Background/Aims: Although gastric atrophy is primarily caused by Helicobacter pylori infection, it is unclear why patients serologically diagnosed with gastric atrophy without H. pylori infection exhibit greater atrophy. We investigated histopathological features in serologically diagnosed gastric atrophy without H. pylori infection. Methods: Thirty-four patients with positive serum pepsinogen and negative serum H. pylori antibody tests underwent gastric biopsy and histological evaluation. The presence of enterochromaffin-like cells (ECL) was also evaluated. Gastric cancer risks for each histological feature according to the Operative Link on Gastritis Assessment (OLGA) and Operative Link on Gastric Intestinal Metaplasia (OLGIM) were assessed. Results: Twenty-five (74%) patients had histological gastric atrophy. Among those, the following histological subgroups were identified: eight had H. pylori but no ECL, 13 had neither H. pylori nor ECL, and 4 had ECL without H. pylori. Nine patients without histological atrophy had neither H. pylori nor ECL. Patients with H. pylori on histological diagnosis had significantly higher scores on OLGA and OLGIM. Conclusions: Various histological features, with significant differences in gastric cancer risk, were identified in the gastric mucosa serologically diagnosed with atrophy without H. pylori infection. Therefore, serological screening for gastric cancer risk tests has several limitations, and additional evaluations should be considered.

1.
Dinis-Ribeiro M, Kuipers EJ. Identification of gastric atrophic changes: from histopathology to endoscopy. Endoscopy. 2015 Jun; 47(6): 533–7.
2.
Adamu MA, Weck MN, Rothenbacher D, Brenner H. Incidence and risk factors for the development of chronic atrophic gastritis: five year follow-up of a population-based cohort study. Int J Cancer. 2011 Apr; 128(7): 1652–8.
3.
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 Sep; 345(11): 784–9.
4.
Miki K, Morita M, Sasajima M, Hoshina R, Kanda E, Urita Y. Usefulness of gastric cancer screening using the serum pepsinogen test method. Am J Gastroenterol. 2003 Apr; 98(4): 735–9.
5.
Miki K, Urita Y. Using serum pepsinogens wisely in a clinical practice. J Dig Dis. 2007 Feb; 8(1): 8–14.
6.
Correa P, Piazuelo MB. The gastric precancerous cascade. J Dig Dis. 2012 Jan; 13(1): 2–9.
7.
Miki K. Gastric cancer screening using the serum pepsinogen test method. Gastric Cancer. 2006; 9(4): 245–53.
8.
Yamaguchi Y, Nagata Y, Hiratsuka R, ­Kawase Y, Tominaga T, Takeuchi S, et al. Gastric Cancer Screening by Combined ­Assay for Serum Anti-Helicobacter pylori IgG Antibody and Serum Pepsinogen Levels—the ABC Method. Digestion. 2016; 93(1): 13–8.
9.
Kudo T, Kakizaki S, Sohara N, Onozato Y, Okamura S, Inui Y, et al. Analysis of ABC (D) stratification for screening patients with gastric cancer. World J Gastroenterol. 2011 Nov; 17(43): 4793–8.
10.
Kishikawa H, Kimura K, Takarabe S, Kaida S, Nishida J. Helicobacter pylori Antibody Titer and Gastric Cancer Screening. Dis Markers. 2015; 2015: 156719.
11.
Ohata H, Kitauchi S, Yoshimura N, Mugitani K, Iwane M, Nakamura H, et al. Progression of chronic atrophic gastritis associated with Helicobacter pylori infection increases risk of gastric cancer. Int J Cancer. 2004 Mar; 109(1): 138–43.
12.
Tatemichi M, Sasazuki S, Inoue M, Tsugane S; JPHC Study Group. Clinical significance of IgG antibody titer against Helicobacter pylori. Helicobacter. 2009 Jun; 14(3): 231–6.
13.
Rugge M, Pennelli G, Pilozzi E, Fassan M, Ingravallo G, Russo VM, et al.; Gruppo ­Italiano Patologi Apparato Digerente (GIPAD); Società Italiana di Anatomia Patologica e Citopatologia Diagnostica/International Academy of Pathology, Italian division (SIAPEC/IAP). Gastritis: the histology report. Dig Liver Dis. 2011 Mar; 43 Suppl 4: S373–84.
14.
Mizuno S, Miki I, Ishida T, Yoshida M, Onoyama M, Azuma T, et al. Prescreening of a high-risk group for gastric cancer by serologically determined Helicobacter pylori infection and atrophic gastritis. Dig Dis Sci. 2010 Nov; 55(11): 3132–7.
15.
Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol. 1996 Oct; 20(10): 1161–81.
16.
Rugge M, Meggio A, Pennelli G, Piscioli F, Giacomelli L, De Pretis G, et al. Gastritis staging in clinical practice: the OLGA staging system. Gut. 2007 May; 56(5): 631–6.
17.
Satoh K, Osawa H, Yoshizawa M, Nakano H, Hirasawa T, Kihira K, et al. Assessment of atrophic gastritis using the OLGA system. Helicobacter. 2008 Jun; 13(3): 225–9.
18.
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 Jun; 71(7): 1150–8.
19.
Sugano K, Tack J, Kuipers EJ, Graham DY, El-Omar EM, Miura S, et al.; faculty members of Kyoto Global Consensus Conference. Kyoto global consensus report on Helicobacter pylori gastritis. Gut. 2015 Sep; 64(9): 1353–67.
20.
