/2 |
|
Medication, PPI, n |
5 |
1 |
4 |
|
Helicobacter pylori infection[1], n |
3 |
0 |
3 |
|
SSBE/LSBE, n |
8/0 |
5/0 |
3/0 |
|
Gastric atrophy, no/mild/moderate, n |
6/2/4 |
5/0/0 |
1/2/4 |
|
Tumor size, mm, median (range) |
28 (5.0 – 53) |
28 (13.0 – 37) |
28(5.0 – 53) |
|
Circumference, %, median (range) |
29.2 (8.3 – 91.7) |
16.7 (8.3 – 58.3) |
33.3 (8.3 – 91.7) |
|
Macroscopic appearance, elevated/flat/depressed, n |
4/3/5 |
1/1/3 |
3/2/2 |
|
Depth of cancer, mucosa/submucosa, n |
8/4 |
4/1 |
4/3 |
ASA PS, American Society of Anesthesiologists Physical Status; PPI, proton pump inhibitor; SSBE, short-segment Barrett’s epithelium; LSBE, long-segment Barrett’s epithelium.
1 Status of Helicobacter pylori in two cases was not investigated.
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Primary endpoints
The complete resection rate was 91.7 % (95 % confidence interval [CI]: 62.5–100.6) (11/12) ([Table 2]). The remaining patient with a positive vertical margin had an EGJ adenocarcinoma with massive submucosal invasion. The rate of negative lateral margins was 100 % (95 % CI: 71.8–103.9), and all lesions were laterally included within the 1-cm safety margin.
ESD, endoscopic submucosal dissection; STE, subsquamous tumor extension.
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Presence of STE
STE was observed in 75 % of patients (9/12; [Table 2]). The median length of the STE was 5.7 mm (range: 1–24.8 mm; [Table 2]). The preoperative diagnostic rates for the four modalities are shown in [Fig. 3]. Magnifying endoscopy with acetic acid application identified STE in 100 % (5/5) of patients with a Barrett’s adenocarcinoma but in only 28.6 % (2/7) of patients with a non-Barrett’s adenocarcinoma. The preoperative diagnostic rates for STE of EGJ adenocarcinomas were 66.7 % using all four modalities, 41.7 % using WLE, 58.3 % using magnifying endoscopy with NBI, and 58.3 % using magnifying endoscopy with acetic acid application. Four patients were misdiagnosed during preoperative endoscopy ([Fig. 4]), all with non-Barret’s adenocarcinoma. Sensitivity and specificity rates for STE of EGJ adenocarcinomas were both 66.7 % using all four modalities ([Table 3]). Histological type was well-differentiated adenocarcinoma in three patients and moderately in one patient. In all cases, invasion depth of STE was the lamina propria mucosa.
CI, confidence interval; EGJ, esophagogastric junction; NBI, narrow-band imaging; NPV, negative predictive value; PPV, positive predictive value; STE, subsquamous tumor extension
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Clinical outcomes
The curative resection rate was 66.7 % (8/12). Two patients had an esophageal stricture. There was no bleeding or perforation in any of the patients ([Table 2]).
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Discussion
This prospective feasibility study revealed that an extra 1-cm safety margin is safe and helpful for achieving negative lateral margins during an ESD for EGJ adenocarcinomas. Despite the difficulty in accurately diagnosing STE preoperatively, all lesions were included within the 1-cm margin. To the best of our knowledge, this is the first prospective study in this setting.
Our findings agree with the previously reported R0 resection rates of 79 % to 89.8 % and AE rates of 3.9 % to 27.3 % after an ESD for EGJ adenocarcinomas [2] [3] [5] [6]. However, these studies included cases with positive lateral margins due to STE (7.5%–18.0 % of cases) [2] [3] [5] [6]. A multicenter retrospective study also revealed a positive lateral margin rate of 7.5 % (24/321 patients) [6]. These patients may require additional surgery and may have an increased risk of local recurrence [5] [8]. Because positive lateral margin has often been reported only on the oral side, we considered it important to address such an incomplete resection. Therefore, we evaluated the STE of the oral side, and we did not identify any patients with positive lateral margins after we included an extra 1-cm safety margin during ESD for EGJ adenocarcinomas, and all lesions were included within this 1-cm margin, regardless of the STE status.
