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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 |
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Jung Won Jeon1 , Soo Jin Kim2
, Jae Young Jang3
, Sun-Moon Kim4
, Chul-Hyun Lim5
, Jae Myung Park5
, Su Jin Hong6
, Chan Gyoo Kim7
, Seong Woo Jeon8
, Si Hyung Lee9
, Jae Kyu Sung10
, Gwang Ho Baik11,12
Correspondence to: Gwang Ho Baik
ORCID https://orcid.org/0000-0003-1419-7484
E-mail baikgh@hallym.or.kr
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(2):225-231. https://doi.org/10.5009/gnl19275
Published online August 10, 2020, Published date March 15, 2021
Copyright © Gut and Liver.
Background/Aims: Some cases of gastric low-grade dysplasia (LGD) and high-grade dysplasia (HGD) on forceps biopsy (FB) are diagnosed as gastric cancer (GC) after endoscopic resection (ER). This study aims to evaluate the clinical outcomes of ER for gastric LGD and HGD on pretreatment FB and to identify the factors that predict pathologic upstaging to GC.
Methods: Patients who underwent ER for LGD and HGD on pretreatment FB from March 2005 to February 2018 in 14 hospitals in South Korea were enrolled, and the patients’ medical records were reviewed retrospectively.
Results: This study included 2,150 cases of LGD and 1,534 cases of HGD diagnosed by pretreatment FB. In total, 589 of 2,150 LGDs (27.4%) were diagnosed as GC after ER. Helicobacter pylori infection, smoking history, tumor location in the lower third of the stomach, tumor size >10 mm, depressed lesion, and ulceration significantly predicted GC. A total of 1,115 out of 1,534 HGDs (72.7%) were diagnosed with GC after ER. Previous history of GC, H. pylori infection, smoking history, tumor location in the lower third of the stomach, tumor size >10 mm, depressed lesion, and ulceration were significantly associated with GC. As the number of risk factors predicting GC increased in both LGD and HGD on pretreatment FB, the rate of upstaging to GC after ER increased.
Conclusions: A substantial proportion of LGDs and HGDs on pretreatment FB were diagnosed as GC after ER. Accurate ER procedures such as endoscopic submucosal dissection should be recommended in cases of LGD and HGD with factors predicting pathologic upstaging to GC.
Keywords: Low-grade dysplasia, High-grade dysplasia, Endoscopic resection, Gastric cancer, Risk factors
In the latest published global cancer statistics, gastric cancer (GC) is ranked as the third most common cause for cancer-related mortality worldwide.1 Early detection and proper management of GC and precancerous lesions are crucial to improving GC-related mortality. Gastric dysplasia is regarded as a precancerous lesion.2 The risk of carcinoma generally increases with the histological grade of the dysplasia (low to high grade). According to the revised Vienna classification,3 gastric low-grade dysplasia (LGD) is classified as category 3, and endoscopic resection (ER) or regular follow-up examination is recommended. Category 4 is defined as noninvasive high-grade neoplasia. Category 4 is further divided into category 4.1 defined as high-grade dysplasia (HGD); 4.2, noninvasive carcinoma (carcinoma
Endoscopic examination is useful in detecting gastric neoplasia in its early stage, and pathological examination of endoscopic forceps biopsy (FB) is the gold standard for an accurate diagnosis. However, cases in which the initial pathological diagnosis on pretreatment FB is corrected after ER are frequently found, due to the difficulty of making solid diagnosis based on small biopsy specimens.4 For this reason, GC may be underdiagnosed as LGD or HGD on pretreatment FB. Previous studies have reported that 12.1% to 63% of LGD lesions are upgraded to HGD or GC after ER.5-15 In addition, gastric HGD has been shown to be GC in about 27% to 80% of cases after ER.16-18
In this study, we aimed to evaluate the clinical outcomes of ER for gastric LGDs and HGDs on pretreatment FB, using the multicenter large-scale endoscopic submucosal dissection (ESD) registry database. In addition, we investigated the factors predicting the pathologic upstage to GC.
We identified and reviewed cases which were treated with ER for LGD and HGD on pretreatment FB and involved in the Korean ESD registry database- an online registry created in 2015. It is a project which collects ESD or endoscopic mucosal resection (EMR) data from multiple centers, each representing its district in South Korea, and is under the control of Korean Society of Gastrointestinal Endoscopy. This registry contains clinical information, endoscopic findings, pathologic results, therapeutic outcomes, and follow-up data related to ER for gastric neoplasms.
This study included patients who had undergone ER for gastric LGD and HGD on pretreatment FB at 14 university hospitals in South Korea from March 2005 to February 2018. Medical records of patients involved in this study were retrospectively reviewed. Patients’ data include age, sex, family history of GC, previous history of GC, the presence of hypertension or diabetes mellitus, aspirin use, smoking history, and
Endoscopic reports of all enrolled lesions were reviewed to determine the features of lesions. The Japanese classification of GC was used to describe the location of lesions.19 The Paris classification was used to define the gross types of superficial lesions, which were divided into elevated, flat, or depressed.20 Ulcers which were defined as breaks in the mucosal surface >5 mm in size with depth to the submucosa, were also evaluated.
Pathologic reports of the resected tissues, which were reported by experienced pathologists in hospitals involved in this study, were reviewed. All of the lesions were classified as gastrointestinal epithelial neoplasia following the Vienna classification.2
Univariate analysis with the chi-square test or Fisher exact test for categorical variables and the Student t-test for continuous variables were performed. Multivariate analysis with a multiple logistic regression model was performed to identify risk factors for GC. The p<0.05 was considered statistically significant. Statistical calculations were performed with SPSS version 21.0 for Windows (IBM Corp., Armonk, NY, USA).
This study was conducted according to the principles expressed in the Declaration of Helsinki, and approved by the Institutional Review Board of Chuncheon Sacred Heart Hospital (IRB number: 2016-87).
