Indexed In : Science Citation Index Expanded(SCIE), MEDLINE,
Pubmed/Pubmed Central, Elsevier Bibliographic, Google Scholar,
Databases(Scopus & Embase), KCI, KoreaMed, DOAJ
Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE
| Yong Chan Lee |
Professor of Medicine Director, Gastrointestinal Research Laboratory Veterans Affairs Medical Center, Univ. California San Francisco San Francisco, USA |
| Jong Pil Im | Seoul National University College of Medicine, Seoul, Korea |
| Robert S. Bresalier | University of Texas M. D. Anderson Cancer Center, Houston, USA |
| Steven H. Itzkowitz | Mount Sinai Medical Center, NY, USA |
All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
The remaining articles are usually sent to two reviewers. It would be very helpful if you could suggest a selection of reviewers and include their contact details. We may not always use the reviewers you recommend, but suggesting reviewers will make our reviewer database much richer; in the end, everyone will benefit. We reserve the right to return manuscripts in which no reviewers are suggested.
The final responsibility for the decision to accept or reject lies with the editors. In many cases, papers may be rejected despite favorable reviews because of editorial policy or a lack of space. The editor retains the right to determine publication priorities, the style of the paper, and to request, if necessary, that the material submitted be shortened for publication.
Split Viewer
Masanori Ito1 
, Shinji Tanaka2 , Kazuaki Chayama3
Correspondence to: Masanori Ito
ORCID https://orcid.org/0000-0002-8218-9059
E-mail maito@hiroshima-u.ac.jp
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Gut Liver 2021;15(3):338-345. https://doi.org/10.5009/gnl19418
Published online April 24, 2020, Published date May 15, 2021
Copyright © Gut and Liver.
The prevalence of gastric cancer after eradication (GCAE) is increasing dramatically in Japan. GCAE has characteristic features, and we must understand these features in endoscopic examinations. Differentiated cancer types were frequently found after eradication and included characteristic endoscopic features such as reddish depression (RD). However, benign RD can be difficult to distinguish from gastric cancer because of histological alterations in the surface structures (nonneoplastic epithelium or epithelium with low-grade atypia [ELA]) as well as multiple appearances of RD. Recently, we clarified similar alterations in genetic mutations between ELA and gastric cancer, suggesting that ELA is derived from gastric cancer. Clinically, submucosal invasive cancer was frequently found in patients after eradication therapy even if they received annual endoscopic surveillance. We can improve the diagnostic ability using image-enhanced endoscopy with magnified observation.
Keywords: Stomach neoplasms, Eradication therapy, Helicobacter pylori, Reddish depression, Epithelium with low-grade atypia
Gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide, accounting for nearly three-quarters a million deaths annually.1
In 2013, the Japanese government approved that national health insurance can cover
Along with the increase in eradication therapy, mortality from gastric cancer is now decreasing gradually. However, eradication therapy has caused another crucial problem, namely the problem of gastric cancer after eradication therapy (GCAE). Gastric cancer develops in some patients even after successful eradication therapy, and recent studies have been clarifying its characteristic features. In the present review, we examine some problems around GCAE and propose effective clinical practices for the diagnosis and treatment for GCAE.
Many studies have indicated that eradication therapy for
First of all, we have to understand the pathogenesis of GCAE. Did GCAE newly develop after eradication therapy or was it already existing before eradication therapy? Clinical features in cases with GCAE, especially the gender of patients and tumor location in the stomach, were reported to be similar to those with conventional gastric cancer (with
We have to recognize that GCAE revealed representative endoscopic feature, namely a superficial depressed feature.16,21-23 In 2005, we reported the morphological alterations of gastric tumors after eradication therapy of
The true pathogenesis of tumor flattering is still unknown. We speculated that a decreased level of serum gastrin may be a reason for this phenomenon. Gastrin is a growth factor for epithelial cells,25,26 and we previously detected the gastric receptor in gastric epithelial cells and gastric cancer cells.27,28 Serum gastrin levels were decreased by eradication therapy in patients with atrophic gastritis;29 therefore, proliferating signals through the gastrin receptor may decline in response to the eradication system followed by flattering the tumor tissue.30 Decreases in cytokine levels in response to eradication therapy may be another reason for the inhibition of tumor growth and flattering of the tumor tissue.31,32
We further found that endoscopic alteration was closely linked to histological features. After eradication, a normal or mild-atypical epithelium appeared on the surface of gastric tumor tissues just covering the tumor tissue.30 After eradication, we found almost normal epithelium on the surface of adenoma tissue and slightly atypical epithelium on the surface of gastric cancer tissue.30 This may be a reason why gastric tumors become indistinct after eradication therapy.
