Published online Sep 21, 2006. doi: 10.3748/wjg.v12.i35.5622
Revised: October 20, 2005
Accepted: October 26, 2005
Published online: September 21, 2006
Although the Sydney Systems (original and updated) for the classification of gastritis have contributed substantially to the uniformity of the reporting of gastric conditions, they lack immediacy in conveying to the user information about gastric cancer risk. In this review, we summarize the current understanding of the gastric lesions associated with an increased risk for cancer, and present the rationale for a proposal for new ways of reporting gastritis. In addition to the traditional histopathological data gathered and evaluated according to the Sydney System rules, pathologists could add an assessment expressed as grading and staging of the gastric inflammatory and atrophic lesions and integrate these findings with pertinent laboratory information on pepsinogens and gastrin levels. Such an integrated report could facilitate clinicians’ approach to the management of patients with gastric conditions.
- Citation: Genta RM, Rugge M. Assessing risks for gastric cancer: New tools for pathologists. World J Gastroenterol 2006; 12(35): 5622-5627
- URL: https://www.wjgnet.com/1007-9327/full/v12/i35/5622.htm
- DOI: https://dx.doi.org/10.3748/wjg.v12.i35.5622
Chronic gastritis is an inflammatory condition of the gastric mucosa characterized by elementary lesions whose type, extent, and distribution are related to their etiology and modulated by host responses and environmental factors[1]. Infection with H pylori, which affects an estimated three to four billion persons worldwide, is by far the most common cause of chronic active gastritis; chemical agents, autoimmune phenomena, and other infections account for a very small proportion of chronic, usually non-active gastritides. H pylori-gastritis is epidemiologically and biologically linked to the development of gastric cancer[2] and H pylori has been listed as a class I carcinogen[3]. Epidemiological and pathological data suggest that extent, intensity, and distribution patterns of gastric inflammation and atrophy are consistently related to the incidence of gastric cancer in a population[4-7]. Although odd-ratios for gastric cancer and peptic ulcer risk in relationship with the type of gastritis have been estimated, most often retrospectively, only in small series and in few populations[5,8-10], it is widely accepted that the accurate histopathological assessment of the gastric mucosa could serve as a reasonably good predictor of cancer risk in an individual patient. In fact, most recent classifications of gastritis have contained the implicit aim of providing a clinico-pathological correlation that could be both synchronous (that is, at the time of the sampling) and, more usefully, diachronic.
When appropriate sampling is available, the histo-pathological features of the gastric mucosa recognized as being part of the neoplastic process and broadly referred to as “pre-neoplastic lesions” (atrophy, pyloric and intestinal metaplasia, epithelial dysplasia) can be accurately evaluated by the microscopic examination of mucosal biopsies. Although classification systems such as the Sydney System[11], its Houston-updated version[12], and the more recent guidelines for the evaluation of atrophy[13] suggest strategies for the formulation of histopathological reports, we still lack a way to translate the pathological information into a standardized report that would convey comprehensive information on the gastric condition while lending itself to a straightforward analysis of cancer risk.
The purpose of this article is to explore ways for pathologists to maximize the predictive value of the gastric evaluation by: (1) streamlining the histopathological report of gastric biopsies, and (2) integrating relevant laboratory information with pathological data.
As a result of seminal field studies conducted by Max Siurala in Finland and Estonia[14-17] and Pelayo Correa in Colombia[4,18-19], as well as the crucial body of knowledge derived from decades of Japanese studies[20,21], the separate entities of chronic superficial gastritis, atrophy, metaplasia, dysplasia and carcinoma were integrated into a hypothetical sequence known as Correa’s cascade[22]. Increasingly well-documented by patho-epidemiological studies, the 1984 multi-step hypothesis of gastric carcinogenesis still lacked an etiological initiator. The missing first step was discovered in the same year[23] and H pylori found its place at the top of the cascade[24].
The histopathological lesions broadly regarded as preneoplastic are chronic gastritis, atrophy, intestinal metaplasia, dysplasia, and neoplasia. Their evolution in a cohort can be viewed as a pyramid with a very large base representing the entire H pylori-infected population; a segment of these subjects (generally larger in developing than in industrialized areas) will progress to atrophic gastritis, mostly accompanied by intestinal metaplasia. A very small minority will progress further to dysplasia with some eventually developing adenocarcinoma. The closer a lesion is to neoplasia, the more likely it will progress into it. Thus, whereas chronic gastritis is a remote and uncertain precursor of gastric cancer that could be better called a “predisposing condition,” high-grade dysplasia is considered already a neoplastic lesion[25,26]. If pathologists could make a reliable assessment of the risk that each patient has, based on a staging of the disease, effective strategies could be developed to detect the early, curable phase of gastric cancer and prevent its progression.
The risk of gastric cancer for a patient with simple, non-atrophic H pylori gastritis is negligible, thus, the decision to treat the infection is based, in most cases, on other considerations. There is, however, one exception. Gastric cancer and atrophic gastritis associated with it have at least some familial predisposition[27-30]; therefore, it would seem wise to treat H pylori infection as early as possible in direct relatives of patients with gastric cancer. This is one of the rare circumstances in which H pylori would be eradicated for the specific purpose of preventing gastric carcinoma in an individual patient.
