—  SHORT COURSE #48  —

Surgical Pathology and Current Molecular Aspects of Dysplasia in the GI Tract

Section 5 - Gastric Metaplasia and Dysplasia

Robert D. Odze, M.D.
Jonathan Glickman, M.D., Ph.D.
Mark Redston, M.D.


The nomenclature and classification of gastritis and gastric dysplasia has undergone considerable evolution over the past decades, rendering some past literature confusing. However, certain themes have persisted despite changing terminology, and the concept that many gastric adenocarcinomas arise through a sequence of epithelial metaplasia and dysplasia is now well established [1, 2].

The recent development of animal models that allow the direct observation of gastric carcinogenesis in the setting of Helicobacter infection has already begun to advance our understanding of the basic epithelial biology of gastric epithelial metaplasia [2]. Indeed, some studies have indicated that bone marrow derived stem cells contribute to metaplastic and dysplastic epithelial lineages [2], challenging traditional assumptions that these changes arise from resident epithelial cells. Further research will be necessary before the impact of these provocative observations on diagnosis and therapy of gastric carcinoma can be appreciated.

1. Intestinal Metaplasia

Clinical Features
Intestinal metaplasia is defined by the updated Sydney system as the "replacement of glandular and/or foveolar epithelium by intestinal epithelium." [3, 4]. Intestinal metaplasia occurs in the setting of chronic gastritis secondary to any etiology, and is more frequent with increasing duration of disease and in individuals greater than 60 years of age. Population-based studies in Japan and in Europe have identified intestinal metaplasia in up to 26-43% of H. pylori-positive individuals [5, 6], with much lower prevalence rates in H.pylori –negative individuals. One study of patients from the U.S.A. disclosed a prevalence rate of 13 % in Caucasian patients and 50% in black and Hispanic patients [7]. However, the sensitivity of mucosal biopsies for detecting intestinal metaplasia in any given individual greatly depends on the number of biopsies obtained. For example, in one recent study of 733 asymptomatic Mexican patients with a high prevalence of H. pylori gastritis, intestinal metaplasia was detected in 135 patients in whom seven gastric biopsies were examined, whereas in 6 (4%) and 24 (18%) patients the metaplasia would have been missed if 5 or 3 biopsies, respectively, had been examined [8]. Intestinal metaplasia may also arise in the setting of autoimmune gastritis related to pernicious anemia, which accounts for approximately 20% of cases of chronic gastritis and preferentially involves the body of the stomach [9, 10].

Microscopic Features
Intestinal metaplasia may be found anywhere in the stomach; its location corresponds to the location of the underlying gastritis. In H.pylori-associated chronic gastritis, intestinal metaplasia arises in the antral-corporal junction in the vicinity of the incisura angularis, but can be found throughout the stomach (antrum, body and cardia) later in the course of disease. Intestinal metaplasia may be classified based on the types of intestinal epithelial cells present and by the use of mucin histochemistry, although the latter technique is not used routinely. "Complete" intestinal metaplasia (type I) is characterized by acid mucin-positive, sulfomucin negative goblet cells and enterocytes, Paneth cells and endocrine cells, whereas "incomplete" intestinal metaplasia (types II or III) shows acid mucin-positive goblet cells surrounded by gastric type mucinous columnar cells (Table 1). Type III metaplasia differs from type II by the presence of sulfomucins (identified by the high iron diamine/Alcian Blue stain) in the mucinous columnar cells. In contrast to Barrett's esophagus, which nearly always has incomplete intestinal metaplasia, gastric intestinal metaplasia secondary to H. pylori gastritis is most commonly a mixture of complete (up to 98% of patients) and incomplete types (up to 78% of patients) of metaplasia [11, 12].

Intestinal metaplasia is frequently accompanied by atrophy of the gastric mucosa, which is defined in the updated Sydney system as "loss of glandular tissue" [3, 4, 13, 14]. However, the histologic diagnosis of atrophy is independent of the finding of intestinal metaplasia. In the gastric body, atrophy of the stomach consists of replacement of oxyntic glands by pyloric or pseudopyloric glands, with or without intestinal metaplasia. Because of a lack of explicit diagnostic criteria for atrophy, there is a high degree of interobserver variability in evaluating this feature in gastric biopsies [15, 16].