From March 2005 to February 2018, 2,277 LGD lesions and 1,620 HGD lesions, which were managed by ER, were enrolled in the Korean ESD registry database. Among these, 127 LGD lesions and 86 HGD lesions were excluded because they were incomplete to be used as valid data. Ultimately, the data from 2,150 LGD lesions and 1,534 HGD lesions were analyzed.
Table 1 shows the clinical and endoscopic characteristics of LGD and HGD on pretreatment FB. The patients’ mean age was 63.89±9.36 years in LGD group and 65.24±9.17 years in HGD group. There were 1,493 (69.4%) males in the LGD group and 1,113 (72.6%) in HGD group. Forty-three cases (2.0%) in the LGD group and 70 cases (4.6%) in HGD group had a previous history of GC. We identified incidence rate of
Pathologic concordance rate was 48.3% (1,038/2,150) in the LGD group and 21.4% (328/1,534) in the HGD group. The 589 of 2,150 cases (27.4%) in the LGD group and 1,115 of 1,534 cases (72.7%) in the HGD group showed pathologic upstage to GC after ER.
Table 2 shows the factors for upgrade diagnosis to GC of LGD in univariate and multivariate analyses. Multivariate analysis revealed that
Table 4 shows the factors for upgrade diagnosis to GC of HGD in univariate and multivariate analyses. Multivariate analysis revealed that previous history for GC (absence of previous history for GC compared with previous history of GC: OR, 0.459; 95% CI, 0.257 to 0.819; p=0.008),
The specimens obtained by endoscopic FB–an essential diagnostic tool for gastric superficial neoplasms, may not be representative of the entire lesion.5 The possible reasons for this discrepancy may be as follows:17 (1) FB samples are small in size, and therefore do not represent the entire lesion; (2) cancer is sometimes hidden in other parts of the lesion; or (3) the atypia of adenoma and adenocarcinoma is too subtle to detect in a small biopsy specimen.
In previous studies, it has been reported that 12.1% to 63% of LGD lesions are upgraded to HGD or GC after ER.5-15 In 2,150 LGD cases of our study, 981 cases (45.6%) showed diagnostic upgrade to HGD or GC after ER, which is similar to the results of previous studies. Diagnostic upgrades to HGD and GC were 392 cases (18.2%) and 589 cases (27.4%), respectively. Likewise, in the case of HGD, previous studies showed that gastric HGD on pretreatment FB was diagnosed as GC in about 27.6% to 80% of cases after ER.16-18 Diagnostic upgrade to GC was found in 72.7% of cases in our study, which is similar to the results of previous studies.
Previous studies reported that several endoscopic findings were associated with the risk of GC.17,21 We investigated the risk factors for GC in LGD and HGD, respectively. In addition, we investigated endoscopic findings as well as clinical characteristics when investigating risk factors for GC. In the case of LGD, previous articles examined factors that could predict HGD as well as GC.5,8,12,13 Although the modified Vienna classification of epithelial neoplasia is used widely,3 differences exist between the Asian and Western pathologists regarding the histological criteria in grading dysplasia.22 Moreover, Western gastroenterologists are more interested in GC than HGD or LGD. For these reasons, this study only focused on risk factors for GC.
Kang
Our study showed that the location in lower third of LGD and HGD, compared with the location in middle third of LGD and upper third of HGD respectively, was associated with histologic upgrade to GC. We assume that investigators could miss LGD or HGD in blind spots of middle or upper third of stomach before the lesions change to cancer and observed clearly.
When we conducted the study, we used the ESD registry database–an online registry created in 2015. ESD registry involved more than 9,000 cases. Of them, we identified and reviewed cases which were treated with ER for LGD and HGD on pretreatment FB. We knew that the percent of
In recent years, ESD has become an accepted curative treatment modality for the treatment of early GC.23 Therefore, it is important to completely remove the lesions identified to be LGD or HGD on pretreatment FB, if risk factors predicting upstage diagnosis to GC are identified. Compared to EMR, ESD can effectively remove LGD or HGD lesions without marginal involvement of the lesion. ESD increases the en bloc resection rate for lesions >10 mm, compared with EMR.5 The Korean National Health Insurance System provides insurance for ESD of LGD and HGD lesions >15 mm. In South Korea, until recently, LGD or HGD lesions between 10 mm and 15 mm were treated with modified EMR involving EMR after precutting or EMR using scope detaching cap in the tip instead of conventional EMR. According to our study, the insurance criteria for the size of the lesion in South Korea may need to be changed. In addition to the size of the lesion, other risk factors involving
Fourteen hospitals in South Korea participated in this study. The researchers participated in this study of each hospital shared respective definitions for the data that they wanted to collect. They checked the low data of the patients enrolled in their hospitals and filled up the missing data as much as possible. Despite these efforts, this study has limitations. This is retrospective study, so for example the percentage of
In conclusion, a substantial proportion of LGD and HGD on pretreatment FB were diagnosed as GC after ER. As the number of risk factors predicting GC increased in both LGD and HGD on pretreatment FB, the rate of upstage diagnosis to GC after ER also increased. Therefore, accurate ER such as ESD should be recommended in cases of LGD and HGD with factors predicting pathologic upstage to GC.
No potential conflict of interest relevant to this article was reported.
Study concept and design: J.W.J., G.H.B. Statistical analysis: S.J.K. Study supervision: S.J.H. Data acquisition: J.Y.J., S.M.K., C.H.L., J.M.P., C.G.K., S.W.J., S.H.L., J.K.S. Writing - original draft: J.W.J. Writing - review and editing: G.H.B., J.W.J., S.J.K. Approval of final manuscript: all authors.