Gotoda T, Ishikawa H, Ohnishi H, Sugano K, Kusano C, Yokoi C, et al. Randomized controlled trial comparing gastric cancer screening by gastrointestinal X-ray with serology for Helicobacter pylori and pepsinogens followed by gastrointestinal endoscopy. Gastric Cancer. 2015 Jul; 18(3): 605–11.
21.
Dinis-Ribeiro M, Yamaki G, Miki K, Costa-Pereira A, Matsukawa M, Kurihara M. Meta-analysis on the validity of pepsinogen test for gastric carcinoma, dysplasia or chronic atrophic gastritis screening. J Med Screen. 2004; 11(3): 141–7.
22.
Weck MN, Brenner H. Association of Helicobacter pylori infection with chronic atrophic gastritis: meta-analyses according to type of disease definition. Int J Cancer. 2008 Aug; 123(4): 874–81.
23.
Rugge M, de Boni M, Pennelli G, de Bona M, Giacomelli L, Fassan M, et al. Gastritis OLGA-staging and gastric cancer risk: a twelve-year clinico-pathological follow-up study. Aliment Pharmacol Ther. 2010 May; 31(10): 1104–11.
24.
Shiotani A, Cen P, Graham DY. Eradication of gastric cancer is now both possible and practical. Semin Cancer Biol. 2013 Dec; 23(6 6 Pt B): 492–501.
25.
Shuto M, Fujioka T, Matsunari O, Okamoto K, Mizukami K, Okimoto T, et al. Association between Gastric Cancer Risk and Serum Helicobacter pylori Antibody Titers. Gastroenterol Res Pract. 2017; 2017: 1286198.
26.
Agréus L, Kuipers EJ, Kupcinskas L, Malfertheiner P, Di Mario F, Leja M, et al. Rationale in diagnosis and screening of atrophic gastritis with stomach-specific plasma biomarkers. Scand J Gastroenterol. 2012 Feb; 47(2): 136–47.
27.
Kitahara F, Kobayashi K, Sato T, Kojima Y, Araki T, Fujino MA. Accuracy of screening for gastric cancer using serum pepsinogen concentrations. Gut. 1999 May; 44(5): 693–7.
28.
Massironi S, Cavalcoli F, Rossi RE, Conte D, Spampatti MP, Ciafardini C, et al. Chronic autoimmune atrophic gastritis associated with primary hyperparathyroidism: a transversal prospective study. Eur J Endocrinol. 2013 Apr; 168(5): 755–61.
29.
Venerito M, Radünz M, Reschke K, Reinhold D, Frauenschläger K, Jechorek D, et al. Autoimmune gastritis in autoimmune thyroid disease. Aliment Pharmacol Ther. 2015 Apr; 41(7): 686–93.
30.
De Aizpurua HJ, Cosgrove LJ, Ungar B, Toh BH. Autoantibodies cytotoxic to gastric parietal cells in serum of patients with pernicious anemia. N Engl J Med. 1983 Sep; 309(11): 625–9.
31.
Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Arch Intern Med. 1999 Jun; 159(12): 1289–98.
32.
Strickland RG, Hooper B. The parietal cell heteroantibody in human sera: prevalence in a normal population and relationship to parietal cell autoantibody. Pathology. 1972 Oct; 4(4): 259–63.
33.
Kuipers EJ, Peña AS, van Kamp G, Uyterlinde AM, Pals G, Pels NF, et al. Seroconversion for Helicobacter pylori. Lancet. 1993 Aug; 342(8867): 328–31.
34.
Kokkola A, Kosunen TU, Puolakkainen P, Sipponen P, Harkonen M, Laxen F, et al. Spontaneous disappearance of Helicobacter pylori antibodies in patients with advanced atrophic corpus gastritis. APMIS. 2003 Jun; 111(6): 619–24.
35.
Rugge M, Di Mario F, Cassaro M, Baffa R, Farinati F, Rubio J Jr, et al. Pathology of the gastric antrum and body associated with Helicobacter pylori infection in non-ulcerous patients: is the bacterium a promoter of intestinal metaplasia? Histopathology. 1993 Jan; 22(1): 9–15.
36.
Minalyan A, Benhammou JN, Artashesyan A, Lewis MS, Pisegna JR. Autoimmune atrophic gastritis: current perspectives. Clin Exp Gastroenterol. 2017 Feb; 10: 19–27.
37.
Toyoshima O, Nishizawa T, Arita M, Kataoka Y, Sakitani K, Yoshida S, et al. Helicobacter pylori infection in subjects negative for high titer serum antibody. World J Gastroenterol. 2018 Apr; 24(13): 1419–28.
38.
Nam JH, Choi IJ, Kook MC, Lee JY, Cho SJ, Nam SY, et al. OLGA and OLGIM stage distribution according to age and Helicobacter pylori status in the Korean population. Helicobacter. 2014 Apr; 19(2): 81–9.
39.
Rugge M, Fassan M, Pizzi M, Zorzetto V, Maddalo G, Realdon S, et al. Autoimmune gastritis: histology phenotype and OLGA staging. Aliment Pharmacol Ther. 2012 Jun; 35(12): 1460–6.
40.
Wang X, Lu B, Meng L, Fan Y, Zhang S, Li M. The correlation between histological ­gastritis staging- ‘OLGA/OLGIM’ and ­serum pepsinogen test in assessment of ­gastric atrophy/intestinal metaplasia in China. Scand J Gastroenterol. 2017 Aug; 52(8): 822–7.
You do not currently have access to this content.