A less common form of metaplasia in the stomach is characterized by the presence of ciliated epithelial cells, which may be found deep in pyloric glands that also show intestinal metaplasia in either the distal or proximal stomach [17]. Ciliated cells have been found in non-neoplastic gastric mucosa in up to 29% of gastrectomies with carcinoma, depending on the patient population [18]. This type of metaplasia is significantly more common among individuals dwelling in East Asia and the Pacific Basin compared to those from Europe and the Atlantic Basin, possible as a result of differing environmental factors [18]. Pancreatic acinar metaplasia is found in the proximal stomach in up to 24-61% of individuals, but may also be found less commonly in the gastric body and antrum [19, 20]. This type of epithelium is comprised of nodules of acinar epithelium with apical eosinophilic granules, with or without mucous cells. The presence of pancreatic acinar metaplasia in the proximal stomach does not correlate with esophagitis, gastritis, or any type of clinical symptoms in some studies [19]. It can also be found in children [21, 22]. Therefore, it has been proposed that this epithelium represents a congenital heterotopia rather than an acquired lesion. However, others have reported an association between pancreatic acinar epithelium and increased inflammation at the gastroesophageal junction [23], and between autoimmune gastritis and the presence of pancreatic acinar epithelium in the gastric corpus [24].

Natural History and Management
Although gastric intestinal metaplasia is recognized as a risk factor in the evolution of gastric carcinoma [25], considerable controversy exists regarding the prognostic significance of this finding and its implications for surveillance of gastric carcinoma. Some studies have associated type III intestinal metaplasia with the highest relative risk (2.7-5.8 times) for the development of gastric carcinoma, and complete intestinal metaplasia with the lowest [26, 27]. However, these studies failed to show that metaplasia is an independent risk factor for carcinoma when controlling for other variables such as patient age, and it is clear that various comorbid conditions and host environmental factors influence the progression to dysplasia or carcinoma [28]. Furthermore, metaplasia is sufficiently common in older age groups and is found at approximately equal frequency in gastric resections either with or without carcinoma [29]. Therefore, the mere presence of intestinal metaplasia (type III or otherwise) is neither sufficiently sensitive nor specific to justify surveillance for gastric carcinoma in low risk populations [6]. Current research interest is focused on identifying ancillary serologic [30] or molecular [31] markers that may help stratify these patients with respect to risk for progression to neoplasia.

2. Dysplasia

Clinical Features
Gastric epithelial dysplasia may develop in the setting of chronic gastritis with intestinal metaplasia, but can develop in mucosa without metaplastic change as well. Most patients are in the fifth to seventh decades of life. The prevalence of dysplasia varies greatly depending on the population under study. One population-based Scandinavian study found a prevalence rate of 5% in individuals with atrophic gastritis [32], whereas studies in higher risk areas such as China (where atrophic gastritis is nearly universal), found prevalence rates of up to 15-20% [33, 34]. Patients with pernicious anemia develop dysplasia in up to 10% of cases when followed prospectively [35]. Retained gastric remnants after distal gastrectomy for peptic ulcer disease are also associated with an increased rate of dysplasia and a mildly increased risk of carcinoma [36], although carcinomas occur in only 2-5% of these patients and require a postoperative interval of at least 10-15 years [36, 37]. Familial adenomatous polyposis (FAP) (see below), hereditary non-polyposis colorectal cancer syndrome and hereditary colonic flat adenoma syndrome are also at increased risk for gastric dysplasia.

Classification
Gastric dysplasia is currently defined as the presence of unequivocal neoplastic epithelium confined to the basement membrane [38, 39]. However, the terminology for gastric epithelial dysplasia is potentially confusing and has undergone considerable evolution since first being recognized as a likely precursor of gastric carcinoma (reviewed in 40,41 and references therein). Early classifications of dysplasia divided lesions into two (low grade and high grade), three (for example slight, moderate or severe), or even four levels (grades 1 to 4). However, most of these systems included regenerative or reactive epithelial changes in the category of "mild" or "low grade" dysplastic, and numerous follow-up studies demonstrated that these lesions frequently regress or show minimal malignant potential [42, 43]. An additional source of confusion among classification systems and published studies relates to the tendency of Japanese pathologists to consider severely dysplastic epithelium as early carcinoma on the basis of cytologic criteria alone (44,45) (see below).

Currently accepted or proposed classification systems for gastric dysplasia, including the Padova/Vienna [38, 45] and WHO [39] systems, follow the same general approach as for Barrett's esophagus-associated and IBD-related dysplasia [46, 47]. They divide lesions into low grade and high-grade dysplasia on the basis of both architectural and cytologic criteria. Lesions that are suspicious for invasive carcinoma, or that show definite invasion of the lamina propria or submucosa, are placed into separate diagnostic categories. Controversy remains among pathologists over whether lesions should be grouped in a purely descriptive manner based on morphologic findings, or based on the favored clinical management (as proposed in the modified Vienna classification, Table 2) [48]. Since management approaches to gastric premalignant and malignant lesions vary significantly among different regions of the world and different medical centers, this controversy appears likely to continue.

