J Gastric Cancer.  2015 Dec;15(4):246-255. 10.5230/jgc.2015.15.4.246.

Helicobacter pylori Eradication Reduces the Metachronous Recurrence of Gastric Neoplasms by Attenuating the Precancerous Process

• Jung DH
• Kim JH
• Lee YC
• Lee SK
• Shin SK
• Park JC
• Chung HS
• Kim H
• Kim H
• Kim YH
• Park JJ
• Youn YH
• Park H

• KMID: 2391559
• DOI: http://doi.org/10.5230/jgc.2015.15.4.246

Abstract

PURPOSE
The importance of Helicobacter pylori eradication after endoscopic resection (ER) of gastric neoplasms remains controversial. In this study, we clarified the importance of H. pylori eradication for metachronous lesions after ER.
MATERIALS AND METHODS
This study included 3,882 patients with gastric neoplasms who underwent ER. We included patients infected with H. pylori who received eradication therapy. Among them, 34 patients with metachronous lesions after ER and 102 age- and sex-matched patients (nonmetachronous group) were enrolled. Background mucosal pathologies such as atrophy and intestinal metaplasia (IM) were evaluated endoscopically. The expression levels of CDX1, CDX2, Sonic hedgehog (SHH), and SOX2 were evaluated based on H. pylori eradication and the development of metachronous lesions.
RESULTS
The eradication failure rate was higher in the metachronous group than in the nonmetachronous group (P=0.036). Open-type atrophy (P=0.003) and moderate-to-severe IM (P=0.001) occurred more frequently in the metachronous group. In patients with an initial diagnosis of dysplasia, the eradication failure rate was higher in the metachronous group than in the nonmetachronous group (P=0.002). In addition, open-type atrophy was more frequent in the metachronous group (P=0.047). In patients with an initial diagnosis of carcinoma, moderate-to-severe IM occurred more frequently in the metachronous group (P=0.003); however, the eradication failure rate was not significantly different between the two groups. SHH and SOX2 expression was increased, and CDX2 expression was decreased in the nonmetachronous group after eradication (P<0.05).
CONCLUSIONS
Open-type atrophy, moderate-to-severe IM, and H. pylori eradication failure were significantly associated with metachronous lesions. However, eradication failure was significantly associated with dysplasia, but not carcinoma, in the metachronous group. Thus, H. pylori eradication may play an important role in preventing metachronous lesions after ER for precancerous lesions before carcinomatous transformation.

Keyword

Helicobacter pylori; Metachronous; Endoscopic resection; Stomach neoplasms

MeSH Terms

Atrophy
Diagnosis
Hedgehogs
Helicobacter pylori*
Helicobacter*
Humans
Metaplasia
Pathology
Recurrence*
Stomach Neoplasms*

Figure

• 

  Fig. 1 Protein expression of SOX2, sonic hedgehog (SHH), CDX2, and CDX1 in the background gastric mucosa (×400). (A, B) Immunohistochemical staining for SOX2. Nuclear SOX2 expression increases after Helicobacter pylori eradication in the nonmetachronous group (A) in which metachronous gastric neoplasms do not arise (B). (C, D) Immunohistochemical staining for CDX2. The nuclear expression of CDX2 decreases after H. pylori eradication in the nonmetachronous group (D) in which metachronous gastric neoplasms do not arise (C). (E, F) Immunohistochemical staining for SHH. Cytoplasmic SHH expression increases after H. pylori eradication in the nonmetachronous group (E) in which metachronous gastric neoplasms do not arise (F). (G, H) Immunohistochemical staining for CDX1. The nuclear expression of CDX1 is not significantly different after H. pylori eradication between the nonmetachronous and metachronous groups. (G) Positive CDX1 expression; (H) negative CDX1 expression.

Reference

1. Correa P, Houghton J. Carcinogenesis of Helicobacter pylori. Gastroenterology. 2007; 133:659–672.

2. Wong BC, Lam SK, Wong WM, Chen JS, Zheng TT, Feng RE, et al. China Gastric Cancer Study Group. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA. 2004; 291:187–194.

3. Fukase K, Kato M, Kikuchi S, Inoue K, Uemura N, Okamoto S, et al. Japan Gast Study Group. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an openlabel, randomised controlled trial. Lancet. 2008; 372:392–397.

4. Bae SE, Jung HY, Kang J, Park YS, Baek S, Jung JH, et al. Effect of Helicobacter pylori eradication on metachronous recurrence after endoscopic resection of gastric neoplasm. Am J Gastroenterol. 2014; 109:60–67.

5. Choi J, Kim SG, Yoon H, Im JP, Kim JS, Kim WH, et al. Eradication of Helicobacter pylori after endoscopic resection of gastric tumors does not reduce incidence of metachronous gastric carcinoma. Clin Gastroenterol Hepatol. 2014; 12:793–800.

6. Tsukamoto T, Mizoshita T, Tatematsu M. Gastric-and-intestinal mixed-type intestinal metaplasia: aberrant expression of transcription factors and stem cell intestinalization. Gastric Cancer. 2006; 9:156–166.