Gastric atrophy is defined as the loss of appropriate glands in a given gastric compartment[13,31]. This purely histopathological definition indicates that the glands expected to be present in the portion of gastric mucosa under examination (for example, oxyntic glands in the mucosa of the corpus) are no longer there, and have been replaced by something else that does not belong to that area. This “something else” may be extracellular matrix, fibroblasts and collagen, or other glands that normally are not there (e.g., intestinal-type glands or pseudo-pyloric glands). Any of these replacements prevents that portion of gastric mucosa from performing its normal functions (e.g., to secrete acid). Thus, the functional correlate of atrophy is strictly related to its extension.
Atrophic gastritis is a condition characterized by the presence of significant areas of atrophy. Its two most common underlying causes are chronic infection with H pylori and the autoimmune gastritis that may become associated with pernicious anemia. In the Updated Sydney System, the term “atrophic gastritis” is used in contrast to “non-atrophic gastritis” or simply “gastritis,” a condition usually more severe in the antrum (hence the term “antral-predominant”) found in most subjects infected with H pylori in the Western industrialized world.
The stomach affected by atrophic gastritis shows a decrease or absence of appropriate glands, an expansion of the antral-type mucosa into the corpus (“antralization” or pseudo-pyloric metaplasia) and usually extensive areas of intestinal metaplasia. This condition has been known for several decades to represent a significant epidemiological risk factor for gastric adenocarcinoma[14,17,24,32-36]; as schematically depicted in Figure 1, its prognostic implications in the individual patient seem to be related to the extent and distribution of the atrophic areas[10,37].
Intestinal metaplasia is the replacement of the normal gastric mucosa with an epithelium similar to that of the intestine. Attempts to classify the different types of intestinal metaplasia have resulted in a confusing terminology (complete vs incomplete, type 1, 2a and 2b, etc.); the classification currently used was proposed by Jass and Filipe[38,39]: Type I (brush border and no sulfomucins); Type II (no brush border, rare sulfomucins); and Type III (no brush border, cellular disarray, abundant sulfomucins). Type I intestinal metaplasia has been often said to pose little increased risk of developing carcinoma, whereas type III has been considered as an already dysplastic lesion[10,40-42]. The classification of the three types of metaplasia requires relatively sophisticated histochemical techniques and is far from being standardized. Furthermore, the data suggesting different cancer risks for the different types of intestinal metaplasia are not unequivocal[43]. Therefore, immunohistochemical sub-typing of intestinal metaplasia should be limited to the clinical research setting and not a part of the routine evaluation of patients with intestinal metaplasia.
Malignancy is the final step of progressive genetic and phenotypic changes that modify the original cellular morphology, eventually generating a biologically new cell characterized by uncontrolled growth and the potential to migrate and implant in locations beyond its original fixed site. This biological process has been called multi-step or step-wise oncogenesis. In epithelial tissues (for example, the squamous lining of the uterine cervix or the columnar lining of the colon) the first of step visible to an observer using a light microscope is a change in the morphology of the cells that form the epithelium. Nuclei are larger, nucleoli may be prominent and the chromatin may be clumped or granular; compared to the larger nucleus, the cytoplasm appear smaller, a phenomenon referred to as “increased nucleo-cytoplasmic ratio”. Various degrees of disarray of the orderly structure of the normal epithelium usually accompanying these changes. Epithelial alterations of this kind occur in two situations: when the epithelium has been injured and is undergoing repair, and when genetic alterations have transformed the cells in a neoplastic growth. It is generally agreed by pathologists that in the former instance one refers to the phenomenon as “regenerative atypia”, whereas in the latter case the term “dysplasia” is used[44].
The importance of recognizing and correctly identifying dysplasia is self-evident: while regenerative atypia is the desired response to epithelial injury and an essential part of an organism’s homeostasis, dysplasia is the harbinger of cancer and requires immediate action. However, the morphological differences between atypia and dysplasia are not always apparent, and significant areas of phenotypic overlap exist between the two. Pathologists have tried for years to standardize the criteria for the diagnosis and grading of dysplasia in tissues accessible to biopsy sampling. Without getting into the complex historical details of the process, for the purpose of this review we say only that, through the efforts of pioneers such as the late Rodger Haggitt, Robert Riddell, Brian Reid, and others, a satisfactory level of agreement has been reached for dysplasia of the colon and of Barrett’s epithelium[44-46]. Gastric dysplasia has received less attention in the past, with only one major consensus article addressing the issue before 1996[47].
In the last decade, the discovery of H pylori and its relationship with gastric cancer has stimulated increasing attention to the preneoplastic lesions of the stomach. The possibility that curing this infection could prevent or even cause the regression of such lesions has highlighted the need for uniform and rigorous definitions and diagnostic criteria. However, unlike metaplasia, whose recognition has always been largely free of major disputes, or atrophy, which has been the focus of major conceptual disagreements among pathologists, dysplasia exposed a novel angle of controversy: a pathological schism between East and West, or, more accurately, between Japan and the West[48].