Baseline Characteristics
Characteristics | LGD on pretreatment FB (n=2,150) |
HGD on pretreatment FB (n=1,534) |
---|---|---|
Age, yr | 63.89±9.36 | 65.24±9.17 |
Male sex | 1,493 (69.4) | 1,113 (72.6) |
Family history of GC | 73 (3.4) | 60 (3.9) |
Previous history of GC | 43 (2.0) | 70 (4.6) |
570 (26.5) | 371 (24.2) | |
Smoking history | 379 (17.6) | 527 (34.4) |
Hypertension | 748 (34.8) | 579 (37.7) |
Diabetes mellitus | 338 (15.7) | 270 (17.6) |
Aspirin use | 232 (10.8) | 180 (11.7) |
Tumor location | ||
Lower third of stomach | 1,217 (56.6) | 952 (62.1) |
Middle third of stomach | 789 (36.7) | 461 (30.0) |
Upper third of stomach | 144 (6.7) | 121 (7.9) |
Tumor size, mm | 13.94±11.28 | 15.89±11.92 |
Gross type | ||
Elevated | 1,249 (58.1) | 851 (55.5) |
Flat | 692 (32.2) | 322 (21.0) |
Depressed | 209 (9.7) | 361 (23.5) |
Ulcer | 91 (4.2) | 220 (14.3) |
Pathologic concordance | 1,038 (48.3) | 328 (21.4) |
Pathologic downstage | 131 (6.1) | 91 (5.9) |
Pathologic upstage to GC | 589 (27.4) | 1,115 (72.7) |
Endoscopic resection method | ||
EMR | 996 (46.3) | 405 (26.4) |
ESD | 1,154 (53.7) | 1,129 (73.6) |
2,085 (97.1) | 1,486 (96.9) | |
Complete resection | 2,092 (97.4) | 1,494 (97.4) |
Data are presented as mean±SD or number (%).
LGD, low-grade dysplasia; HGD, high-grade dysplasia; FB, forceps biopsy; GC, gastric cancer; EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection.
Risk Factors for Upgrading of LGD to GC in Univariate and Multivariate Analysis
Factor | Univariate analysis | Multivariate analysis | |||||
---|---|---|---|---|---|---|---|
OR | 95% CI | p-value | OR | 95% CI | p-value | ||
Age >65 yr | 1.234 | 1.012–1.504 | 0.038 | 1.102 | 0.827–1.469 | 0.508 | |
Male sex | 1.150 | 0.924–1.430 | 0.034 | 0.808 | 0.590–1.107 | 0.185 | |
Family history of GC | 0.926 | 0.451–1.904 | 0.835 | ||||
Absence of previous history of GC | 2.421 | 1.211–4.839 | 0.012 | 0.838 | 0.340–2.066 | 0.701 | |
Absence of |
0.755 | 0.579–0.984 | 0.038 | 0.686 | 0.498–0.945 | 0.021 | |
Smoking history | 5.374 | 4.149–6.960 | <0.001 | 4.928 | 3.290–7.383 | <0.001 | |
Hypertension | 1.130 | 0.919–1.389 | 0.247 | 1.264 | 0.935–1.709 | 0.128 | |
Diabetes mellitus | 1.113 | 0.846–1.163 | 0.445 | 0.738 | 0.497–1.096 | 0.132 | |
Aspirin use | 0.815 | 0.590–1.127 | 0.217 | 0.949 | 0.601–1.498 | 0.821 | |
Tumor location | |||||||
Lower third of stomach (reference) | 1.000 | 1.000 | |||||
Middle third of stomach | 0.785 | 0.635–0.971 | 0.025 | 0.654 | 0.487–0.878 | 0.005 | |
Upper third of stomach | 0.963 | 0.651–1.426 | 0.851 | 1.161 | 0.636–2.121 | 0.626 | |
Tumor size >10 mm | 2.730 | 2.200–3.389 | <0.001 | 3.467 | 2.571–4.675 | <0.001 | |
Gross type | |||||||
Elevated (reference) | 1.000 | 1.000 | |||||
Flat | 0.468 | 0.368–0.596 | <0.001 | 0.790 | 0.577–1.084 | 0.144 | |
Depressed | 2.320 | 1.661–3.239 | <0.001 | 3.270 | 2.067–5.171 | <0.001 | |
Absence of ulcer | 0.226 | 0.176–0.291 | <0.001 | 0.203 | 0.147–0.282 | <0.001 |
LGD, low-grade dysplasia; GC, gastric cancer; OR, odds ratio; CI, confidence interval.
The Effect of the Presence of 0–6 Risk Factors upon Upstaging of LGD to GC
No. of risk factors |
LGD or downgrade diagnostic group (n=1,169) |
GC group (n=589) |
Total (n=1,778) |
---|---|---|---|
0 | 3 | 0 | 3 |
1 | 65 | 1 | 66 |
2 | 394 | 39 | 433 |
3 | 462 | 162 | 624 |
4 | 222 | 234 | 456 |
5 | 23 | 134 | 157 |
6 | 0 | 19 | 19 |
Date are presented as number. Risk factors:
LGD, low-grade dysplasia; GC, gastric cancer.
Factors Associated with Upstaging of HGD to GC in Univariate and Multivariate Analysis
Factor | Univariate analysis | Multivariate analysis | |||||
---|---|---|---|---|---|---|---|
OR | 95% CI | p-value | OR | 95% CI | p-value | ||
Age >65 yr | 0.868 | 0.691–1.090 | 0.223 | 0.789 | 0.600–1.039 | 0.092 | |
Male sex | 1.307 | 1.020–1.675 | 0.034 | 0.862 | 0.625–1.189 | 0.366 | |
Family history of GC | 0.714 | 0.365–1.398 | 0.326 | ||||
Absence of previous history of GC | 0.622 | 0.378–1.023 | 0.061 | 0.459 | 0.257–0.819 | 0.008 | |
Absence of |
0.655 | 0.197–0.863 | 0.003 | 0.585 | 0.430–0.795 | 0.001 | |
Smoking history | 2.399 | 1.844–3.121 | <0.001 | 2.527 | 1.790–3.567 | <0.001 | |
Hypertension | 1.016 | 0.806–1.281 | 0.892 | ||||
Diabetes mellitus | 1.115 | 0.826–1.506 | 0.475 | ||||
Aspirin use | 0.944 | 0.668–1.334 | 0.744 | ||||
Tumor location | |||||||
Lower third of stomach (reference) | 1.000 | 1.000 | |||||
Middle third of stomach | 0.846 | 0.660–1.084 | 0.185 | 0.849 | 0.628–1.147 | 0.285 | |
Upper third of stomach | 0.702 | 0.468–1.053 | 0.087 | 0.544 | 0.332–0.890 | 0.015 | |
Tumor size >10 mm | 1.293 | 1.015–1.649 | 0.038 | 1.934 | 1.438–2.600 | <0.001 | |
Gross type | |||||||
Elevated (reference) | 1.000 | 1.000 | |||||
Flat | 0.874 | 0.661–1.156 | 0.346 | 1.048 | 0.752–1.461 | 0.780 | |
Depressed | 2.430 | 1.747–3.381 | <0.001 | 2.551 | 1.731–3.758 | <0.001 | |
Absence of ulcer | 0.627 | 0.484–0.812 | <0.001 | 0.537 | 0.388–0.743 | <0.001 |
HGD, high-grade dysplasia; GC, gastric cancer; OR, odds ratio; CI, confidence interval.