In cases with gastric adenoma, Gotoda
On the other hand, we could find slightly atypical (not completely normal) epithelium covering gastric cancer tissue (Fig. 1). We named this feature as epithelium with low-grade atypia (ELA) and defined it according to the following criteria: (1) ELA must lie on the surface of gastric cancer tissue; (2) ELA must be columnar epithelium with spindle or oval nuclei; (3) nuclear polarity must be present in the ELA; and (4) the ELA must be separated and distinguished from the surrounding nonneoplastic mucosa.36 Previously, we have presented that ELA appeared not only on gastric cancer after
Furthermore, we examined the pathogenesis of this epithelium. Small numbers of nonneoplastic glands were detected within the gastric cancer tissue, and these glands were recognized as nonneoplastic without difficulty. However, we also detected another type of epithelium termed ELA, which was different from both nonneoplastic epithelium and tumor tissue, on the tumor surface. It should be clarified whether ELA comes from normal tissue (indicating that ELA is from regenerative changes from nonneoplastic epithelium) or tumor tissue (where ELA comes from the re-differentiation of gastric cancer by eradication). We extracted DNA from gastric cancer tissue, normal gastric mucosa, and ELA by laser-microdissection.40 We used the NCC Oncopanel (National Cancer Center and Sysmex Cancer Innovation Laboratory, Tokyo, Japan) and examined gene alterations for 125 genes using deep-sequencing.41 The mutation profile of ELA was quite similar to that in gastric cancer tissue, suggesting that ELA was derived from gastric cancer tissue, and gastric cancer tissue can be histologically restored by eradication therapy. ELA was not from normal epithelium contaminating the tumor tissue but from gastric cancer tissue. In animal model, adenocarcinoma tissue can be restored by genetic manipulation.42 This may be a first report describing that human gastric cancer tissue can be histologically restored by eradication therapy.
Clinically, this phenomenon is supposed to evoke the difficulty in endoscopic diagnosis of GCAE as well as the gastric adenomas described above. Previously, we reported that submucosal invasive GCAE showed extensive ELA on the surface of gastric cancer tissue in patients receiving annual endoscopic examination after eradication.36 The appearance of ELA may interrupt the detection of GCAE in earlier stages, as a result these tumors are likely to be detected at more advanced stages. Moreover, it has been reported that there is a noticeably increased prevalence of GCAE showing submucosal invasion compared with that for
Thereafter, we retrospectively analyzed the clinicopathological characteristics of GCAE patients who received annual endoscopic examinations after eradication, and compared incident of gastric cancer with submucosal invasion between GCAE and controls. The prevalence of early gastric cancer with submucosal invasion was significantly higher in the eradicated group than in the control group after propensity score matching (16.0% vs 4.9%, respectively; p=0.021) (Table 1).45,46 We could not detect a statistically significant difference in any features, including sex, age, previous cancer history, location, macroscopic type, and tumor size between two groups.46
For accurate endoscopic examination in patients with successful eradication, we have to understand that the typical endoscopic features of GCAE were reddish depression (RD). Diffuse redness, which is a typical feature of
First, we tried to diagnose malignant RD lesions (RDLs) with white-light imaging (WLI) based on reports described by Yao
In the M-NBI group, biopsy was performed in 21 patients (20%), and nine were diagnosed as adenocarcinoma. Biopsy was required in fewer patients, and the positive predictive value of biopsy was statistically higher in the M-NBI group than in the WLI group (Table 2).52 These findings suggested that M-NBI demonstrated significantly superior diagnostic efficacy with respect to RDL to select malignant RD endoscopically. However, it may be difficult to diagnose these lesions only by WLI at present. For accurate diagnosis, we reported the usefulness of magnifying NBI methods. Recently, several reports from Japan described the usefulness of image-enhanced endoscopy in the diagnosis of GCAE.55-57
The final goal of our strategy was to diminish mortality from gastric cancer. Primary prevention by eradication therapy may be the best way to achieve our goal. The Japanese Society of Helicobacter Research demonstrated a total care program against
Risk stratification should be helpful for supplying effective surveillance of patients after eradication. Atrophic gastritis in the corpus or intestinal metaplasia is considered to be a risk factor for the development of GCAE.59-64 In 2015, the Kyoto Global Consensus Conference on
In Japan, test-and-treat for
No potential conflict of interest relevant to this article was reported.