Japan is one of the countries with the highest incidence of adenocarcinoma of the stomach in the world; at the same time, it also has the world’s best survival rates for gastric cancer. Although the effective early detection programs, innovative endoscopic techniques, and daring and successful therapeutic endoscopists have been invoked to explain the Japanese success in this area, another explanation has been suggested, mostly in a veiled or oblique manner. To state it simply, it has been implied that, to have such good survival rates the Japanese must call cancer what others call dysplasia. The question has been propelled into the international scientific forum only recently, through the efforts of RJ Schlemper, who in 1996 organized a workshop to address the issue. This workshop resulted in a seminal paper entitled “Differences in diagnostic criteria for gastric carcinoma between Japanese and Western pathologists,” published in the Lancet in 1997[49]. Following the workshop and publication of its findings, several other groups have formed to tackle the problem in the traditional pathologists’ fashion: by trying to measure the level of agreement (or disagreement) amongst observers. These groups included various proportions of Japanese and Western pathologists, and the ultimate aim was to reach a consensus that classification, if used globally, would allow comparative studies performed in different countries. As a result, new issues have emerged and new classifications have been proposed. The classification currently accepted by the World Health Organization[50] is largely modeled on the consensus agreement reached in Padua, Italy, in 1998[26], and summarizes one of the most recent proposals for an integrated therapeutic and pathological approach[51].
The Padova model is based: (1) on the definition of dysplasia as pre-invasive neoplasia; and (2) on a five-category classification of gastric neoplasia which includes: 1, negative for dysplasia; 2, indefinite for dysplasia; 3, non-invasive neoplasia; 4, suspicious for invasive cancer; 5, gastric cancer. The numerical prefix assigned to each diagnostic category essentially corresponds to the diagnostic categories of the Japanese Classification for Gastric Cancer[52]. Within each category one or more sub-categories are hierarchically ordered to cover the spectrum of epithelial alterations.
The topographic distribution of inflammatory infiltrates, lymphoid follicles, atrophy, and metaplasia is an essential determinant used for all classifications of gastritis. These changes may be patchily distributed and their relative intensity in different parts of the stomach may be highly variable. Furthermore, the inflammatory and atrophic processes have different phenotypical expressions in different regions of the stomach. Therefore, to obtain an accurate picture of gastritis, pathologists must have a set of specimens representative of each gastric compartment. Each specimen is examined according to uniform criteria, a general impression of the intensity of the features of gastritis is extrapolated from the various specimens from each compartment, and finally this information is amalgamated in a topographical diagnosis. The location of the biopsy specimens recommended by the Updated Sydney System[12] is depicted in the left panel of Figure 2. A suggestion has been made to replace the original sites with others, purportedly more likely to yield information about the extension of intestinal metaplasia[53], but in the absence of independent testing no proposal in this sense has been presented.
Irrespective of the protocol used, gastroenterologists must keep in mind that the predictive information they can get from their pathologist is only as good as the biopsy sampling submitted for examination. The Sydney System 5-biopsy protocol is a compromise between what is practically doable in routine practice and the ideal need for maximal topographic information. As depicted in Figure 2, right panel, in special situations such as the diagnosis and follow-up of gastric mucosa-associated lymphoid tissue B-cell lymphomas or the diachronic investigation of dysplasia much more extensive sampling protocols need to be applied[48,54-56].
The determination of serum pepsinogens I (PG I) and II(PGII), gastrin-17 (G-17) and IgG anti-H pylori antibodies by ELISA has been proposed as an array of non-invasive markers for the assessment of both morphological and functional status of the gastric mucosa[57]. The rationale for this approach, described by its enthusiastic supporters as the “serological biopsy,” rests on the fact that PGI is exclusively secreted by oxyntic glands and represents an excellent marker of the secretory ability of the gastric corpus. In contrast, PG II is produced by all types of gastric and duodenal glands and its production is influenced by gastric inflammation[58,59]. Although these molecules are secreted into the gastric lumen, small amounts seep out into the bloodstream and can be measured. Gastrin-17 (G-17), produced in the antrum and secreted directly into the blood, is a specific marker of G cell function[60]. Several studies have now shown that serum levels of PG I, PG II and G-17 are high in subjects with H pylori non-atrophic chronic gastritis[61]. Both PG I and PGII concentrations are found to decrease significantly two months after the eradication of H pylori[62,63]. Furthermore, the ratio of PGI and G-17 levels have been found to correlate well with the histopathological diagnosis of atrophic body gastritis and, in some studies, to be associated with the presence of gastric cancer[64-66].
In a recent study, De Mario and his colleagues[67] demonstrated that the analysis of serum pepsinogens, G-17 and anti-H pylori IgG levels provide consistent and reproducible information regarding gastric atrophy and its association with H pylori. The authors suggest that dyspeptic patients with normal PG I, PGII, G-17 and a negative serological test for H pylori can be reassured that they are unlikely to have peptic ulcer disease and can be treated symptomatically. In contrast, patients with panel test results indicating H pylori-related chronic gastritis, with or without atrophy, could either be treated for H pylori or referred for endoscopy, depending on the type and severity of their manifestations.