The Effect of the Presence of 0–7 Risk Factors upon Upstaging of HGD to GC
No. of risk factors |
HGD or downgrade diagnostic group (n=419) |
GC group (n=1,115) |
Total (n=1,534) |
---|---|---|---|
0 | 1 | 0 | 1 |
1 | 9 | 3 | 12 |
2 | 54 | 63 | 117 |
3 | 175 | 266 | 441 |
4 | 120 | 445 | 565 |
5 | 51 | 246 | 297 |
6 | 9 | 84 | 93 |
7 | 0 | 8 | 8 |
Date are presented as number. Risk factors: previous history of GC,
HGD, high-grade dysplasia; GC, gastric cancer.
Gut and Liver 2021; 15(2): 225-231
Published online March 15, 2021 https://doi.org/10.5009/gnl19275
Copyright © Gut and Liver.
Jung Won Jeon1 , Soo Jin Kim2
, Jae Young Jang3
, Sun-Moon Kim4
, Chul-Hyun Lim5
, Jae Myung Park5
, Su Jin Hong6
, Chan Gyoo Kim7
, Seong Woo Jeon8
, Si Hyung Lee9
, Jae Kyu Sung10
, Gwang Ho Baik11,12
1Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University College of Medicine, 2Institute of Medical Science, Kyung Hee University Hospital at Gangdong, 3Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, 4Department of Internal Medicine, Konyang University College of Medicine, Daejeon, 5Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, 6Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, 7Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, Goyang, 8Department of Internal Medicine, School of Medicine, Kyungpook National University, 9Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, 10Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 11Department of Internal Medicine, Hallym University College of Medicine, Chuncheon Sacred Heart Hospital, and 12Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon, Korea
Correspondence to:Gwang Ho Baik
ORCID https://orcid.org/0000-0003-1419-7484
E-mail baikgh@hallym.or.kr
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.
Background/Aims: Some cases of gastric low-grade dysplasia (LGD) and high-grade dysplasia (HGD) on forceps biopsy (FB) are diagnosed as gastric cancer (GC) after endoscopic resection (ER). This study aims to evaluate the clinical outcomes of ER for gastric LGD and HGD on pretreatment FB and to identify the factors that predict pathologic upstaging to GC.
Methods: Patients who underwent ER for LGD and HGD on pretreatment FB from March 2005 to February 2018 in 14 hospitals in South Korea were enrolled, and the patients’ medical records were reviewed retrospectively.
Results: This study included 2,150 cases of LGD and 1,534 cases of HGD diagnosed by pretreatment FB. In total, 589 of 2,150 LGDs (27.4%) were diagnosed as GC after ER. Helicobacter pylori infection, smoking history, tumor location in the lower third of the stomach, tumor size >10 mm, depressed lesion, and ulceration significantly predicted GC. A total of 1,115 out of 1,534 HGDs (72.7%) were diagnosed with GC after ER. Previous history of GC, H. pylori infection, smoking history, tumor location in the lower third of the stomach, tumor size >10 mm, depressed lesion, and ulceration were significantly associated with GC. As the number of risk factors predicting GC increased in both LGD and HGD on pretreatment FB, the rate of upstaging to GC after ER increased.
Conclusions: A substantial proportion of LGDs and HGDs on pretreatment FB were diagnosed as GC after ER. Accurate ER procedures such as endoscopic submucosal dissection should be recommended in cases of LGD and HGD with factors predicting pathologic upstaging to GC.
Keywords: Low-grade dysplasia, High-grade dysplasia, Endoscopic resection, Gastric cancer, Risk factors
In the latest published global cancer statistics, gastric cancer (GC) is ranked as the third most common cause for cancer-related mortality worldwide.1 Early detection and proper management of GC and precancerous lesions are crucial to improving GC-related mortality. Gastric dysplasia is regarded as a precancerous lesion.2 The risk of carcinoma generally increases with the histological grade of the dysplasia (low to high grade). According to the revised Vienna classification,3 gastric low-grade dysplasia (LGD) is classified as category 3, and endoscopic resection (ER) or regular follow-up examination is recommended. Category 4 is defined as noninvasive high-grade neoplasia. Category 4 is further divided into category 4.1 defined as high-grade dysplasia (HGD); 4.2, noninvasive carcinoma (carcinoma
Endoscopic examination is useful in detecting gastric neoplasia in its early stage, and pathological examination of endoscopic forceps biopsy (FB) is the gold standard for an accurate diagnosis. However, cases in which the initial pathological diagnosis on pretreatment FB is corrected after ER are frequently found, due to the difficulty of making solid diagnosis based on small biopsy specimens.4 For this reason, GC may be underdiagnosed as LGD or HGD on pretreatment FB. Previous studies have reported that 12.1% to 63% of LGD lesions are upgraded to HGD or GC after ER.5-15 In addition, gastric HGD has been shown to be GC in about 27% to 80% of cases after ER.16-18
In this study, we aimed to evaluate the clinical outcomes of ER for gastric LGDs and HGDs on pretreatment FB, using the multicenter large-scale endoscopic submucosal dissection (ESD) registry database. In addition, we investigated the factors predicting the pathologic upstage to GC.