Pathologic Features
Dysplasia usually occurs in endoscopically flat mucosa, but may occasionally form a polyp or mass lesion (see adenoma, below). Microscopically, dysplastic glandular epithelium shows a range of cytologic and architectural abnormalities. Dysplastic epithelium may occupy the superficial or glandular portions of the mucosa, or both. Similar to BE (see above), gastric dysplasia may be divided into intestinal "adenoma-like" and gastric "foveolar" (or non-adenoma-like) types on the basis of cytologic features. Adenoma-like dysplasia (see below) is more common and resembles the epithelium found in colorectal adenomas, whereas foveolar dysplasia is comprised of cells resembling gastric foveolar epithelium. However, this distinction appears to be of no clinical significance. Also, some studies have reported enlarged atypical epithelial cells located in the foveolar regions of the gastric glands ("tubule neck" or "globoid" dysplasia) and postulated that these cells represent the precursor of diffuse type gastric carcinoma [49]. However, this is controversial and has not been extensively studied.

Low-grade dysplastic epithelium contains cells that show mild nuclear enlargement and pseudostratification limited to the basal half of the cell cytoplasm, hyperchromatic chromatin, inconspicuous nucleoli, and occasional mitoses (Table 3). Architectural changes are usually modest and include the formation of tubular or papillary structures and slight crowding. In contrast, high-grade dysplasia shows a greater degree of nuclear pleomorphism, irregular or rounded nuclei, clumped chromatin, prominent nucleoli, and frequent mitoses including atypical forms. Nuclear stratification frequently involves the full thickness of the cell. High-grade dysplasia also displays a greater degree of architectural complexity and loss of epithelial polarity compared to low-grade dysplasia, with marked glandular crowding, back-to-back glands, branching, and cribriforming. Biopsies that show mild architectural distortion and cytologic features of low grade dysplasia, but occur in the context of significant active inflammation or ulceration, are best classified as indefinite for dysplasia. Histologic features of low grade and high grade dysplasia are summarized in Table 2.

Different criteria for "dysplasia" and "carcinoma" exist between Eastern and Western pathologists and have led to significant variability in interpretation between investigators in the two geographic regions. In one study, a group of Japanese and Western pathologists interpreted a series of 100 gastric biopsies, each using their own classification schemes. Although each group showed good intragroup correlation, the intergroup concordance was lower (kappa coefficient 0.54). A principal source of disagreement involved biopsies that were regarded as dysplasia by Western pathologists but as carcinoma by Japanese pathologists [44]. Nevertheless, when a group of Japanese and Western pathologists was asked to categorize a series of lesions as negative/indefinite for dysplasia, dysplastic, or suspicious/ definite carcinoma according to a single classification scheme, they agreed 78% of the time (kappa coefficient 0.63, good agreement) [38, 45].

Differential Diagnosis
Gastric epithelial dysplasia must be distinguished from reactive foveolar hyperplasia that occurs in the setting of gastritis, ulcer disease, bile reflux, or radiation/ chemotherapy for esophageal carcinoma. Indeed, these distinctions represent a major source of diagnostic disagreement, particularly with regard to the differential diagnosis of low-grade dysplasia versus reactive changes [50]. Mucosa adjacent to ulcers, or in cases of chemical gastropathy, may show elongated, tortuous foveolar epithelium with mucin depletion, nuclear enlargement and hyperchromasia, and an increased mitotic index. However, unlike dysplasia, reactive foveolar cells do not show coarse chromatin, atypical mitoses or loss of nuclear polarity. Furthermore, the overall architecture and surface maturation are usually well preserved. In addition to the above features, chemotherapy related epithelial atypia may show prominent nucleoli, and abundant eosinophilic or vacuolated cytoplasm, features that are not normally observed in dysplasia [51].

Occasionally, particularly in small or poorly oriented biopsies, distinction between dysplasia and intramucosal, or invasive, adenocarcinoma may be difficult. The presence of markedly irregular glandular profiles, confluent clusters of cells, or the presence of single cells in the lamina propria or deeper in the wall, support a diagnosis of invasive adenocarcinoma. Biopsies that show severely dysplastic epithelium bordering on adenocarcinoma should be rebiopsied, if necessary, or considered suspicious for invasion and treated as such.