Magnifying endoscopy with NBI and acetic acid application is reportedly useful for diagnosing STE [7] [8] [10]. A questionnaire survey revealed that the rates of STE diagnosis were 55 % (97/175 patients) with WLE and 60 % (42/70 cases) with magnifying endoscopy with NBI [8]. In another study, review of endoscopic images after histological examination of ESD specimens revealed STE diagnostic rates of 50 % (5/10 patients) with WLE, 43 % (3/7 patients) with magnifying endoscopy and NBI, and 100 % (6/6 patients) with magnifying endoscopy and acetic acid application [8].
The diagnostic rates in the present study were similar to those reported for WLE and magnifying endoscopy with NBI previously; however, the diagnostic rate for acetic acid application was lower than that in a previous report. This might be caused by the difference in the method of diagnosis. In a previous report, the endoscopic images of STE were reviewed retrospectively only in cases that yielded pathological results after ESD [8]. This study revealed that magnifying endoscopy with acetic acid application had higher accuracy in diagnosing STE of Barrett’s adenocarcinomas than that of non-Barrett’s adenocarcinomas, with the shorter length of STE of non-Barrett’s adenocarcinoma being a possible explanation for the reduced accuracy. The median lengths of STE of Barrett’s adenocarcinoma and non-Barrett’s adenocarcinoma were 6.2 (5.7–21) mm and 3.6 (1.0–24.8) mm, and in two patients with non-Barrett’s adenocarcinoma, the lengths of STEs were not detected endoscopically. In addition, because PPI use and preceding biopsy are known to occasionally result in non-cancerous squamous epithelium covering the existing tumor [12], they might contribute to a difference in diagnosis.
Nonetheless, our study is unique in that we prospectively applied the four imaging modalities in all patients, which revealed that magnifying endoscopy with acetic acid application was more accurate for diagnosing STE of Barrett’s adenocarcinomas than for diagnosing the STE of non-Barrett’s adenocarcinomas.
This study has several strengths, including its prospective design and the use of all four imaging modalities for all patients, which allowed us to calculate each modality’s diagnostic ability for STE. Another strength includes the accurate measurement of the 1-cm margin using a mark that was placed 1cm from the tip of the device’s sheath. Finally, it is notable that the length of the STE was effectively evaluated using a photograph of the fresh specimen, based on the positional relationship between the STE and the 1-cm safety margin.
The present study also has several limitations, the first being its small single-center design; hence, there is a need for larger multicenter studies that will validate our findings. Secondary, we did not evaluate long-term outcomes. Further well-designed studies are needed to address these issues.
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Conclusions
Our findings suggest that an extra 1-cm safety margin is useful for achieving complete resection of EGJ adenocarcinomas during ESD, warranting validation in a large cohort study.
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Competing interests
The authors declare that they have no conflict of interest.