The article reporting the Updated Sydney System, published in October 1996, has recently passed the 1000-citation milestone[68], suggesting that the semi-quantitative scoring system it advocated remains a useful tool for clinical research. Nevertheless, the same pathologists who use it when assessing biopsies for clinical studies find it too cumbersome to use in their routine diagnostic activities.
Using the framework provided by the Sydney System’s and the Atrophy Club’s analytic approach, we have recently put forward a proposal for a grading and staging scheme that integrates the relevant histopathological data gathered and interpreted by the pathologist and delivers them in the form of a simple, yet information-rich report[69]. We have suggested that the method is both feasible and practical, and that staging and grading (preceded by a description of the histological findings in the biopsy samples) could represent the concluding message of the histological report. This scheme could be do for chronic gastritis what the grading and staging system introduced by the International Group of Hepatologists in 1995 did for chronic hepatitis: make prognostically significant and reproducible information immediately available in the clinical practice[70,71].
Briefly, the proposal consists of summarizing the combined intensity of mononuclear and scoring granulocytic inflammation in both antral and oxyntic biopsy samples in a grade from 0 (no inflammation) to 4 (a very dense infiltrate in all the biopsy samples). The extent of atrophy, with or without intestinal metaplasia, would be reported as a stage from 0 (no atrophy) to 4 (pan-atrophy involving all antral and oxyntic samples). The latter would convey information on the anatomical extent of the atrophic-metaplastic changes related to cancer risk. Figure 1 shows the progression from stage 0 (left) to stage 4 (right).
A pathologist who had access to the results of the “serological biopsy” and applied the grading and staging principles outlined in this scheme could generate a comprehensive informative integrated report that could be used by clinicians as a solid base for the management of patients with gastric conditions.
This proposal has been discussed at an international consensus group of gastroenterologists and pathologists (Operative Link for Gastritis Assessment-OLGA) that gathered in Parma, Italy, in April 2005. The group included Massimo Rugge, Padova, Italy; Pelayo Correa, New Orleans, Louisiana, USA; Francesco Di Mario, Parma, Italy; Emad El-Omar, Aberdeen, Scotland, UK; Roberto Fiocca, Genova, Italy; Karel Geboes, Leuven, Belgium; David Y Graham, Houston, Texas, USA; Takanori Hattori, Shiga, Japan; Peter Malfertheiner, Magdeburg, Germany; Pentti Sipponen, Espoo, Finland; Joseph Sung, Hong Kong, China; Wilfred Weinstein, Los Angeles, California, USA; Michael Vieth, Bayreuth, Germany; and Robert M Genta, Geneva, Switzerland.
After deliberations that led to a number of modifi-cations of the original proposal, the OLGA group has agreed that an international staging method is needed to advance research in gastritis and is preparing to test its feasibility and reproducibility both in retrospective and prospective multi-center studies.
S- Editor Wang J L- Editor Ma JY E- Editor Bai SH
1. | Genta RM. Inflammatory Disorders of the Stomach. Surgical Pathology of the GI TRact, Liver, Biliary Tract, and Pancreas. Philadelphia: Saunders 2004; 143-176. [Cited in This Article: ] |
2. | Correa P. A human model of gastric carcinogenesis. Cancer Res. 1988;48:3554-3560. [PubMed] [Cited in This Article: ] |
3. | Schistosomes , liver flukes and Helicobacter pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7-14 June 1994. IARC Monogr Eval Carcinog Risks Hum. 1994;61:1-241. [PubMed] [Cited in This Article: ] |
4. | Correa P, Cuello C, Duque E, Burbano LC, Garcia FT, Bolanos O, Brown C, Haenszel W. Gastric cancer in Colombia. III. Natural history of precursor lesions. J Natl Cancer Inst. 1976;57:1027-1035. [PubMed] [Cited in This Article: ] |
5. | 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. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 2] [Reference Citation Analysis (0)] |
6. | You WC, Zhang L, Gail MH, Li JY, Chang YS, Blot WJ, Zhao CL, Liu WD, Li HQ, Ma JL. Precancerous lesions in two counties of China with contrasting gastric cancer risk. Int J Epidemiol. 1998;27:945-948. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 40] [Cited by in F6Publishing: 44] [Article Influence: 1.7] [Reference Citation Analysis (0)] |
7. | Correa P. The biological model of gastric carcinogenesis. IARC Sci Publ. 2004;301-310. [PubMed] [Cited in This Article: ] |