Natural History
The natural history of gastric dysplasia is incompletely understood. Retrospective studies have found that high-grade dysplasia is associated with a synchronous invasive adenocarcinoma in up to 50% of cases. Prospective follow-up studies have shown that patients with "severe" dysplasia progressed to carcinoma in 57-80% of cases, whereas patients with "mild" or "moderate" dysplasia progressed in 20-35% of cases and even regressed in 25-40% of cases, over a follow-up period that ranged from 2 to 10 years [42, 43, 50, 52, 53, 54]. Recently, one prospective study utilizing the Padova classification and an extensive biopsy sampling protocol, found that patients with low and high grade dysplasia progressed to carcinoma in 9% and 69% of cases, and regressed in 53% and 6% of cases, respectively [55].

Management Currently there are no generally accepted guidelines in the U.S. for surveillance of patients with gastric dysplasia. Because of the high rate of progression and the relatively high rate of association with adenocarcinoma, patients with a biopsy diagnosis of high grade dysplasia should probably be reendoscoped with extensive mapping biopsies in order to rule out carcinoma. If the dysplasia is occurring in association with a mass lesion, it may be presumed that the biopsy probably represents the surface of a carcinoma and a gastrectomy is usually warranted. In Japan , as well as in some Western centers, an initial diagnosis of flat high-grade dysplasia or intramucosal carcinoma is also considered an indication for endoscopic mucosal resection [56]. Treatment of patients with low-grade dysplasia is unclear. However, close and regular endoscopic surveillance (within 3 to 12 months) is usually advisable to rule out either concurrent high grade dysplasia or carcinoma, or the subsequent development of either of these lesions.

3. Dysplasia in Gastric Adenomas
Gastric adenomas are defined by the WHO classification as "circumscribed, benign lesions… showing intraepithelial neoplasia" [39]. By this definition, any endoscopically discrete (usually elevated) dysplastic mucosal lesion, whether pedunculated or sessile, is classified as an "adenoma", whereas dysplasia that occurs in flat mucosa is classified as gastric epithelial "dysplasia". However, this is controversial since polypoid dysplasia may occur in association with chronic gastritis and, in this circumstance, it is unclear if this type of lesion should be considered and "adenoma." Adenomas account for approximately 5-10% of all gastric mucosal polyps [57, 58]. In Japan , the term "adenoma" encompasses flat or depressed lesions as well [59]. Gastric adenomas are rare in normal individuals but are seen at increased frequency in patients with chronic gastritis and intestinal metaplasia [60] or with hereditary polyposis such as FAP and the hereditary flat adenoma syndrome [61, 62]. The epithelium in adenomas may show low grade or high-grade dysplasia similar to that found in flat dysplasia. Adenocarcinoma may be present in up to 20% of adenomas, usually in those greater than 2 cm in greatest dimension, or in lesions with high-grade dysplasia [63, 64]. Adenomas with intestinalized epithelium are more likely to contain carcinoma [65]. However, the precise risk of progression of the lesions to carcinoma, or the rate at which this process may occur, is uncertain. Because of these considerations, all adenomas should be removed, in total, with negative margins, and thoroughly examined for focal malignant change.

4. Dysplasia in Hyperplastic Polyps
Hyperplastic polyps are among the most common type of gastric polyps [57, 58], with an overall prevalence rate of approximately 0.1%. They are more common in patients with chronic gastritis, being present in up to 10% of affected individuals [66, 67]. Grossly, they may be located anywhere in the stomach, but are most common in the antrum. They show intestinal metaplasia in 15-25% of cases. Dysplasia has been reported in 2% to 19% of polyps, particularly in those greater than 2 cm in size [68]. Adenocarcinoma may be present in up to 15% of polyps with dysplasia [64, 68, 69, 70]. Some authors have suggested that an intestinal phenotype is more commonly seen in polyps with high-grade dysplasia or carcinoma [71].

5. Dysplasia in Fundic Gland Polyps
Fundic gland polyps (FGPs) are the second most common type of gastric polyp, with a prevalence rate estimated between 0.1-1% of the general population [72, 73, 74]. Although they were first described in FAP, being present in 50-100% of affected patients [61, 75, 76], sporadic lesions are, in fact, more common [77]. Most FGPs are small (less than 1 cm) sessile lesions located in the body of the stomach. Approximately 40% of non-FAP patients have multiple FGPs, compared to 80-100% of FAP patients.

Dysplasia of the surface, and/or glandular, epithelium is present in up to 25% of FAP-associated FGPs, but is extremely uncommon in sporadic FGPs [75, 78, 79]. Dysplasia in FGPs is generally low grade, and must be differentiated from reactive epithelial changes associated with inflammation and surface erosion. The development of high-grade dysplasia or adenocarcinoma in these lesions is extremely uncommon [80, 81]. Therefore, FGPs are associated with a minimal risk of malignancy in both the general population and FAP patients. In fact, in Western countries, the risk of gastric cancer in FAP patients is not increased compared to the general population [82].