We identified and reviewed cases which were treated with ER for LGD and HGD on pretreatment FB and involved in the Korean ESD registry database- an online registry created in 2015. It is a project which collects ESD or endoscopic mucosal resection (EMR) data from multiple centers, each representing its district in South Korea, and is under the control of Korean Society of Gastrointestinal Endoscopy. This registry contains clinical information, endoscopic findings, pathologic results, therapeutic outcomes, and follow-up data related to ER for gastric neoplasms.
This study included patients who had undergone ER for gastric LGD and HGD on pretreatment FB at 14 university hospitals in South Korea from March 2005 to February 2018. Medical records of patients involved in this study were retrospectively reviewed. Patients’ data include age, sex, family history of GC, previous history of GC, the presence of hypertension or diabetes mellitus, aspirin use, smoking history, and
Endoscopic reports of all enrolled lesions were reviewed to determine the features of lesions. The Japanese classification of GC was used to describe the location of lesions.19 The Paris classification was used to define the gross types of superficial lesions, which were divided into elevated, flat, or depressed.20 Ulcers which were defined as breaks in the mucosal surface >5 mm in size with depth to the submucosa, were also evaluated.
Pathologic reports of the resected tissues, which were reported by experienced pathologists in hospitals involved in this study, were reviewed. All of the lesions were classified as gastrointestinal epithelial neoplasia following the Vienna classification.2
Univariate analysis with the chi-square test or Fisher exact test for categorical variables and the Student t-test for continuous variables were performed. Multivariate analysis with a multiple logistic regression model was performed to identify risk factors for GC. The p<0.05 was considered statistically significant. Statistical calculations were performed with SPSS version 21.0 for Windows (IBM Corp., Armonk, NY, USA).
This study was conducted according to the principles expressed in the Declaration of Helsinki, and approved by the Institutional Review Board of Chuncheon Sacred Heart Hospital (IRB number: 2016-87).
From March 2005 to February 2018, 2,277 LGD lesions and 1,620 HGD lesions, which were managed by ER, were enrolled in the Korean ESD registry database. Among these, 127 LGD lesions and 86 HGD lesions were excluded because they were incomplete to be used as valid data. Ultimately, the data from 2,150 LGD lesions and 1,534 HGD lesions were analyzed.
Table 1 shows the clinical and endoscopic characteristics of LGD and HGD on pretreatment FB. The patients’ mean age was 63.89±9.36 years in LGD group and 65.24±9.17 years in HGD group. There were 1,493 (69.4%) males in the LGD group and 1,113 (72.6%) in HGD group. Forty-three cases (2.0%) in the LGD group and 70 cases (4.6%) in HGD group had a previous history of GC. We identified incidence rate of
Pathologic concordance rate was 48.3% (1,038/2,150) in the LGD group and 21.4% (328/1,534) in the HGD group. The 589 of 2,150 cases (27.4%) in the LGD group and 1,115 of 1,534 cases (72.7%) in the HGD group showed pathologic upstage to GC after ER.
Table 2 shows the factors for upgrade diagnosis to GC of LGD in univariate and multivariate analyses. Multivariate analysis revealed that
Table 4 shows the factors for upgrade diagnosis to GC of HGD in univariate and multivariate analyses. Multivariate analysis revealed that previous history for GC (absence of previous history for GC compared with previous history of GC: OR, 0.459; 95% CI, 0.257 to 0.819; p=0.008),
The specimens obtained by endoscopic FB–an essential diagnostic tool for gastric superficial neoplasms, may not be representative of the entire lesion.5 The possible reasons for this discrepancy may be as follows:17 (1) FB samples are small in size, and therefore do not represent the entire lesion; (2) cancer is sometimes hidden in other parts of the lesion; or (3) the atypia of adenoma and adenocarcinoma is too subtle to detect in a small biopsy specimen.
In previous studies, it has been reported that 12.1% to 63% of LGD lesions are upgraded to HGD or GC after ER.5-15 In 2,150 LGD cases of our study, 981 cases (45.6%) showed diagnostic upgrade to HGD or GC after ER, which is similar to the results of previous studies. Diagnostic upgrades to HGD and GC were 392 cases (18.2%) and 589 cases (27.4%), respectively. Likewise, in the case of HGD, previous studies showed that gastric HGD on pretreatment FB was diagnosed as GC in about 27.6% to 80% of cases after ER.16-18 Diagnostic upgrade to GC was found in 72.7% of cases in our study, which is similar to the results of previous studies.
Previous studies reported that several endoscopic findings were associated with the risk of GC.17,21 We investigated the risk factors for GC in LGD and HGD, respectively. In addition, we investigated endoscopic findings as well as clinical characteristics when investigating risk factors for GC. In the case of LGD, previous articles examined factors that could predict HGD as well as GC.5,8,12,13 Although the modified Vienna classification of epithelial neoplasia is used widely,3 differences exist between the Asian and Western pathologists regarding the histological criteria in grading dysplasia.22 Moreover, Western gastroenterologists are more interested in GC than HGD or LGD. For these reasons, this study only focused on risk factors for GC.
Kang
Our study showed that the location in lower third of LGD and HGD, compared with the location in middle third of LGD and upper third of HGD respectively, was associated with histologic upgrade to GC. We assume that investigators could miss LGD or HGD in blind spots of middle or upper third of stomach before the lesions change to cancer and observed clearly.