8. | Maaroos HI, Kekki M, Sipponen P, Salupere V, Villako K. Grade of Helicobacter pylori colonisation, chronic gastritis and relative risks of contracting high gastric ulcers: a seven-year follow-up. Scand J Gastroenterol Suppl. 1991;186:65-72. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 13] [Cited by in F6Publishing: 13] [Article Influence: 0.4] [Reference Citation Analysis (0)] |
9. | Sipponen P, Kekki M, Haapakoski J, Ihamäki T, Siurala M. Gastric cancer risk in chronic atrophic gastritis: statistical calculations of cross-sectional data. Int J Cancer. 1985;35:173-177. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 254] [Cited by in F6Publishing: 262] [Article Influence: 6.7] [Reference Citation Analysis (0)] |
10. | Cassaro M, Rugge M, Gutierrez O, Leandro G, Graham DY, Genta RM. Topographic patterns of intestinal metaplasia and gastric cancer. Am J Gastroenterol. 2000;95:1431-1438. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 183] [Cited by in F6Publishing: 192] [Article Influence: 8.0] [Reference Citation Analysis (0)] |
11. | Price AB, Misiewicz JJ. Sydney classification for gastritis. Lancet. 1991;337:174. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 12] [Cited by in F6Publishing: 13] [Article Influence: 0.4] [Reference Citation Analysis (0)] |
12. | 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;20:1161-1181. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 3221] [Cited by in F6Publishing: 3408] [Article Influence: 121.7] [Reference Citation Analysis (3)] |
13. | Rugge M, Correa P, Dixon MF, Fiocca R, Hattori T, Lechago J, Leandro G, Price AB, Sipponen P, Solcia E. Gastric mucosal atrophy: interobserver consistency using new criteria for classification and grading. Aliment Pharmacol Ther. 2002;16:1249-1259. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 246] [Cited by in F6Publishing: 247] [Article Influence: 11.2] [Reference Citation Analysis (0)] |
14. | Ihamäki T, Saukkonen M, Siurala M. Long-term observation of subjects with normal mucosa and with superficial gastritis: results of 23--27 years' follow-up examinations. Scand J Gastroenterol. 1978;13:771-775. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 54] [Cited by in F6Publishing: 56] [Article Influence: 1.2] [Reference Citation Analysis (0)] |
15. | Ihamäki T, Kekki M, Sipponen P, Siurala M. The sequelae and course of chronic gastritis during a 30- to 34-year bioptic follow-up study. Scand J Gastroenterol. 1985;20:485-491. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 80] [Cited by in F6Publishing: 79] [Article Influence: 2.0] [Reference Citation Analysis (0)] |
16. | Kekki M, Ihamäki T, Varis K, Isokoski M, Lehtola J, Hovinen E, Siurala M. Age of gastric cancer patients and susceptibility to chronic gastritis in their relatives. A mathematical approach using Poisson's process and scoring of gastritis state. Scand J Gastroenterol. 1973;8:673-679. [PubMed] [Cited in This Article: ] |
17. | Kekki M, Villako K, Tamm A, Siurala M. Dynamics of antral and fundal gastritis in an Estonian rural population sample. Scand J Gastroenterol. 1977;12:321-324. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 23] [Cited by in F6Publishing: 22] [Article Influence: 0.5] [Reference Citation Analysis (0)] |
18. | Cuello C, Correa P, Haenszel W, Gordillo G, Brown C, Archer M, Tannenbaum S. Gastric cancer in Colombia. I. Cancer risk and suspect environmental agents. J Natl Cancer Inst. 1976;57:1015-1020. [PubMed] [Cited in This Article: ] |
19. | Haenszel W, Correa P, Cuello C, Guzman N, Burbano LC, Lores H, Muñoz J. Gastric cancer in Colombia. II. Case-control epidemiologic study of precursor lesions. J Natl Cancer Inst. 1976;57:1021-1026. [PubMed] [Cited in This Article: ] |
20. | Kimura K. Chronological transition of the fundic-pyloric border determined by stepwise biopsy of the lesser and greater curvatures of the stomach. Gastroenterology. 1972;63:584-592. [PubMed] [Cited in This Article: ] |
21. | Hattori T. Development of adenocarcinomas in the stomach. Cancer. 1986;57:1528-1534. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 3] [Reference Citation Analysis (0)] |
22. | Correa P. Chronic gastritis as a cancer precursor. Scand J Gastroenterol Suppl. 1984;104:131-136. [PubMed] [Cited in This Article: ] |
23. | Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984;1:1311-1315. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 3302] [Cited by in F6Publishing: 3158] [Article Influence: 79.0] [Reference Citation Analysis (0)] |
24. | 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. [PubMed] [Cited in This Article: ] |
25. | Schlemper RJ, Riddell RH, Kato Y, Borchard F, Cooper HS, Dawsey SM, Dixon MF, Fenoglio-Preiser CM, Fléjou JF, Geboes K. The Vienna classification of gastrointestinal epithelial neoplasia. Gut. 2000;47:251-255. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1463] [Cited by in F6Publishing: 1495] [Article Influence: 62.3] [Reference Citation Analysis (0)] |
