EDITORIAL Helicobacter pylori Eradication and Metachronous Gastric Cancer n this issue, Choi and coworkers report their study regarding whether Helicobacter pylori eradication reduced the rate of metachronous gastric cancers after endoscopic resection of an early gastric cancer or dysplasia.1 This question was originally raised by Uemura and coworkers,2 who followed Japanese patients for 3 years after endoscopic resection of early gastric cancer; metachronous gastric cancer developed in 0 of 65 with eradication versus 6 (9%) of 67 without (P ¼ .011). A subsequent prospective multicenter randomized study followed 544 patients after early gastric cancer removal who were randomly assigned to H pylori eradication (n ¼ 272) or not (n ¼ 272).3 Metachronous gastric carcinoma developed in 9 treated patients versus 24 control subjects (odds ratio, 0.353; 95% conﬁdence interval, 0.161–0.775; P ¼ .009). There have been a number of subsequent retrospective analyses of metachronous cancer after endoscopic resection of early gastric cancer and not all agreed that H pylori eradication signiﬁcantly reduces the rate of metachronous cancer (reviewed in1). Intestinal-type gastric cancer is a product of chronic H pylori infection. H pylori infection is a necessary but insufﬁcient causative factor with the cancer appearing after decades of chronic inﬂammation. H pylori cause inﬂammation and also genetic and epigenetic changes resulting in genetic instability.4 In addition, mucosal damage produces hypochlorhydria and achlorhydria, which may allow overgrowth of non–H pylori bacteria that promote biotransformation of ingested or secreted compounds (eg, nitrates) to produce carcinogens.5 Helicobacter pylori infection is acquired in childhood and after a long latent period the population risk of gastric cancer increases exponentially (Figure 1). This rapid increase is associated with, and a surrogate for, the development of atrophic gastritis/gastric atrophy. The strong association of gastric cancer risk with atrophic gastritis was recognized in the late 19th century, extensively investigated through the early 1950s,6 and ﬁnally codiﬁed in the 1970s.7 The basic features and relationships are well known; however, the details regarding interactions between the organism and development of cancer remain unclear. There are also many largely unexplored host, environmental, and bacterial interactions that underlie why, in the absence of H pylori infection, autoimmune-associated gastritis/gastric atrophy rarely results in gastric cancer8 or why in tropical regions H pylori is common but atrophic changes and gastric cancer are rare.
Cancer Risk and Gastric Histology Intestinal-type gastric cancer, the most common form, is associated with severe and extensive alterations in the
gastric mucosa. H pylori are unable to survive in a very acid environment and are initially largely restricted to the non–acid-secreting antrum and to the superﬁcial mucosa of the gastric body. Atrophic gastritis of the gastric corpus occurs as an advancing front during which a band of intense inﬂammation progresses proximally from the antrum into the corpus leaving behind a zone or lawn of metaplastic epithelium called pyloric, pseudopyloric, or mucus metaplasia. Most recently this has been termed “spasmolytic polypeptide-expressing epithelium.” Pyloric metaplasia was difﬁcult to identify9 until it was found that it was easily seen following immunostaining for spasmolytic polypeptide.10 Spasmolytic polypeptide-expressing cells are thought to arise by transdifferentiation of chief cells10,11 and both intestinal metaplasia and gastric cancer are now thought to arise from spasmolytic polypeptide-expressing epithelium.10,11 Over time H pylori infection–induced genetic instability can eventuate in intramucosal neoplasia and subsequently invasive malignancy. Helicobacter pylori eradication stops the progression and may reverse some of the damage to the mucosa. After H pylori eradication in the presence of a nonatrophic mucosa the cancer risk remains minimal. The beneﬁt of eradication is proportional to the baseline cancer risk present when H pylori eradication occurs. Eradication should stabilize risk so that the patient’s cancer risk does not continue to increase exponentially. If parietal cells remain but are suppressed by inﬂammatory mediators (eg, interleukin 1b) the resulting improvement in acid secretion would further reduce or eliminate untoward effects associated with overgrowth with non–H pylori bacteria.
Metachronous Cancers After Resection of an Early Gastric Cancer Gastric cancer develops in the soil of extensive chronic atrophic gastritis and the entire mucosa is exposed to the same processes (ie, ﬁeld carcinogenesis). Prior studies that carefully examined stomachs resected for gastric cancer have found that 4%–15% of resected stomachs contained foci of cancer.12 These ﬁndings are consistent with the high risk of metachronous cancer that occurs after simply removing a small area of mucosa. Is the effect of H pylori eradication on the rate of metachronous cancers of only academic interest or does it have clinical use? Academics focus on understanding “why,” whereas clinicians typically want information about “what” to do. By the time a gastric cancer becomes visible one should expect that that stomach likely harbors areas containing premalignant and possibly malignant microlesions. H pylori eradication could result in their regression or a change in growth rate. However, regression seems unlikely. H pylori eradication can still positively inﬂuence outcome Clinical Gastroenterology and Hepatology 2014;12:801–803
David Y. Graham
Clinical Gastroenterology and Hepatology Vol. 12, No. 5
Figure 1. Increase in gastric cancer with age and state of disease. The basic data represent the incidence of gastric cancer in Japanese men in the late 1960s and are representative of a population with a high incidence of Helicobacter pylori and atrophic gastritis. (A) The incidence of gastric cancer is plotted logarithmically. The incidence in those with atrophic gastritis/ gastric atrophy is also shown, as is the incidence of metachronous cancers after endoscopic resection of an early gastric cancer. (B) Latent period and the period of exponential increase, which correlate with increasing extent and severity of atrophic gastritis.
because it promotes healing of gastritis with regression of the inﬂammatory reaction, especially inﬁltration with acute inﬂammatory cells and cytokines, which may have tumorpromoting activity.13 In addition, continuing H pylori– related genetic damage is curtailed with down-regulation of activation-induced cytidine deaminase and as yet poorly understood factors leading to double-stranded DNA breaks and microsatellite instability.4 H pylori eradication also stops and possibly reverses epigenetic damage associated with H pylori–induced DNA methylation and aberrant expression of miRNAs.14 Finally, as noted above, any return of or improvement in acid secretion would reduce or eliminate bacterial overgrowth and its deleterious effects.4,15 Because the stomach of patients with endoscopically removable early gastric cancers likely also contains other undetectable lesions, these patients are potentially ideal candidates for cancer immunotherapy to eliminate residual disease. Their early gastric cancers might also provide antigens needed for patient-speciﬁc vaccination.
