Chronic atrophic gastritis and intestinal metaplasia surrounding diffuse-type gastric cancer: Are they just bystanders in the process of carcinogenesis?

Autoři: Seung Yong Shin aff001;  Jie-Hyun Kim aff002;  Jaeyoung Chun aff002;  Young Hoon Yoon aff002;  Hyojin Park aff002
Působiště autorů: Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea aff001;  Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article



Gastric cancer (GC) is categorized as diffuse- and intestinal-type adenocarcinoma. Intestinal-type GC is associated with chronic gastritis, atrophic gastritis (AG), and intestinal metaplasia (IM), precursors of dysplastic changes. Diffuse-type GC is generally known to undergo de novo carcinogenesis and is not associated with chronic mucosal changes. However, clinically, AG and IM are frequently observed surrounding diffuse-type GC. This study aimed to evaluate the role of AG and IM in diffuse-type GC.


We retrospectively reviewed the data of patients undergoing surgery for early GC. We divided patients with diffuse-type GC into two groups according to the presence of AG and IM based on Kyoto classification of gastritis. The clinicopathological characteristics were compared between the groups.


Among patients with diffuse-type GC, 52.5% patients had AG and 18.4% had severe AG. With regard to IM, 42.1% patients had IM and 17.1% had severe IM. Diffuse-type GC combined with severe AG or IM showed larger tumor size and higher submucosal invasion rate than that without severe AG or IM. However, the lymph node metastasis (LNM) rate was not significantly different between the two groups. In multivariate analysis, severe AG or IM was not an independent risk factor for LNM.


Severe AG or IM surrounding diffuse-type gastric cancer suggests a collapse of normal mucosal barriers and leads to the spread of cancer cells. Although the association between chronic mucosal changes and LNM is unclear, more caution is needed during endoscopy especially for complete resection of diffuse-type GC with these features.

Klíčová slova:

Adenocarcinomas – Carcinogenesis – Endoscopy – Gastric cancer – Gastritis – Gastrointestinal tract – Helicobacter pylori – Lesions



2. Shah MA, Khanin R, Tang L, Janjigian YY, Klimstra DS, Gerdes H, et al. Molecular classification of gastric cancer: a new paradigm. Clin Cancer Res. 2011;17: 2693–2701. doi: 10.1158/1078-0432.CCR-10-2203 21430069

3. Kunz PL, Gubens M, Fisher GA, Ford JM, Lichtensztajn DY, Clarke CA. Long-term survivors of gastric cancer: a California population-based study. J Clin Oncol. 2012;30: 3507–3515. doi: 10.1200/JCO.2011.35.8028 22949151

4. Laine L, Takeuchi K, Tarnawski A. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology. 2008;135: 41–60. doi: 10.1053/j.gastro.2008.05.030 18549814

5. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process—First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992;52: 6735–6740 1458460

6. Sipponen P, Kekki M, Siurala M. Atrophic chronic gastritis and intestinal metaplasia in gastric carcinoma. Comparison with a representative population sample. Cancer. 1983;52: 1062–1068 doi: 10.1002/1097-0142(19830915)52:6<1062::aid-cncr2820520622>;2-p 6883274

7. Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345: 784–789. doi: 10.1056/NEJMoa001999 11556297

8. Satoh K, Osawa H, Yoshizawa M, Nakano H, Hirasawa T, Kihira K, et al. Assessment of atrophic gastritis using the OLGA system. Helicobacter. 2008;13: 225–229. doi: 10.1111/j.1523-5378.2008.00599.x 18466398

9. Capelle LG, de Vries AC, Haringsma J, Ter Borg F, de Vries RA, Bruno MJ, et al. The staging of gastritis with the OLGA system by using intestinal metaplasia as an accurate alternative for atrophic gastritis. Gastrointest Endosc. 2010;71: 1150–1158. doi: 10.1016/j.gie.2009.12.029 20381801

10. Tsugane S, Kabuto M, Imai H, Gey F, Tei Y, Hanaoka T, et al. Helicobacter pylori, dietary factors, and atrophic gastritis in five Japanese populations with different gastric cancer mortality. Cancer Causes Control. 1993;4: 297–305 doi: 10.1007/bf00051331 8347778

11. Azuma T, Ito S, Sato F, Yamazaki Y, Miyaji H, Ito Y, et al. The role of the HLA-DQA1 gene in resistance to atrophic gastritis and gastric adenocarcinoma induced by Helicobacter pylori infection. Cancer. 1998;82: 1013–1018 doi: 10.1002/(sici)1097-0142(19980315)82:6<1013::aid-cncr2>;2-f 9506344

12. Adachi Y, Yasuda K, Inomata M, Sato K, Shiraishi N, Kitano S. Pathology and prognosis of gastric carcinoma: well versus poorly differentiated type. Cancer. 2000;89: 1418–1424 11013353

13. Sugimoto M, Ban H, Ichikawa H, Sahara S, Otsuka T, Inatomi O, et al. Efficacy of the Kyoto Classification of Gastritis in Identifying Patients at High Risk for Gastric Cancer. Intern Med. 2017;56: 579–586. doi: 10.2169/internalmedicine.56.7775 28321054

14. Shichijo S, Hirata Y, Niikura R, Hayakawa Y, Yamada A, Koike K. Association between gastric cancer and the Kyoto classification of gastritis. J Gastroenterol Hepatol. 2017;32: 1581–1586. doi: 10.1111/jgh.13764 28217843