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References
- 1 Nagami Y, Ominami M, Otani K. et al. Endoscopic submucosal dissection for adenocarcinomas of the esophagogastric junction. Digestion 2018; 97: 38-44
- 2 Yoshinaga S, Gotoda T, Kusano C. et al. Clinical impact of endoscopic submucosal dissection for superficial adenocarcinoma located at the esophagogastric junction. Gastrointest Endosc 2008; 67: 202-209
- 3 Hoteya S, Matsui A, Iizuka T. et al. Comparison of the clinicopathological characteristics and results of endoscopic submucosal dissection for esophagogastric junction and non-junctional cancers. Digestion 2013; 87: 29-33
- 4 Nagami Y, Machida H, Shiba M. et al. Clinical efficacy of endoscopic submucosal dissection for adenocarcinomas of the esophagogastric junction. Endosc Int Open 2014; 2: E15-E20
- 5 Hobel S, Dautel P, Baumbach R. et al. Single center experience of endoscopic submucosal dissection (ESD) in early Barrett's adenocarcinoma. Surg Endosc 2015; 29: 1591-1597
- 6 Abe S, Ishihara R, Takahashi H. et al. Long-term outcomes of endoscopic resection and metachronous cancer after endoscopic resection for adenocarcinoma of the esophagogastric junction in Japan. Gastrointest Endosc 2019; 89: 1120-1128
- 7 Goda K, Singh R, Oda I. et al. Current status of endoscopic diagnosis and treatment of superficial Barrett's adenocarcinoma in Asia-Pacific region. Dig Endosc 2013; 25: 146-150
- 8 Yamagata T, Hirasawa D, Fujita N. et al. Efficacy of acetic acid-spraying method in diagnosing extension of Barrettʼs cancer under the squamous epithelium. Dig Endosc 2012; 24: 309-314
- 9 Japan Esophageal Society. Japanese Classification of Esophageal Cancer, 11th Edition: part I. Esophagus 2017; 14: 1-36
- 10 Ishihara R, Arima M, Iizuka T. et al. Endoscopic submucosal dissection/endoscopic mucosal resection guidelines for esophageal cancer. Dig Endosc 2020; 32: 452-493
- 11 Ishihara R, Oyama T, Abe S. et al. Risk of metastasis in adenocarcinoma of the esophagus: a multicenter retrospective study in a Japanese population. J Gastroenterol 2017; 52: 800-808
- 12 Takubo K, Vieth M, Aida J. et al. Histopathological diagnosis of adenocarcinoma in Barrett's esophagus. Dig Endosc 2014; 26: 322-330
Corresponding author
Publication History
Received: 19 February 2022
Accepted after revision: 01 September 2022
Accepted Manuscript online:
05 September 2022
Article published online:
15 November 2022
© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
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References
- 1 Nagami Y, Ominami M, Otani K. et al. Endoscopic submucosal dissection for adenocarcinomas of the esophagogastric junction. Digestion 2018; 97: 38-44
- 2 Yoshinaga S, Gotoda T, Kusano C. et al. Clinical impact of endoscopic submucosal dissection for superficial adenocarcinoma located at the esophagogastric junction. Gastrointest Endosc 2008; 67: 202-209
- 3 Hoteya S, Matsui A, Iizuka T. et al. Comparison of the clinicopathological characteristics and results of endoscopic submucosal dissection for esophagogastric junction and non-junctional cancers. Digestion 2013; 87: 29-33
- 4 Nagami Y, Machida H, Shiba M. et al. Clinical efficacy of endoscopic submucosal dissection for adenocarcinomas of the esophagogastric junction. Endosc Int Open 2014; 2: E15-E20
- 5 Hobel S, Dautel P, Baumbach R. et al. Single center experience of endoscopic submucosal dissection (ESD) in early Barrett's adenocarcinoma. Surg Endosc 2015; 29: 1591-1597
- 6 Abe S, Ishihara R, Takahashi H. et al. Long-term outcomes of endoscopic resection and metachronous cancer after endoscopic resection for adenocarcinoma of the esophagogastric junction in Japan. Gastrointest Endosc 2019; 89: 1120-1128
- 7 Goda K, Singh R, Oda I. et al. Current status of endoscopic diagnosis and treatment of superficial Barrett's adenocarcinoma in Asia-Pacific region. Dig Endosc 2013; 25: 146-150
- 8 Yamagata T, Hirasawa D, Fujita N. et al. Efficacy of acetic acid-spraying method in diagnosing extension of Barrettʼs cancer under the squamous epithelium. Dig Endosc 2012; 24: 309-314
- 9 Japan Esophageal Society. Japanese Classification of Esophageal Cancer, 11th Edition: part I. Esophagus 2017; 14: 1-36
- 10 Ishihara R, Arima M, Iizuka T. et al. Endoscopic submucosal dissection/endoscopic mucosal resection guidelines for esophageal cancer. Dig Endosc 2020; 32: 452-493
- 11 Ishihara R, Oyama T, Abe S. et al. Risk of metastasis in adenocarcinoma of the esophagus: a multicenter retrospective study in a Japanese population. J Gastroenterol 2017; 52: 800-808
- 12 Takubo K, Vieth M, Aida J. et al. Histopathological diagnosis of adenocarcinoma in Barrett's esophagus. Dig Endosc 2014; 26: 322-330