Summary The presence of an early gastric cancer identiﬁes a patient at high risk for subsequent gastric malignancies. The available data are consistent with the hypothesis that H pylori eradication does no harm and likely changes the milieu in favor of an improved outcome. In some studies patients seem to do better than in others. To understand why, we need to identify prognostic or
predictive biomarkers regarding subsequent risk. Studies in those with multiple gastric cancers have suggested microsatellite instability as a potential marker.16 Ideally, studies would evaluate patients before and after H pylori eradication. Noninvasive markers might be identiﬁed by study of the presence, titers, and changes over time of anti–H pylori IgG or anti-CagA antibodies, or the levels and changes in serum pepsinogens, gastrins, and miRNAs.17 Other parameters might include the location, extent, and severity of inﬂammation and other histologic changes before and after H pylori eradication and the effects on acid secretion and the gastric microbiome. Studies need to match patients in terms of potential prognostic factors. There is no prize for proof that H pylori eradication does, or does not, reliably reduce the incidence of metachronous cancers. Carefully thought-out prospective studies are needed to address the why and provide us with the what to do for individual patients. DAVID Y. GRAHAM, MD Department of Medicine Michael E. DeBakey VA Medical Center and Baylor College of Medicine Houston, Texas
References 1. Choi J, Kim SG, Yoon H, 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.
May 2014 2. Uemura N, Mukai T, Okamoto S, et al. Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer. Cancer Epidemiol Biomarkers Prev 1997;6:639–642. 3. Fukase K, Kato M, Kikuchi S, et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet 2008;372:392–397. 4. Shiotani A, Cen P, Graham DY. Eradication of gastric cancer is now both possible and practical. Semin Cancer Biol 2013;23:492–501. 5. Correa P, Cuello C, Gordillo G, et al. The gastric microenvironment in populations at high risk to stomach cancer. Natl Cancer Inst Monogr 1979;53:167–170. 6. Graham DY, Asaka M. Eradication of gastric cancer and more efﬁcient gastric cancer surveillance in Japan: two peas in a pod. J Gastroenterol 2010;45:1–8.
13. Mantovani A, Cassatella MA, Costantini C, et al. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 2011;11:519–531. 14. Nishizawa T, Suzuki H. The role of microRNA in gastric malignancy. Int J Mol Sci 2013;14:9487–9496. 15. Graham DY, Shiotani A, El–Zimaity HM. Chromoendoscopy points the way to understanding recovery of gastric function after Helicobacter pylori eradication. Gastrointest Endosc 2006; 64:686–690. 16. Miyoshi E, Haruma K, Hiyama T, et al. Microsatellite instability is a genetic marker for the development of multiple gastric cancers. Int J Cancer 2001;95:350–353. 17. Shiotani A, Murao T, Kimura Y, et al. Identiﬁcation of serum miRNAs as novel non-invasive biomarkers for detection of high risk for early gastric cancer. Br J Cancer 2013; 109:2323–2330.
7. Correa P, Haenszel W, Cuello C, et al. A model for gastric cancer epidemiology. Lancet 1975;2:58–60. 8. Rugge M, Fassan M, Pizzi M, et al. Letter: gastric cancer and pernicious anaemia—often Helicobacter pylori in disguise. Aliment Pharmacol Ther 2013;37:764–765. 9. El–Zimaity HM, Ota H, Graham DY, et al. Patterns of gastric atrophy in intestinal type gastric carcinoma. Cancer 2002; 94:1428–1436. 10. Schmidt PH, Lee JR, Joshi V, et al. Identiﬁcation of a metaplastic cell lineage associated with human gastric adenocarcinoma. Lab Invest 1999;79:639–646. 11. Goldenring JR, Nam KT. Oxyntic atrophy, metaplasia, and gastric cancer. Prog Mol Biol Transl Sci 2010;96:117–131. 12. Peng J, Wang Y. Epidemiology, pathology and clinical management of multiple gastric cancers: a mini-review. Surg Oncol 2010; 19:e110–e114.
Conﬂicts of interest The author discloses the following: Dr Graham is an unpaid consultant for Novartis in relation to vaccine development for treatment or prevention of Helicobacter pylori infection. Dr Graham is a paid consultant for RedHill Biopharma regarding novel H pylori therapies and for Otsuka Pharmaceuticals regarding diagnostic testing. Dr Graham has received royalties from Baylor College of Medicine patents covering materials related to 13C-urea breath test. Funding Dr Graham is supported in part by the Ofﬁce of Research and Development Medical Research Service Department of Veterans Affairs, Public Health Service grant DK56338, which funds the Texas Medical Center Digestive Diseases Center and DK067366. The contents are solely the responsibility of the author and do not necessarily represent the ofﬁcial views of the Veteran Administration or the National Institutes of Health. http://dx.doi.org/10.1016/j.cgh.2013.10.029