Fig. 1.The patient was a woman in her 60s. (A) A reddish depressed lesion (arrows) was observed on the lesser curvature of the gastric corpus. (B) Histologically, low-grade atypia (between the blue and red arrows) covered the surface of the tumor tissue. Tumor tissue and normal epithelium were noted on the left side of the blue arrow and on the right side of the red arrow, respectively.
Fig. 2.The patients were a woman in her 60s without gastric cancer (A, B) and a man in his 60s with gastric cancer (well-differentiated tubular adenocarcinoma; C, D). Endoscopic image of a reddish depressed lesion acquired by white light endoscopy (A, C; indicated by the yellow arrows). By using magnifying narrow-band imaging, regular (B) or irregular (D) microsurface pattern and microvascular pattern were observed in each lesion.
Prevalence of SM Invasive Cancer Discovered after Eradication Therapy
| Depth (SM invasion) | Eradicated | Control | p-value |
|---|---|---|---|
| Maehata |
17/96 (18) | 8/96 (8) | 0.051 |
| Hata |
13/81 (16) | 4/81 (5) | 0.021 |
Data are presented as number/number (%).
SM, submucosal.
Comparison of the Diagnostic Efficacy of White Light Imaging and Magnifying NBI for GCAE
| Using white light imaging (n=117) |
Using magnifying NBI (n=104) |
|
|---|---|---|
| Lesions needed biopsy | 83/117 (71)* | 21/104 (20)* |
| Positive predictive value of biopsy | 2/83 (2)* | 9/21 (43)* |
Data are presented as number/number (%).
NBI, narrow-band imaging; GCAE, gastric cancer after eradication.
*p<0.01 (between two groups).
Gut and Liver 2021; 15(3): 338-345
Published online May 15, 2021 https://doi.org/10.5009/gnl19418
Copyright © Gut and Liver.
Masanori Ito1 , Shinji Tanaka2 , Kazuaki Chayama3
Departments of 1General Internal Medicine, 2Endoscopy, and 3Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
Correspondence to:Masanori Ito
ORCID https://orcid.org/0000-0002-8218-9059
E-mail maito@hiroshima-u.ac.jp
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
The prevalence of gastric cancer after eradication (GCAE) is increasing dramatically in Japan. GCAE has characteristic features, and we must understand these features in endoscopic examinations. Differentiated cancer types were frequently found after eradication and included characteristic endoscopic features such as reddish depression (RD). However, benign RD can be difficult to distinguish from gastric cancer because of histological alterations in the surface structures (nonneoplastic epithelium or epithelium with low-grade atypia [ELA]) as well as multiple appearances of RD. Recently, we clarified similar alterations in genetic mutations between ELA and gastric cancer, suggesting that ELA is derived from gastric cancer. Clinically, submucosal invasive cancer was frequently found in patients after eradication therapy even if they received annual endoscopic surveillance. We can improve the diagnostic ability using image-enhanced endoscopy with magnified observation.
Keywords: Stomach neoplasms, Eradication therapy, Helicobacter pylori, Reddish depression, Epithelium with low-grade atypia
Gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide, accounting for nearly three-quarters a million deaths annually.1
In 2013, the Japanese government approved that national health insurance can cover
Along with the increase in eradication therapy, mortality from gastric cancer is now decreasing gradually. However, eradication therapy has caused another crucial problem, namely the problem of gastric cancer after eradication therapy (GCAE). Gastric cancer develops in some patients even after successful eradication therapy, and recent studies have been clarifying its characteristic features. In the present review, we examine some problems around GCAE and propose effective clinical practices for the diagnosis and treatment for GCAE.