Other polyposis syndromes such as juvenile polyposis, Cowden's disease, and Cronkhite-Canada syndrome, may also involve the stomach, but polyps associated with these syndromes are only rarely associated with dysplasia or carcinoma.
Table 1: Histologic Subtypes of Intestinal Metaplasia

Intestinal Metaplasia Type Goblet Cells Mucinous Columnar Cells Other Cell types (Paneth, absorptive) Cancer Risk? Stomach BE
Complete
(Type I) 		Sialomucin +
Sulphomucin + 		Not present Present No + -/+
Incomplete
(Type II) 		Sialomucin +
Sulphomucin + 		Sialomucin +
Sulphomucin - 		+/- Yes? + +
Incomplete
(Type III) 		Sialomucin +
Sulphomucin + 		Sialomucin +
Sulphomcin + 		+/- Yes? + +
Table 2: Revised Vienna Classification for Gastric Dysplasia

Diagnosis Suggested Management
Negative for dysplasia Optional follow-up
Indefinite for dysplasia Follow-up
Mucosal low-grade neoplasia
Low-grade adenoma
Low-grade dysplasia 		Followup or endoscopic resection
Mucosal high-grade neoplasia
High-grade adenoma/dysplasia
Non-invasive carcinoma
Suspicious for invasive carcinoma
Intramucosal carcinoma		Endoscopic or surgical local resection (vs. close followup, rebiopsy)
Submucosal invasion by carcinoma Surgical resection

From Ref 48
Table 3: Histologic Features of Gastric Dysplasia

  Dysplasia
Histologic Feature Reactive Indefinite Low Grade High Grade
Surface maturation + +/- - -
Villiform architecture +/- +/- +/- +/-
Mucin depletion +/- + + ++
Irregular glands - +/- + ++
Glandular crowding - +/- + ++
Cribriform glands - - - +
Increased N/C ratio +/- + ++ +++
Nuclear pseudostratification - -/+ ++ +++
Nuclear pleomorphism - +/- + ++
Increased mitotic rate + + + ++
Abnormal mitoses - - -/+ ++
Inflammation ++ + +/- +/-

References
  1. Lauwers GY. Defining the pathologic diagnosis of metaplasia, atrophy, dysplasia, and gastric adenocarcinoma. J Clin Gastroenterol. 2003;36(5 Suppl):S37-43

  2. Houghton J and Wang TC. Helicobacter pylori and gastric cancer: a new paradigm for inflammation-associated epithelial cancers. Gastroenterology. 2005;128:1567-78.

  3. Dixon MF, Genta RM, Yardley JH et al. Classification and grading of gastritis. The Updated Sydney System. Am J Surg Pathol 1996; 20:1161-1181.

  4. Rugge M, Genta RM. Staging and grading of chronic gastritis. Hum Pathol. 2005;36:228-33.

  5. Asaka M, Sugiyama T, Nobuta A, Kato M, Takeda H, Graham DY. Atrophic gastritis and intestinal metaplasia in Japan : results of a large multicenter study. Helicobacter 2001;6:294-9.

  6. Chen XY, Der Hulst RW, Shi Y, Xiao SD, Tytgat GN, ten Kate FJ. Comparison of precancerous conditions: atrophy and intestinal metaplasia in Helicobacter pylori gastritis among Chinese and Dutch patients. J Clin Pathol 2001;54:367-70.

  7. Fennerty MB. Gastric intestinal metaplasia on routine endoscopic biopsy. Gastroenterology 2003; 125:586-590.

  8. Guarner J, Herrera-Goepfert R, Mohar A et al. Diagnostic yield of gastric biopsy specimens when screening for preneoplastic lesions. Hum Pathol. 2003;34:28-31.

  9. Torbenson M, Abraham SC, Boitnott J et al.Autoimmune gastritis: distinct histological and immunohistochemical findings before complete loss of oxyntic glands. Mod Pathol. 2002;15:102-9.

  10. Sari R, Ozen S, Aydogdu I, Yildirim B, Sevinc A. The pathological examinations of gastric mucosa in patients with Helicobacter pylori-positive and -negative pernicious anemia. Helicobacter 2000;5:215-21.

  11. 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.

  12. Craanen ME, Blok P, Dekker W, Ferwerda J, Tytgat GN. Subtypes of intestinal metaplasia and Helicobacter pylori. Gut 1992;33:597-600.

  13. Guarner J, Herrera-Goepfert R, Mohar A et al. Gastric atrophy and extent of intestinal metaplasia in a cohort of Helicobacter pylori-infected patients. Hum Pathol 2001;32:31-5.