15. Kamada T, Haruma K, Inoue K, Shiotani A. [Helicobacter pylori infection and endoscopic gastritis -Kyoto classification of gastritis]. Nihon Shokakibyo Gakkai Zasshi. 2015;112: 982–993. doi: 10.11405/nisshoshi.112.982 26050720

16. Kimura K, Satoh K, Ido K, Taniguchi Y, Takimoto T, Takemoto T. Gastritis in the Japanese stomach. Scand J Gastroenterol Suppl. 1996;214: 17–20; discussion 21–13 doi: 10.3109/00365529609094509 8722400

17. Lee JY, Gong EJ, Chung EJ, Park HW, Bae SE, Kim EH, et al. The Characteristics and Prognosis of Diffuse-Type Early Gastric Cancer Diagnosed during Health Check-Ups. Gut Liver. 2017;11: 807–812. doi: 10.5009/gnl17033 28798286

18. Lee SH, Jee SR, Kim JH, Seol SY. Intramucosal gastric cancer: the rate of lymph node metastasis in signet ring cell carcinoma is as low as that in well-differentiated adenocarcinoma. Eur J Gastroenterol Hepatol. 2015;27: 170–174. doi: 10.1097/MEG.0000000000000258 25503738

19. Asaka M, Takeda H, Sugiyama T, Kato M. What role does Helicobacter pylori play in gastric cancer? Gastroenterology. 1997;113: S56–60. doi: 10.1016/s0016-5085(97)80013-3 9394761

20. Correa P, Haenszel W, Cuello C, Tannenbaum S, Archer M. A model for gastric cancer epidemiology. Lancet. 1975;2: 58–60. doi: 10.1016/s0140-6736(75)90498-5 49653

21. El-Omar EM, Oien K, El-Nujumi A, Gillen D, Wirz A, Dahill S, et al. Helicobacter pylori infection and chronic gastric acid hyposecretion. Gastroenterology. 1997;113: 15–24. doi: 10.1016/s0016-5085(97)70075-1 9207257

22. Kishino M, Nakamura S, Shiratori K. Clinical and Endoscopic Features of Undifferentiated Gastric Cancer in Patients with Severe Atrophic Gastritis. Intern Med. 2016;55: 857–862. doi: 10.2169/internalmedicine.55.4841 27086796

23. Inoue K, Fujisawa T, Chinuki D, Kushiyama Y. Characteristics of gastric mucosa in gastric cancer improvement-examination from a clinical survey by endoscopy. Stomach and Intestine. 2009;44: 1367–1373

24. Kim HJ, Choi BY, Byun TJ, Eun CS, Song KS, Kim YS, et al. [The prevalence of atrophic gastritis and intestinal metaplasia according to gender, age and Helicobacter pylori infection in a rural population]. J Prev Med Public Health. 2008;41: 373–379. doi: 10.3961/jpmph.2008.41.6.373 19037166

25. Tsukita S, Furuse M. Pores in the wall: claudins constitute tight junction strands containing aqueous pores. J Cell Biol. 2000;149: 13–16 doi: 10.1083/jcb.149.1.13 10747082

26. Tsukita S, Furuse M. The structure and function of claudins, cell adhesion molecules at tight junctions. Ann N Y Acad Sci. 2000;915: 129–135 doi: 10.1111/j.1749-6632.2000.tb05235.x 11193568

27. Caron TJ, Scott KE, Fox JG, Hagen SJ. Tight junction disruption: Helicobacter pylori and dysregulation of the gastric mucosal barrier. World J Gastroenterol. 2015;21: 11411–11427. doi: 10.3748/wjg.v21.i40.11411 26523106

28. Kim H, Kim JH, Lee YC, Kim H, Youn YH, Park H, et al. Growth Patterns of Signet Ring Cell Carcinoma of the Stomach for Endoscopic Resection. Gut Liver. 2015;9: 720–726. doi: 10.5009/gnl14203 25473081

29. Seo JH, Park JC, Kim YJ, Shin SK, Lee YC, Lee SK. Undifferentiated histology after endoscopic resection may predict synchronous and metachronous occurrence of early gastric cancer. Digestion. 2010;81: 35–42. doi: 10.1159/000235921 20029207

30. Yoshimura T, Shimoyama T, Fukuda S, Tanaka M, Axon AT, Munakata A. Most gastric cancer occurs on the distal side of the endoscopic atrophic border. Scand J Gastroenterol. 1999;34: 1077–1081. doi: 10.1080/003655299750024850 10582756

31. Cho SY, Park JW, Liu Y, Park YS, Kim JH, Yang H, et al. Sporadic Early-Onset Diffuse Gastric Cancers Have High Frequency of Somatic CDH1 Alterations, but Low Frequency of Somatic RHOA Mutations Compared With Late-Onset Cancers. Gastroenterology. 2017;153: 536–549.e526. doi: 10.1053/j.gastro.2017.05.012 28522256

32. Grady WM, Willis J, Guilford PJ, Dunbier AK, Toro TT, Lynch H, et al. Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nat Genet. 2000;26: 16–17. doi: 10.1038/79120 10973239

33. Kakiuchi M, Nishizawa T, Ueda H, Gotoh K, Tanaka A, Hayashi A, et al. Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet. 2014;46: 583–587. doi: 10.1038/ng.2984 24816255

34. Ghatak S, Chakraborty P, Sarkar SR, Chowdhury B, Bhaumik A, Kumar NS. Novel APC gene mutations associated with protein alteration in diffuse type gastric cancer. BMC Med Genet. 2017;18: 61. doi: 10.1186/s12881-017-0427-2 28576136

Článek vyšel v časopise


2019 Číslo 12
Nejčtenější tento týden