26. | Rugge M, Correa P, Dixon MF, Hattori T, Leandro G, Lewin K, Riddell RH, Sipponen P, Watanabe H. Gastric dysplasia: the Padova international classification. Am J Surg Pathol. 2000;24:167-176. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 254] [Cited by in F6Publishing: 240] [Article Influence: 10.0] [Reference Citation Analysis (0)] |
27. | Kekki M, Ihamäki T, Varis K, Siurala M. Chronic gastritis profiles in sibs of probands calculated to carry a highly increased risk of gastric carcinoma. Scand J Gastroenterol Suppl. 1991;186:29-32. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 7] [Cited by in F6Publishing: 7] [Article Influence: 0.2] [Reference Citation Analysis (0)] |
28. | Bonney GE, Elston RC, Correa P, Haenszel W, Zavala DE, Zarama G, Collazos T, Cuello C. Genetic etiology of gastric carcinoma: I. Chronic atrophic gastritis. Genet Epidemiol. 1986;3:213-224. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 45] [Cited by in F6Publishing: 44] [Article Influence: 1.2] [Reference Citation Analysis (0)] |
29. | Brenner H, Arndt V, Stürmer T, Stegmaier C, Ziegler H, Dhom G. Individual and joint contribution of family history and Helicobacter pylori infection to the risk of gastric carcinoma. Cancer. 2000;88:274-279. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 7] [Reference Citation Analysis (0)] |
30. | Ihamäki T. Susceptibility to chronic gastritis in first degree relatives of gastric carcinoma patients. Effect of histological type of carcinoma and location of tumour. Ann Clin Res. 1984;16:183-187. [PubMed] [Cited in This Article: ] |
31. | Ruiz B, Garay J, Johnson W, Li D, Rugge M, Dixon MF, Fiocca R, Genta RM, Hattori T, Lechago J. Morphometric assessment of gastric antral atrophy: comparison with visual evaluation. Histopathology. 2001;39:235-242. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 34] [Cited by in F6Publishing: 34] [Article Influence: 1.5] [Reference Citation Analysis (0)] |
32. | Ihamäki T, Sipponen P, Varis K, Kekki M, Siurala M. Characteristics of gastric mucosa which precede occurrence of gastric malignancy: results of long-term follow-up of three family samples. Scand J Gastroenterol Suppl. 1991;186:16-23. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 24] [Cited by in F6Publishing: 26] [Article Influence: 0.8] [Reference Citation Analysis (0)] |
33. | Siurala M, Kekki M, Varis K, Isokoski M, Ihamäki T. Gastritis and gastric cancer. Br Med J. 1972;3:530-531. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 11] [Cited by in F6Publishing: 12] [Article Influence: 0.2] [Reference Citation Analysis (0)] |
34. | Correa P. Helicobacter pylori and gastric cancer: state of the art. Cancer Epidemiol Biomarkers Prev. 1996;5:477-481. [PubMed] [Cited in This Article: ] |
35. | Miehlke S, Hackelsberger A, Meining A, Hatz R, Lehn N, Malfertheiner P, Stolte M, Bayerdörffer E. Severe expression of corpus gastritis is characteristic in gastric cancer patients infected with Helicobacter pylori. Br J Cancer. 1998;78:263-266. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 69] [Cited by in F6Publishing: 74] [Article Influence: 2.8] [Reference Citation Analysis (0)] |
36. | Walker IR, Strickland RG, Ungar B, Mackay IR. Simple atrophic gastritis and gastric carcinoma. Gut. 1971;12:906-911. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 112] [Cited by in F6Publishing: 113] [Article Influence: 2.1] [Reference Citation Analysis (0)] |
37. | Sipponen P, Stolte M. Clinical impact of routine biopsies of the gastric antrum and body. Endoscopy. 1997;29:671-678. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 53] [Cited by in F6Publishing: 56] [Article Influence: 2.1] [Reference Citation Analysis (0)] |
38. | Jass JR, Filipe MI. Sulphomucins and precancerous lesions of the human stomach. Histopathology. 1980;4:271-279. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 81] [Cited by in F6Publishing: 77] [Article Influence: 1.8] [Reference Citation Analysis (0)] |
39. | Jass JR, Filipe MI. The mucin profiles of normal gastric mucosa, intestinal metaplasia and its variants and gastric carcinoma. Histochem J. 1981;13:931-939. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 131] [Cited by in F6Publishing: 120] [Article Influence: 2.8] [Reference Citation Analysis (0)] |
40. | Tosi P, Filipe MI, Luzi P, Miracco C, Santopietro R, Lio R, Sforza V, Barbini P. Gastric intestinal metaplasia type III cases are classified as low-grade dysplasia on the basis of morphometry. J Pathol. 1993;169:73-78. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 38] [Cited by in F6Publishing: 39] [Article Influence: 1.3] [Reference Citation Analysis (0)] |