When we conducted the study, we used the ESD registry database–an online registry created in 2015. ESD registry involved more than 9,000 cases. Of them, we identified and reviewed cases which were treated with ER for LGD and HGD on pretreatment FB. We knew that the percent of
In recent years, ESD has become an accepted curative treatment modality for the treatment of early GC.23 Therefore, it is important to completely remove the lesions identified to be LGD or HGD on pretreatment FB, if risk factors predicting upstage diagnosis to GC are identified. Compared to EMR, ESD can effectively remove LGD or HGD lesions without marginal involvement of the lesion. ESD increases the en bloc resection rate for lesions >10 mm, compared with EMR.5 The Korean National Health Insurance System provides insurance for ESD of LGD and HGD lesions >15 mm. In South Korea, until recently, LGD or HGD lesions between 10 mm and 15 mm were treated with modified EMR involving EMR after precutting or EMR using scope detaching cap in the tip instead of conventional EMR. According to our study, the insurance criteria for the size of the lesion in South Korea may need to be changed. In addition to the size of the lesion, other risk factors involving
Fourteen hospitals in South Korea participated in this study. The researchers participated in this study of each hospital shared respective definitions for the data that they wanted to collect. They checked the low data of the patients enrolled in their hospitals and filled up the missing data as much as possible. Despite these efforts, this study has limitations. This is retrospective study, so for example the percentage of
In conclusion, a substantial proportion of LGD and HGD on pretreatment FB were diagnosed as GC after ER. As the number of risk factors predicting GC increased in both LGD and HGD on pretreatment FB, the rate of upstage diagnosis to GC after ER also increased. Therefore, accurate ER such as ESD should be recommended in cases of LGD and HGD with factors predicting pathologic upstage to GC.
No potential conflict of interest relevant to this article was reported.
Study concept and design: J.W.J., G.H.B. Statistical analysis: S.J.K. Study supervision: S.J.H. Data acquisition: J.Y.J., S.M.K., C.H.L., J.M.P., C.G.K., S.W.J., S.H.L., J.K.S. Writing - original draft: J.W.J. Writing - review and editing: G.H.B., J.W.J., S.J.K. Approval of final manuscript: all authors.
Baseline Characteristics
Characteristics | LGD on pretreatment FB (n=2,150) |
HGD on pretreatment FB (n=1,534) |
---|---|---|
Age, yr | 63.89±9.36 | 65.24±9.17 |
Male sex | 1,493 (69.4) | 1,113 (72.6) |
Family history of GC | 73 (3.4) | 60 (3.9) |
Previous history of GC | 43 (2.0) | 70 (4.6) |
570 (26.5) | 371 (24.2) | |
Smoking history | 379 (17.6) | 527 (34.4) |
Hypertension | 748 (34.8) | 579 (37.7) |
Diabetes mellitus | 338 (15.7) | 270 (17.6) |
Aspirin use | 232 (10.8) | 180 (11.7) |
Tumor location | ||
Lower third of stomach | 1,217 (56.6) | 952 (62.1) |
Middle third of stomach | 789 (36.7) | 461 (30.0) |
Upper third of stomach | 144 (6.7) | 121 (7.9) |
Tumor size, mm | 13.94±11.28 | 15.89±11.92 |
Gross type | ||
Elevated | 1,249 (58.1) | 851 (55.5) |
Flat | 692 (32.2) | 322 (21.0) |
Depressed | 209 (9.7) | 361 (23.5) |
Ulcer | 91 (4.2) | 220 (14.3) |
Pathologic concordance | 1,038 (48.3) | 328 (21.4) |
Pathologic downstage | 131 (6.1) | 91 (5.9) |
Pathologic upstage to GC | 589 (27.4) | 1,115 (72.7) |
Endoscopic resection method | ||
EMR | 996 (46.3) | 405 (26.4) |
ESD | 1,154 (53.7) | 1,129 (73.6) |
2,085 (97.1) | 1,486 (96.9) | |
Complete resection | 2,092 (97.4) | 1,494 (97.4) |
Data are presented as mean±SD or number (%).
LGD, low-grade dysplasia; HGD, high-grade dysplasia; FB, forceps biopsy; GC, gastric cancer; EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection.
Risk Factors for Upgrading of LGD to GC in Univariate and Multivariate Analysis
Factor | Univariate analysis | Multivariate analysis | |||||
---|---|---|---|---|---|---|---|
OR | 95% CI | p-value | OR | 95% CI | p-value | ||
Age >65 yr | 1.234 | 1.012–1.504 | 0.038 | 1.102 | 0.827–1.469 | 0.508 | |
Male sex | 1.150 | 0.924–1.430 | 0.034 | 0.808 | 0.590–1.107 | 0.185 | |
Family history of GC | 0.926 | 0.451–1.904 | 0.835 | ||||
Absence of previous history of GC | 2.421 | 1.211–4.839 | 0.012 | 0.838 | 0.340–2.066 | 0.701 | |
Absence of |
0.755 | 0.579–0.984 | 0.038 | 0.686 | 0.498–0.945 | 0.021 | |
Smoking history | 5.374 | 4.149–6.960 | <0.001 | 4.928 | 3.290–7.383 | <0.001 | |
Hypertension | 1.130 | 0.919–1.389 | 0.247 | 1.264 | 0.935–1.709 | 0.128 | |
Diabetes mellitus | 1.113 | 0.846–1.163 | 0.445 | 0.738 | 0.497–1.096 | 0.132 | |
Aspirin use | 0.815 | 0.590–1.127 | 0.217 | 0.949 | 0.601–1.498 | 0.821 | |
Tumor location | |||||||
Lower third of stomach (reference) | 1.000 | 1.000 | |||||
Middle third of stomach | 0.785 | 0.635–0.971 | 0.025 | 0.654 | 0.487–0.878 | 0.005 | |
Upper third of stomach | 0.963 | 0.651–1.426 | 0.851 | 1.161 | 0.636–2.121 | 0.626 | |
Tumor size >10 mm | 2.730 | 2.200–3.389 | <0.001 | 3.467 | 2.571–4.675 | <0.001 | |
Gross type | |||||||
Elevated (reference) | 1.000 | 1.000 | |||||
Flat | 0.468 | 0.368–0.596 | <0.001 | 0.790 | 0.577–1.084 | 0.144 | |
Depressed | 2.320 | 1.661–3.239 | <0.001 | 3.270 | 2.067–5.171 | <0.001 | |
Absence of ulcer | 0.226 | 0.176–0.291 | <0.001 | 0.203 | 0.147–0.282 | <0.001 |
LGD, low-grade dysplasia; GC, gastric cancer; OR, odds ratio; CI, confidence interval.