  14. Genta RM, Rugge M. Gastric precancerous lesions: heading for an international consensus. Gut 1999;45 Suppl 1:I5-I8.

  15. Guarner J, Herrera-Goepfert R, Mohar A et al. Interobserver variability in application of the revised Sydney classification for gastritis. Hum Pathol 1999; 30:1431-4.

  16. Offerhaus GJ, Price AB, Haot J et al. Observer agreement on the grading of gastric atrophy. Histopathology 1999;34:320-5.

  17. Rubio C, Hayashi T, Stemmermann G. Ciliated gastric cells: a study of their phenotypic characteristics. Mod Pathol 1990; 3:720-723.

  18. Rubio CA, Nesi G, Campi GC et al. Gastric ciliated metaplasia. A study of 3406 gastrectomy specimens from dwellers of the Atlantic and the Pacific basins. J Clin Pathol. 2005;58:605-10.

  19. Wang HH, Zeroogian JM, Spechler SJ, Goyal RK, Antonioli DA. Prevalence and significance of pancreatic acinar metaplasia at the gastroesophageal junction. Am J Surg Pathol 1996;20:1507-10.

  20. Sarbia M, Donner A, Gabbert HE. Histopathology of the gastroesophageal junction: a study on 36 operation specimens. Am J Surg Pathol 2002;26:1207-12.

  21. Glickman JN, Fox V, Wang HH, Antonioli DA, Odze RD. Morphology of the cardia and significance of carditis in pediatric patients. Am J Surg Pathol 2002; 26:1032-1039.

  22. Integlia MJ, Krishnamurthy S, Berhane R Pancreatic metaplasia of the gastric mucosa in pediatric patients. Am J Gastroenterol. 1997;92:1553-6.

  23. Polkowski W, van Lanschott JJ, ten Kate FJ et al. Intestinal and pancreatic metaplasia at the esophagogastric junction in patients without Barrett's esophagus. Am J Gastroenterol 2000; 95:617-625.

  24. Jhala NC, Montemor M, Jhala D et al. Pancreatic acinar cell metaplasia in autoimmune gastritis. Arch Pathol Lab Med. 2003;127:854-7.

  25. Uemura N, Okamoto S, Yamamoto S et al. Helicobacter pylori infection and the development of gastric cancer.N Engl J Med. 2001; 345:784-9.

  26. Dinis-Ribeiro M, Lopes C, da Costa-Pereira A. A follow up model for patients with atrophic chronic gastritis and intestinal metaplasia. J Clin Pathol. 2004;57:177-82.

  27. Filipe MI, Munoz N, Matko I et al. Intestinal metaplasia types and the risk of gastric cancer: a cohort study in Slovenia . Int J Cancer 1994;57:324-9.

  28. Leung WK, Lin SR, Ching JY et al. Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication. Gut 2004; 53:1244-9.

  29. Rubio CA, Jessurum J, de Ruiz PA. Geographic variations in the histologic characteristics of the gastric mucosa. Am J Clin Pathol 1991;96:330-3.

  30. Shiotani A, Ishii H, Uedo N et al Histologic and serum risk markers for noncardia early gastric cancer. Int J Cancer. 2005;115:463-9.

  31. Meireles SI, Cristo EB, Carvalho EF et al. Molecular classifiers for gastric cancer and nonmalignant diseases of the gastric mucosa. Cancer Res. 2004;64(4):1255-65.

  32. Varis K, Taylor PR, Sipponen P et al. Gastric cancer and premalignant lesions in atrophic gastritis: a controlled trial on the effect of supplementation with alpha-tocopherol and beta-carotene. The Helsinki Gastritis Study Group. Scand J Gastroenterol 1998;33:294-300.

  33. You WC, Blot WJ, Li JY et al. Precancerous gastric lesions in a population at high risk of stomach cancer. Cancer Res 1993;53:1317-21.

  34. You WC, Zhang L, Gail MH et al. Precancerous lesions in two counties of China with contrasting gastric cancer risk. Int J Epidemiol 1998;27:945-8.

  35. Armbrecht U, Stockbrugger RW, Rode J et al. Development of gastric dysplasia in pernicious anaemia: a clinical and endoscopic follow up study of 80 patients. Gut 1990; 31:1105-1109.

  36. Offerhaus GJ, van de SJ, Huibregtse K, Tersmette AC, Tytgat GN. The mucosa of the gastric remnant harboring malignancy. Histologic findings in the biopsy specimens of 504 asymptomatic patients 15 to 46 years after partial gastrectomy with emphasis on nonmalignant lesions. Cancer 1989;64:698-703.