41. | Filipe MI, Potet F, Bogomoletz WV, Dawson PA, Fabiani B, Chauveinc P, Fenzy A, Gazzard B, Goldfain D, Zeegen R. Incomplete sulphomucin-secreting intestinal metaplasia for gastric cancer. Preliminary data from a prospective study from three centres. Gut. 1985;26:1319-1326. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 138] [Cited by in F6Publishing: 149] [Article Influence: 3.8] [Reference Citation Analysis (0)] |
42. | Filipe MI, Muñoz N, Matko I, Kato I, Pompe-Kirn V, Jutersek A, Teuchmann S, Benz M, Prijon T. Intestinal metaplasia types and the risk of gastric cancer: a cohort study in Slovenia. Int J Cancer. 1994;57:324-329. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 298] [Cited by in F6Publishing: 285] [Article Influence: 9.5] [Reference Citation Analysis (0)] |
43. | Leung WK, Sung JJ. Review article: intestinal metaplasia and gastric carcinogenesis. Aliment Pharmacol Ther. 2002;16:1209-1216. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 106] [Cited by in F6Publishing: 100] [Article Influence: 4.5] [Reference Citation Analysis (0)] |
44. | Riddell RH, Goldman H, Ransohoff DF, Appelman HD, Fenoglio CM, Haggitt RC, Ahren C, Correa P, Hamilton SR, Morson BC. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol. 1983;14:931-968. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1348] [Cited by in F6Publishing: 1183] [Article Influence: 28.9] [Reference Citation Analysis (0)] |
45. | Haggitt RC. Barrett's esophagus, dysplasia, and adenocarcinoma. Hum Pathol. 1994;25:982-993. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 457] [Cited by in F6Publishing: 437] [Article Influence: 14.6] [Reference Citation Analysis (0)] |
46. | Reid BJ, Haggitt RC, Rubin CE, Roth G, Surawicz CM, Van Belle G, Lewin K, Weinstein WM, Antonioli DA, Goldman H. Observer variation in the diagnosis of dysplasia in Barrett's esophagus. Hum Pathol. 1988;19:166-178. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 584] [Cited by in F6Publishing: 523] [Article Influence: 14.5] [Reference Citation Analysis (0)] |
47. | Ming SC, Bajtai A, Correa P, Elster K, Jarvi OH, Munoz N, Nagayo T, Stemmerman GN. Gastric dysplasia. Significance and pathologic criteria. Cancer. 1984;54:1794-1801. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
48. | Genta RM. Gastric Dysplasia in the East and West. Current Gastroenterology Reports 2; In press. . [Cited in This Article: ] |
49. | Schlemper RJ, Itabashi M, Kato Y, Lewin KJ, Riddell RH, Shimoda T, Sipponen P, Stolte M, Watanabe H, Takahashi H. Differences in diagnostic criteria for gastric carcinoma between Japanese and western pathologists. Lancet. 1997;349:1725-1729. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 265] [Cited by in F6Publishing: 238] [Article Influence: 8.8] [Reference Citation Analysis (0)] |
50. | Fenoglio-Preiser CM, Carneiro F, Correa P, Guilford P, Lambert R, Megraud F et al. Gastric carcinoma. World Health Organization Classification of Tumors. Pathology and Genetics of Tumours of the Digestive System. Lyon: IARC Press 2000; 37-68. [Cited in This Article: ] |
51. | Schlemper RJ, Kato Y, Stolte M. Diagnostic criteria for gastrointestinal carcinomas in Japan and Western countries: proposal for a new classification system of gastrointestinal epithelial neoplasia. J Gastroenterol Hepatol. 2000;15 Suppl:G49-G57. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 82] [Cited by in F6Publishing: 88] [Article Influence: 3.7] [Reference Citation Analysis (0)] |
52. | Japanese Research Society for Gastric Cancer. Japanese Classification of Gastric Carcinoma. 1st ed. English Edition. Tokyo: Kanehara & Co., Ltd 1995; . [Cited in This Article: ] |
53. | El-Zimaity HM, Graham DY. Evaluation of gastric mucosal biopsy site and number for identification of Helicobacter pylori or intestinal metaplasia: role of the Sydney System. Hum Pathol. 1999;30:72-77. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 87] [Cited by in F6Publishing: 90] [Article Influence: 3.6] [Reference Citation Analysis (0)] |
54. | Rugge M, Farinati F, Baffa R, Sonego F, Di Mario F, Leandro G, Valiante F. Gastric epithelial dysplasia in the natural history of gastric cancer: a multicenter prospective follow-up study. Interdisciplinary Group on Gastric Epithelial Dysplasia. Gastroenterology. 1994;107:1288-1296. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 153] [Cited by in F6Publishing: 187] [Article Influence: 6.2] [Reference Citation Analysis (0)] |
55. | Rugge M, Cassaro M, Di Mario F, Leo G, Leandro G, Russo VM, Pennelli G, Farinati F. The long term outcome of gastric non-invasive neoplasia. Gut. 2003;52:1111-1116. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 132] [Cited by in F6Publishing: 130] [Article Influence: 6.2] [Reference Citation Analysis (0)] |
56. | Genta RM, Graham DY. Primary gastric MALT lymphoma: trivial condition or serious disease. Helicobacter. 1997;2 Suppl 1:S56-S60. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 6] [Cited by in F6Publishing: 6] [Article Influence: 0.2] [Reference Citation Analysis (0)] |