The Effect of the Presence of 0–6 Risk Factors upon Upstaging of LGD to GC
No. of risk factors |
LGD or downgrade diagnostic group (n=1,169) |
GC group (n=589) |
Total (n=1,778) |
---|---|---|---|
0 | 3 | 0 | 3 |
1 | 65 | 1 | 66 |
2 | 394 | 39 | 433 |
3 | 462 | 162 | 624 |
4 | 222 | 234 | 456 |
5 | 23 | 134 | 157 |
6 | 0 | 19 | 19 |
Date are presented as number. Risk factors:
LGD, low-grade dysplasia; GC, gastric cancer.
Factors Associated with Upstaging of HGD to GC in Univariate and Multivariate Analysis
Factor | Univariate analysis | Multivariate analysis | |||||
---|---|---|---|---|---|---|---|
OR | 95% CI | p-value | OR | 95% CI | p-value | ||
Age >65 yr | 0.868 | 0.691–1.090 | 0.223 | 0.789 | 0.600–1.039 | 0.092 | |
Male sex | 1.307 | 1.020–1.675 | 0.034 | 0.862 | 0.625–1.189 | 0.366 | |
Family history of GC | 0.714 | 0.365–1.398 | 0.326 | ||||
Absence of previous history of GC | 0.622 | 0.378–1.023 | 0.061 | 0.459 | 0.257–0.819 | 0.008 | |
Absence of |
0.655 | 0.197–0.863 | 0.003 | 0.585 | 0.430–0.795 | 0.001 | |
Smoking history | 2.399 | 1.844–3.121 | <0.001 | 2.527 | 1.790–3.567 | <0.001 | |
Hypertension | 1.016 | 0.806–1.281 | 0.892 | ||||
Diabetes mellitus | 1.115 | 0.826–1.506 | 0.475 | ||||
Aspirin use | 0.944 | 0.668–1.334 | 0.744 | ||||
Tumor location | |||||||
Lower third of stomach (reference) | 1.000 | 1.000 | |||||
Middle third of stomach | 0.846 | 0.660–1.084 | 0.185 | 0.849 | 0.628–1.147 | 0.285 | |
Upper third of stomach | 0.702 | 0.468–1.053 | 0.087 | 0.544 | 0.332–0.890 | 0.015 | |
Tumor size >10 mm | 1.293 | 1.015–1.649 | 0.038 | 1.934 | 1.438–2.600 | <0.001 | |
Gross type | |||||||
Elevated (reference) | 1.000 | 1.000 | |||||
Flat | 0.874 | 0.661–1.156 | 0.346 | 1.048 | 0.752–1.461 | 0.780 | |
Depressed | 2.430 | 1.747–3.381 | <0.001 | 2.551 | 1.731–3.758 | <0.001 | |
Absence of ulcer | 0.627 | 0.484–0.812 | <0.001 | 0.537 | 0.388–0.743 | <0.001 |
HGD, high-grade dysplasia; GC, gastric cancer; OR, odds ratio; CI, confidence interval.
The Effect of the Presence of 0–7 Risk Factors upon Upstaging of HGD to GC
No. of risk factors |
HGD or downgrade diagnostic group (n=419) |
GC group (n=1,115) |
Total (n=1,534) |
---|---|---|---|
0 | 1 | 0 | 1 |
1 | 9 | 3 | 12 |
2 | 54 | 63 | 117 |
3 | 175 | 266 | 441 |
4 | 120 | 445 | 565 |
5 | 51 | 246 | 297 |
6 | 9 | 84 | 93 |
7 | 0 | 8 | 8 |
Date are presented as number. Risk factors: previous history of GC,
HGD, high-grade dysplasia; GC, gastric cancer.
Table 1 Baseline Characteristics
Characteristics | LGD on | HGD on |
---|---|---|
Age, yr | 63.89±9.36 | 65.24±9.17 |
Male sex | 1,493 (69.4) | 1,113 (72.6) |
Family history of GC | 73 (3.4) | 60 (3.9) |
Previous history of GC | 43 (2.0) | 70 (4.6) |
570 (26.5) | 371 (24.2) | |
Smoking history | 379 (17.6) | 527 (34.4) |
Hypertension | 748 (34.8) | 579 (37.7) |
Diabetes mellitus | 338 (15.7) | 270 (17.6) |
Aspirin use | 232 (10.8) | 180 (11.7) |
Tumor location | ||
Lower third of stomach | 1,217 (56.6) | 952 (62.1) |
Middle third of stomach | 789 (36.7) | 461 (30.0) |
Upper third of stomach | 144 (6.7) | 121 (7.9) |
Tumor size, mm | 13.94±11.28 | 15.89±11.92 |
Gross type | ||
Elevated | 1,249 (58.1) | 851 (55.5) |
Flat | 692 (32.2) | 322 (21.0) |
Depressed | 209 (9.7) | 361 (23.5) |
Ulcer | 91 (4.2) | 220 (14.3) |
Pathologic concordance | 1,038 (48.3) | 328 (21.4) |
Pathologic downstage | 131 (6.1) | 91 (5.9) |
Pathologic upstage to GC | 589 (27.4) | 1,115 (72.7) |
Endoscopic resection method | ||
EMR | 996 (46.3) | 405 (26.4) |
ESD | 1,154 (53.7) | 1,129 (73.6) |
2,085 (97.1) | 1,486 (96.9) | |
Complete resection | 2,092 (97.4) | 1,494 (97.4) |
Data are presented as mean±SD or number (%).
LGD, low-grade dysplasia; HGD, high-grade dysplasia; FB, forceps biopsy; GC, gastric cancer; EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection.