  37. Offerhaus GJ, Tersmette AC, Huibregste K et al. Mortality caused by stomach cancer after remote partial gastrectomy for benign conditions: 40 years of follow up of an Amsterdam cohort of 2633 postgastrectomy patients. Gut. 1988; 29:1588-90.

  38. Schlemper RJ et al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut. 2000 Aug;47(2):251-5.

  39. Hamilton SR, Aaltonen LA eds. World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Digestive System. IARC Press, Lyon 2000.

  40. Antonioli DA. Precursors of gastric carcinoma: a critical review with a brief description of early (curable) gastric cancer. Hum Pathol 1994; 25:994-1005.

  41. Misdraji J, Lauwers GY. Gastric epithelial dysplasia. Semin Diagn Pathol. 2002;19(1):20-30.

  42. Burke AP, Sobin LH, Shekitka KM, Helwig EB. Dysplasia of the stomach and Barrett esophagus: a follow-up study. Mod Pathol 1991;4:336-41.

  43. Saraga EP, Gardiol D, Costa J. Gastric dysplasia. A histological follow-up study. Am J Surg Pathol 1987;11:788-96.

  44. Lauwers GY, Shimizu M, Correa P et al. Evaluation of gastric biopsies for neoplasia: differences between Japanese and Western pathologists. Am J Surg Pathol 1999;23:511-8.

  45. Schlemper RJ, Kato Y, Stolte M. Review of histological classifications of gastrointestinal epithelial neoplasia: differences in diagnosis of early carcinomas between Japanese and Western pathologists. J Gastroenterol 2001;36:445-56.

  46. Riddell RH, Goldman H, Ransohoff DF et al. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol. 1983; 14:931-68.

  47. Reid BJ, Haggitt RC, Rubin CE et al. Observer variation in the diagnosis of dysplasia in Barrett's esophagus. Hum Pathol 1988; 19:166-178.

  48. Dixon MF. Gastrointestinal epithelial neoplasia: Vienna revisited. Gut. 2002;51(1):130-1.

  49. Ghandur-Mnaymneh L, Paz J, Roldan E, Cassady J. Dysplasia of nonmetaplastic gastric mucosa. A proposal for its classification and its possible relationship to diffuse-type gastric carcinoma. Am J Surg Pathol.1988; 12:96-114.

  50. Fertitta AM, Comin U, Terruzzi V et al. Clinical significance of gastric dysplasia: a multicenter follow-up study. Gastrointestinal Endoscopic Pathology Study Group. Endoscopy 1993;25:265-8.

  51. Brien TP, Farraye FA, Odze RD. Gastric dysplasia-like epithelial atypia associated with chemoradiotherapy for esophageal cancer: a clinicopathologic and immunohistochemical study of 15 cases. Mod Pathol. 2001; 14:389-96.

  52. Rugge M, Farinati F, Baffa R et al. Gastric epithelial dysplasia in the natural history of gastric cancer: a multicenter prospective follow-up study. Interdisciplinary Group on Gastric Epithelial Dysplasia. Gastroenterology 1994;107:1288-96.

  53. Bearzi I, Brancorsini D, Santinelli A, Rezai B, Mannello B, Ranaldi R. Gastric dysplasia: a ten-year follow-up study. Pathol Res Pract 1994;190:61-8.

  54. Kokkola A, Haapiainen R, Laxen F et al. Risk of gastric carcinoma in patients with mucosal dysplasia associated with atrophic gastritis: a follow up study. J Clin Pathol 1996;49:979-84.

  55. Rugge M, Cassaro M, Di Mario F et al. The long term outcome of gastric non-invasive neoplasia. Gut 2003; 52:1111-1116.

  56. Lauwers GY, Ban S, Mino M et al. Endoscopic mucosal resection for gastric epithelial neoplasms: a study of 39 cases with emphasis on the evaluation of specimens and recommendations for optimal pathologic analysis. Mod Pathol 2004;17:2-8.

  57. Deppisch LM, Rona VT. Gastric epithelial polyps. A 10-year study. J Clin Gastroenterol. 1989; 11:110-5.

  58. Stolte M, Sticht T, Eidt S et al. Frequency, location, and age and sex distribution of various types of gastric polyp. Endoscopy. 1994; 26:659-65.

  59. Nakamura K, Sakaguchi H, Enjoji M. Depressed adenoma of the stomach. Cancer 1988; 62:2197.

  60. Nakano H, Persson B, Slezak P. Study of the gastric mucosal background in patients with gastric polyps. Gastrointest Endosc 1990; 36:39-42.