Many studies have indicated that eradication therapy for
First of all, we have to understand the pathogenesis of GCAE. Did GCAE newly develop after eradication therapy or was it already existing before eradication therapy? Clinical features in cases with GCAE, especially the gender of patients and tumor location in the stomach, were reported to be similar to those with conventional gastric cancer (with
We have to recognize that GCAE revealed representative endoscopic feature, namely a superficial depressed feature.16,21-23 In 2005, we reported the morphological alterations of gastric tumors after eradication therapy of
The true pathogenesis of tumor flattering is still unknown. We speculated that a decreased level of serum gastrin may be a reason for this phenomenon. Gastrin is a growth factor for epithelial cells,25,26 and we previously detected the gastric receptor in gastric epithelial cells and gastric cancer cells.27,28 Serum gastrin levels were decreased by eradication therapy in patients with atrophic gastritis;29 therefore, proliferating signals through the gastrin receptor may decline in response to the eradication system followed by flattering the tumor tissue.30 Decreases in cytokine levels in response to eradication therapy may be another reason for the inhibition of tumor growth and flattering of the tumor tissue.31,32
We further found that endoscopic alteration was closely linked to histological features. After eradication, a normal or mild-atypical epithelium appeared on the surface of gastric tumor tissues just covering the tumor tissue.30 After eradication, we found almost normal epithelium on the surface of adenoma tissue and slightly atypical epithelium on the surface of gastric cancer tissue.30 This may be a reason why gastric tumors become indistinct after eradication therapy.
In cases with gastric adenoma, Gotoda
On the other hand, we could find slightly atypical (not completely normal) epithelium covering gastric cancer tissue (Fig. 1). We named this feature as epithelium with low-grade atypia (ELA) and defined it according to the following criteria: (1) ELA must lie on the surface of gastric cancer tissue; (2) ELA must be columnar epithelium with spindle or oval nuclei; (3) nuclear polarity must be present in the ELA; and (4) the ELA must be separated and distinguished from the surrounding nonneoplastic mucosa.36 Previously, we have presented that ELA appeared not only on gastric cancer after
Furthermore, we examined the pathogenesis of this epithelium. Small numbers of nonneoplastic glands were detected within the gastric cancer tissue, and these glands were recognized as nonneoplastic without difficulty. However, we also detected another type of epithelium termed ELA, which was different from both nonneoplastic epithelium and tumor tissue, on the tumor surface. It should be clarified whether ELA comes from normal tissue (indicating that ELA is from regenerative changes from nonneoplastic epithelium) or tumor tissue (where ELA comes from the re-differentiation of gastric cancer by eradication). We extracted DNA from gastric cancer tissue, normal gastric mucosa, and ELA by laser-microdissection.40 We used the NCC Oncopanel (National Cancer Center and Sysmex Cancer Innovation Laboratory, Tokyo, Japan) and examined gene alterations for 125 genes using deep-sequencing.41 The mutation profile of ELA was quite similar to that in gastric cancer tissue, suggesting that ELA was derived from gastric cancer tissue, and gastric cancer tissue can be histologically restored by eradication therapy. ELA was not from normal epithelium contaminating the tumor tissue but from gastric cancer tissue. In animal model, adenocarcinoma tissue can be restored by genetic manipulation.42 This may be a first report describing that human gastric cancer tissue can be histologically restored by eradication therapy.