Table 2 Risk Factors for Upgrading of LGD to GC in Univariate and Multivariate Analysis
Factor | Univariate analysis | Multivariate analysis | |||||
---|---|---|---|---|---|---|---|
OR | 95% CI | p-value | OR | 95% CI | p-value | ||
Age >65 yr | 1.234 | 1.012–1.504 | 0.038 | 1.102 | 0.827–1.469 | 0.508 | |
Male sex | 1.150 | 0.924–1.430 | 0.034 | 0.808 | 0.590–1.107 | 0.185 | |
Family history of GC | 0.926 | 0.451–1.904 | 0.835 | ||||
Absence of previous history of GC | 2.421 | 1.211–4.839 | 0.012 | 0.838 | 0.340–2.066 | 0.701 | |
Absence of | 0.755 | 0.579–0.984 | 0.038 | 0.686 | 0.498–0.945 | 0.021 | |
Smoking history | 5.374 | 4.149–6.960 | <0.001 | 4.928 | 3.290–7.383 | <0.001 | |
Hypertension | 1.130 | 0.919–1.389 | 0.247 | 1.264 | 0.935–1.709 | 0.128 | |
Diabetes mellitus | 1.113 | 0.846–1.163 | 0.445 | 0.738 | 0.497–1.096 | 0.132 | |
Aspirin use | 0.815 | 0.590–1.127 | 0.217 | 0.949 | 0.601–1.498 | 0.821 | |
Tumor location | |||||||
Lower third of stomach (reference) | 1.000 | 1.000 | |||||
Middle third of stomach | 0.785 | 0.635–0.971 | 0.025 | 0.654 | 0.487–0.878 | 0.005 | |
Upper third of stomach | 0.963 | 0.651–1.426 | 0.851 | 1.161 | 0.636–2.121 | 0.626 | |
Tumor size >10 mm | 2.730 | 2.200–3.389 | <0.001 | 3.467 | 2.571–4.675 | <0.001 | |
Gross type | |||||||
Elevated (reference) | 1.000 | 1.000 | |||||
Flat | 0.468 | 0.368–0.596 | <0.001 | 0.790 | 0.577–1.084 | 0.144 | |
Depressed | 2.320 | 1.661–3.239 | <0.001 | 3.270 | 2.067–5.171 | <0.001 | |
Absence of ulcer | 0.226 | 0.176–0.291 | <0.001 | 0.203 | 0.147–0.282 | <0.001 |
LGD, low-grade dysplasia; GC, gastric cancer; OR, odds ratio; CI, confidence interval.
Table 3 The Effect of the Presence of 0–6 Risk Factors upon Upstaging of LGD to GC
No. of | LGD or | GC group | Total |
---|---|---|---|
0 | 3 | 0 | 3 |
1 | 65 | 1 | 66 |
2 | 394 | 39 | 433 |
3 | 462 | 162 | 624 |
4 | 222 | 234 | 456 |
5 | 23 | 134 | 157 |
6 | 0 | 19 | 19 |
Date are presented as number. Risk factors:
LGD, low-grade dysplasia; GC, gastric cancer.
Table 4 Factors Associated with Upstaging of HGD to GC in Univariate and Multivariate Analysis
Factor | Univariate analysis | Multivariate analysis | |||||
---|---|---|---|---|---|---|---|
OR | 95% CI | p-value | OR | 95% CI | p-value | ||
Age >65 yr | 0.868 | 0.691–1.090 | 0.223 | 0.789 | 0.600–1.039 | 0.092 | |
Male sex | 1.307 | 1.020–1.675 | 0.034 | 0.862 | 0.625–1.189 | 0.366 | |
Family history of GC | 0.714 | 0.365–1.398 | 0.326 | ||||
Absence of previous history of GC | 0.622 | 0.378–1.023 | 0.061 | 0.459 | 0.257–0.819 | 0.008 | |
Absence of | 0.655 | 0.197–0.863 | 0.003 | 0.585 | 0.430–0.795 | 0.001 | |
Smoking history | 2.399 | 1.844–3.121 | <0.001 | 2.527 | 1.790–3.567 | <0.001 | |
Hypertension | 1.016 | 0.806–1.281 | 0.892 | ||||
Diabetes mellitus | 1.115 | 0.826–1.506 | 0.475 | ||||
Aspirin use | 0.944 | 0.668–1.334 | 0.744 | ||||
Tumor location | |||||||
Lower third of stomach (reference) | 1.000 | 1.000 | |||||
Middle third of stomach | 0.846 | 0.660–1.084 | 0.185 | 0.849 | 0.628–1.147 | 0.285 | |
Upper third of stomach | 0.702 | 0.468–1.053 | 0.087 | 0.544 | 0.332–0.890 | 0.015 | |
Tumor size >10 mm | 1.293 | 1.015–1.649 | 0.038 | 1.934 | 1.438–2.600 | <0.001 | |
Gross type | |||||||
Elevated (reference) | 1.000 | 1.000 | |||||
Flat | 0.874 | 0.661–1.156 | 0.346 | 1.048 | 0.752–1.461 | 0.780 | |
Depressed | 2.430 | 1.747–3.381 | <0.001 | 2.551 | 1.731–3.758 | <0.001 | |
Absence of ulcer | 0.627 | 0.484–0.812 | <0.001 | 0.537 | 0.388–0.743 | <0.001 |
HGD, high-grade dysplasia; GC, gastric cancer; OR, odds ratio; CI, confidence interval.
Table 5 The Effect of the Presence of 0–7 Risk Factors upon Upstaging of HGD to GC
No. of risk | HGD or | GC group | Total |
---|---|---|---|
0 | 1 | 0 | 1 |
1 | 9 | 3 | 12 |
2 | 54 | 63 | 117 |
3 | 175 | 266 | 441 |
4 | 120 | 445 | 565 |
5 | 51 | 246 | 297 |
6 | 9 | 84 | 93 |
7 | 0 | 8 | 8 |
Date are presented as number. Risk factors: previous history of GC,
HGD, high-grade dysplasia; GC, gastric cancer.