57. | Korstanje A, den Hartog G, Biemond I, Lamers CB. The serological gastric biopsy: a non-endoscopical diagnostic approach in management of the dyspeptic patient: significance for primary care based on a survey of the literature. Scand J Gastroenterol Suppl. 2002;22-26. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 29] [Cited by in F6Publishing: 38] [Article Influence: 1.8] [Reference Citation Analysis (0)] |
58. | Di Mario F, Kusstatscher S, Ferrana M, Dal Bo' N, Plebani M, Rugge M. Helicobacter pylori eradication and serum pepsinogens. Gut. 1996;38:793. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 4] [Cited by in F6Publishing: 4] [Article Influence: 0.1] [Reference Citation Analysis (0)] |
59. | Di Mario F, Moussa AM, Caruana P, Merli R, Cavallaro LG, Cavestro GM, Dal Bò N, Iori V, Pilotto A, Leandro G. 'Serological biopsy' in first-degree relatives of patients with gastric cancer affected by Helicobacter pylori infection. Scand J Gastroenterol. 2003;38:1223-1227. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 27] [Cited by in F6Publishing: 31] [Article Influence: 1.5] [Reference Citation Analysis (0)] |
60. | Sipponen P, Härkönen M, Alanko A, Suovaniemi O. Diagnosis of atrophic gastritis from a serum sample. Clin Lab. 2002;48:505-515. [PubMed] [Cited in This Article: ] |
61. | Mårdh E, Mårdh S, Mårdh B, Borch K. Diagnosis of gastritis by means of a combination of serological analyses. Clin Chim Acta. 2002;320:17-27. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 33] [Cited by in F6Publishing: 37] [Article Influence: 1.7] [Reference Citation Analysis (0)] |
62. | Plebani M, Di Mario F, Vianello F, Farini R, Piccoli A, Lazzaretto L, Perobelli L, Naccarato R, Burlina A. Actual role of pepsinogen group I in the study of upper gastrointestinal diseases. Clin Biochem. 1983;16:310-312. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 9] [Cited by in F6Publishing: 9] [Article Influence: 0.2] [Reference Citation Analysis (0)] |
63. | Plebani M, Di Mario F, Stanghellini V, Delle Fave G. Serological tests to monitor treatment of Helicobacter pylori. Lancet. 1992;340:51-52. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 19] [Cited by in F6Publishing: 19] [Article Influence: 0.6] [Reference Citation Analysis (0)] |
64. | Farinati F, Di Mario F, Plebani M, Cielo R, Fanton MC, Valiante F, Masiero M, De Boni M, Della Libera G, Burlina A. Pepsinogen A/pepsinogen C or pepsinogen A multiplied by gastrin in the diagnosis of gastric cancer. Ital J Gastroenterol. 1991;23:194-196. [PubMed] [Cited in This Article: ] |
65. | Varis K, Kekki M, Härkönen M, Sipponen P, Samloff IM. Serum pepsinogen I and serum gastrin in the screening of atrophic pangastritis with high risk of gastric cancer. Scand J Gastroenterol Suppl. 1991;186:117-123. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 33] [Cited by in F6Publishing: 35] [Article Influence: 1.1] [Reference Citation Analysis (0)] |
66. | Varis K, Sipponen P, Laxén F, Samloff IM, Huttunen JK, Taylor PR, Heinonen OP, Albanes D, Sande N, Virtamo J. Implications of serum pepsinogen I in early endoscopic diagnosis of gastric cancer and dysplasia. Helsinki Gastritis Study Group. Scand J Gastroenterol. 2000;35:950-956. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 80] [Cited by in F6Publishing: 81] [Article Influence: 3.4] [Reference Citation Analysis (0)] |
67. | Germaná B, Di Mario F, Cavallaro LG, Moussa AM, Lecis P, Liatoupolou S, Comparato G, Carloni C, Bertiato G, Battiestel M. Clinical usefulness of serum pepsinogens I and II, gastrin-17 and anti-Helicobacterpylori antibodies in the management of dyspeptic patients in primary care. Dig Liver Dis. 2005;37:501-508. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 37] [Cited by in F6Publishing: 50] [Article Influence: 2.6] [Reference Citation Analysis (0)] |
68. | ISI Web of Science-Citation Index. Science Citation Index Expanded (SCI-Expanded)-1945-present, 2004. . [Cited in This Article: ] |
69. | Rugge M, Genta RM. Staging and grading of chronic gastritis. Hum Pathol. 2005;36:228-233. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 152] [Cited by in F6Publishing: 170] [Article Influence: 8.9] [Reference Citation Analysis (0)] |
70. | Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology. 1994;19:1513-1520. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1582] [Cited by in F6Publishing: 1470] [Article Influence: 49.0] [Reference Citation Analysis (0)] |
71. | Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, Desmet V, Korb G, MacSween RN. Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22:696-699. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 3521] [Cited by in F6Publishing: 3629] [Article Influence: 125.1] [Reference Citation Analysis (1)] |