7. Shiotani A, Uedo N, Iishi H, Tatsuta M, Ishiguro S, Nakae Y, et al. Re-expression of sonic hedgehog and reduction of CDX2 after Helicobacter pylori eradication prior to incomplete intestinal metaplasia. Int J Cancer. 2007; 121:1182–1189.

8. Hammerschmidt M, Brook A, McMahon AP. The world according to hedgehog. Trends Genet. 1997; 13:14–21.

9. Bitgood MJ, McMahon AP. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev Biol. 1995; 172:126–138.

10. Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell. 1993; 75:1417–1430.

11. van den Brink GR, Hardwick JC, Nielsen C, Xu C, ten Kate FJ, Glickman J, et al. Sonic hedgehog expression correlates with fundic gland differentiation in the adult gastrointestinal tract. Gut. 2002; 51:628–633.

12. van den Brink GR, Hardwick JC, Tytgat GN, Brink MA, Ten Kate FJ, Van Deventer SJ, et al. Sonic hedgehog regulates gastric gland morphogenesis in man and mouse. Gastroenterology. 2001; 121:317–328.

13. Shiotani A, Iishi H, Uedo N, Ishiguro S, Tatsuta M, Nakae Y, et al. Evidence that loss of sonic hedgehog is an indicator of Helicobater pylori-induced atrophic gastritis progressing to gastric cancer. Am J Gastroenterol. 2005; 100:581–587.

14. Mizoshita T, Inada K, Tsukamoto T, Kodera Y, Yamamura Y, Hirai T, et al. Expression of Cdx1 and Cdx2 mRNAs and relevance of this expression to differentiation in human gastrointestinal mucosa: with special emphasis on participation in intestinal metaplasia of the human stomach. Gastric Cancer. 2001; 4:185–191.

15. Tsukamoto T, Inada K, Tanaka H, Mizoshita T, Mihara M, Ushijima T, et al. Down-regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes, Cdx1 and Cdx2: inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia. J Cancer Res Clin Oncol. 2004; 130:135–145.

16. Ito S, Azuma T, Murakita H, Hirai M, Miyaji H, Ito Y, et al. Profile of Helicobacter pylori cytotoxin derived from two areas of Japan with different prevalence of atrophic gastritis. Gut. 1996; 39:800–806.

17. Lim JH, Kim N, Lee HS, Choe G, Jo SY, Chon I, et al. Correlation between Endoscopic and Histological Diagnoses of Gastric Intestinal Metaplasia. Gut Liver. 2013; 7:41–50.

18. Soetikno R, Kaltenbach T, Yeh R, Gotoda T. Endoscopic mucosal resection for early cancers of the upper gastrointestinal tract. J Clin Oncol. 2005; 23:4490–4498.

19. Choi MK, Kim GH, Park do Y, Song GA, Kim DU, Ryu DY, et al. Long-term outcomes of endoscopic submucosal dissection for early gastric cancer: a single-center experience. Surg Endosc. 2013; 27:4250–4258.

20. Jang JS, Choi SR, Qureshi W, Kim MC, Kim SJ, Jeung JS, et al. Long-term outcomes of endoscopic submucosal dissection in gastric neoplastic lesions at a single institution in South Korea. Scand J Gastroenterol. 2009; 44:1315–1322.

21. Isomoto H, Shikuwa S, Yamaguchi N, Fukuda E, Ikeda K, Nishiyama H, et al. Endoscopic submucosal dissection for early gastric cancer: a large-scale feasibility study. Gut. 2009; 58:331–336.

22. Nasu J, Doi T, Endo H, Nishina T, Hirasaki S, Hyodo I. Characteristics of metachronous multiple early gastric cancers after endoscopic mucosal resection. Endoscopy. 2005; 37:990–993.

23. Kwon YH, Heo J, Lee HS, Cho CM, Jeon SW. Failure of Helicobacter pylori eradication and age are independent risk factors for recurrent neoplasia after endoscopic resection of early gastric cancer in 283 patients. Aliment Pharmacol Ther. 2014; 39:609–618.

24. Gutierrez-Gonzalez L, Graham TA, Rodriguez-Justo M, Leedham SJ, Novelli MR, Gay LJ, et al. The clonal origins of dysplasia from intestinal metaplasia in the human stomach. Gastroenterology. 2011; 140:1251–1260.

25. Sugano K. Premalignant conditions of gastric cancer. J Gastroenterol Hepatol. 2013; 28:906–911.

26. Bornschein J, Tóth K, Selgrad M, Kuester D, Wex T, Molnár B, et al. Dysregulation of CDX1, CDX2 and SOX2 in patients with gastric cancer also affects the non-malignant mucosa. J Clin Pathol. 2013; 66:819–822.

27. Mutoh H, Sakurai S, Satoh K, Tamada K, Kita H, Osawa H, et al. Development of gastric carcinoma from intestinal metaplasia in Cdx2-transgenic mice. Cancer Res. 2004; 64:7740–7747.

28. Tsukamoto T, Mizoshita T, Mihara M, Tanaka H, Takenaka Y, Yamamura Y, et al. Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and-intestinal-mixed phenotypes. Histopathology. 2005; 46:649–658.