Clinically, this phenomenon is supposed to evoke the difficulty in endoscopic diagnosis of GCAE as well as the gastric adenomas described above. Previously, we reported that submucosal invasive GCAE showed extensive ELA on the surface of gastric cancer tissue in patients receiving annual endoscopic examination after eradication.36 The appearance of ELA may interrupt the detection of GCAE in earlier stages, as a result these tumors are likely to be detected at more advanced stages. Moreover, it has been reported that there is a noticeably increased prevalence of GCAE showing submucosal invasion compared with that for
Thereafter, we retrospectively analyzed the clinicopathological characteristics of GCAE patients who received annual endoscopic examinations after eradication, and compared incident of gastric cancer with submucosal invasion between GCAE and controls. The prevalence of early gastric cancer with submucosal invasion was significantly higher in the eradicated group than in the control group after propensity score matching (16.0% vs 4.9%, respectively; p=0.021) (Table 1).45,46 We could not detect a statistically significant difference in any features, including sex, age, previous cancer history, location, macroscopic type, and tumor size between two groups.46
For accurate endoscopic examination in patients with successful eradication, we have to understand that the typical endoscopic features of GCAE were reddish depression (RD). Diffuse redness, which is a typical feature of
First, we tried to diagnose malignant RD lesions (RDLs) with white-light imaging (WLI) based on reports described by Yao
In the M-NBI group, biopsy was performed in 21 patients (20%), and nine were diagnosed as adenocarcinoma. Biopsy was required in fewer patients, and the positive predictive value of biopsy was statistically higher in the M-NBI group than in the WLI group (Table 2).52 These findings suggested that M-NBI demonstrated significantly superior diagnostic efficacy with respect to RDL to select malignant RD endoscopically. However, it may be difficult to diagnose these lesions only by WLI at present. For accurate diagnosis, we reported the usefulness of magnifying NBI methods. Recently, several reports from Japan described the usefulness of image-enhanced endoscopy in the diagnosis of GCAE.55-57
The final goal of our strategy was to diminish mortality from gastric cancer. Primary prevention by eradication therapy may be the best way to achieve our goal. The Japanese Society of Helicobacter Research demonstrated a total care program against
Risk stratification should be helpful for supplying effective surveillance of patients after eradication. Atrophic gastritis in the corpus or intestinal metaplasia is considered to be a risk factor for the development of GCAE.59-64 In 2015, the Kyoto Global Consensus Conference on
In Japan, test-and-treat for
No potential conflict of interest relevant to this article was reported.
Prevalence of SM Invasive Cancer Discovered after Eradication Therapy
| Depth (SM invasion) | Eradicated | Control | p-value |
|---|---|---|---|
| Maehata |
17/96 (18) | 8/96 (8) | 0.051 |
| Hata |
13/81 (16) | 4/81 (5) | 0.021 |
Data are presented as number/number (%).
SM, submucosal.
Comparison of the Diagnostic Efficacy of White Light Imaging and Magnifying NBI for GCAE
| Using white light imaging (n=117) |
Using magnifying NBI (n=104) |
|
|---|---|---|
| Lesions needed biopsy | 83/117 (71)* | 21/104 (20)* |
| Positive predictive value of biopsy | 2/83 (2)* | 9/21 (43)* |
Data are presented as number/number (%).
NBI, narrow-band imaging; GCAE, gastric cancer after eradication.
*p<0.01 (between two groups).
Table 2 Comparison of the Diagnostic Efficacy of White Light Imaging and Magnifying NBI for GCAE
| Using white light imaging (n=117) | Using magnifying NBI (n=104) | |
|---|---|---|
| Lesions needed biopsy | 83/117 (71)* | 21/104 (20)* |
| Positive predictive value of biopsy | 2/83 (2)* | 9/21 (43)* |
Data are presented as number/number (%).
NBI, narrow-band imaging; GCAE, gastric cancer after eradication.
*p<0.01 (between two groups).
pISSN 1976-2283
eISSN 2005-1212
Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE
| Yong Chan Lee |
Professor of Medicine Director, Gastrointestinal Research Laboratory Veterans Affairs Medical Center, Univ. California San Francisco San Francisco, USA |
| Jong Pil Im | Seoul National University College of Medicine, Seoul, Korea |
| Robert S. Bresalier | University of Texas M. D. Anderson Cancer Center, Houston, USA |
| Steven H. Itzkowitz | Mount Sinai Medical Center, NY, USA |
All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
The remaining articles are usually sent to two reviewers. It would be very helpful if you could suggest a selection of reviewers and include their contact details. We may not always use the reviewers you recommend, but suggesting reviewers will make our reviewer database much richer; in the end, everyone will benefit. We reserve the right to return manuscripts in which no reviewers are suggested.
The final responsibility for the decision to accept or reject lies with the editors. In many cases, papers may be rejected despite favorable reviews because of editorial policy or a lack of space. The editor retains the right to determine publication priorities, the style of the paper, and to request, if necessary, that the material submitted be shortened for publication.
PDF
Standard view
Export citation
Share 
Download
Download