  61. Marcello PW, Asbun HJ, Veidenheimer MC et al. Gastroduodenal polyps in familial adenomatous polyposis. Surg Endosc 1996;10:418-21.

  62. Spigelman AD, Williams CB, Talbot IC, Domizio P, Phillips RK. Upper gastrointestinal cancer in patients with familial adenomatous polyposis. Lancet 1989;2:783-5.

  63. Nakamura T, Nakano G. Histopathological classification and malignant change in gastric polyps. J Clin Pathol 1985;38:754-64.

  64. Orlowska J, Jarosz D, Pachlewski J, Butruk E. Malignant transformation of benign epithelial gastric polyps. Am J Gastroenterol 1995;90:2152-9.

  65. Abraham SC, Montgomery EA, Singh VK, Yardley JH, Wu TT. Gastric adenomas: intestinal-type and gastric-type adenomas differ in the risk of adenocarcinoma and presence of background mucosal pathology. Am J Surg Pathol 2002;26:1276-85.

  66. Cristallini EG, Ascani S, Bolis GB. Association between histologic type of polyp and carcinoma in the stomach. Gastrointest Endosc. 1992; 38:481-4.

  67. Dirchmid K, Plautz-Baudin C, Stolte M. Why is the hyperplastic polyp a marker for the precancerous condition of the gastric mucosa? Virchows Arch. 2005;:1-5

  68. Abraham SC, Singh VK, Yardley JH, Wu TT. Hyperplastic polyps of the stomach: associations with histologic patterns of gastritis and gastric atrophy. Am J Surg Pathol 2001;25:500-7.

  69. Zea-Iriarte WL, Sekine I, Itsuno M et al. Carcinoma in gastric hyperplastic polyps. A phenotypic study. Dig Dis Sci 1996;41:377-86.

  70. Ohkusa T, Takashimizu I, Fujiki K et al. Disappearance of hyperplastic polyps in the stomach after eradication of Helicobacter pylori. A randomized, clinical trial. Ann Intern Med. 1998; 129:712-5.

  71. Yao T, Kajiwara M, Kuroiwa S et al. Malignant transformation of gastric hyperplastic polyps: alteration of phenotypes, proliferative activity, and p53 expression. Hum Pathol 2002; 33:1016-22.

  72. Kinoshita Y, Tojo M, Yano T et al. Incidence of fundic gland polyps in patients without familial adenomatous polyposis. Gastrointest Endosc. 1993 ;39:161-3.

  73. Marcial MA, Villafana M, Hernandez-Denton J et al. Fundic gland polyps: prevalence and clinicopathologic features. Am J Gastroenterol. 1993; 88:1711-3.

  74. Iida M, Yao T, Watanabe H, et al: Fundic gland polyposis in patients without familial adenomatosis coli: its incidence and clinical features. Gastroenterology 1984; 86:1437.

  75. Bertoni G, Sassatelli R, Nigrisoli E et al. Dysplastic changes in gastric fundic gland polyps of patients with familial adenomatous polyposis. Ital J Gastroenterol Hepatol 1999;31:192-7.

  76. Sarre RG, Frost AG, Jagelman DG et al. Gastric and duodenal polyps in familial adenomatous polyposis: a prospective study of the nature and prevalence of upper gastrointestinal polyps. Gut. 1987; 28:306-14.

  77. Choudhry U, Boyce HW, Jr., Coppola D. Proton pump inhibitor-associated gastric polyps: a retrospective analysis of their frequency, and endoscopic, histologic, and ultrastructural characteristics. Am J Clin Pathol 1998;110:615-21.

  78. Odze RD, Marcial MA, Antonioli D. Gastric fundic gland polyps: a morphological study including mucin histochemistry, stereometry, and MIB-1 immunohistochemistry. Hum Pathol. 1996; 27:896-903.

  79. Wu TT, Kornacki S, Rashid A, Yardley JH, Hamilton SR. Dysplasia and dysregulation of proliferation in foveolar and surface epithelia of fundic gland polyps from patients with familial adenomatous polyposis. Am J Surg Pathol 1998;22:293-8.

  80. Zwick A, Munir M, Ryan CK et al. Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli. Gastroenterology 1997;113:659-63.

  81. Hofgartner WT, Thorp M, Ramus MW et al. Gastric adenocarcinoma associated with fundic gland polyps in a patient with attenuated familial adenomatous polyposis. Am J Gastroenterol 1999; 94:2275-81.

  82. Offerhaus GJ, Giardello FM, Krush AJ et al. The risk of upper gastrointestinal cancer in familial adenomatous polyposis. Gastroenterology. 1992; 102:1980-2.