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ORIGINAL CONTRIBUTIONS

Received: August 21^th 2014

Accepted: October 9^th 2014

Atrophy in the mucosa neighboring an intestinal-type gastric adenocarcinoma by comparing the Sydney vs. OLGA systems

Pablo Ramírez-Mendoza,^a Liliana Hernández-Briseño,^b Moisés Casarrubias-Ramírez,^c Isabel Alvarado-Cabrero,^d Ulises Ángeles-Garay^e

^aDepartamento de Patología, Hospital de Especialidades

^bDepartamento de Patología, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Jalapa, Veracruz, México

^cDepartamento de Medicina Interna, Hospital de Especialidades

^dDepartamento de Patología, Hospital de Oncología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Distrito Federal, México

^eServicio de Epidemiología Clínica, Hospital de Especialidades

^a,c,eCentro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Distrito Federal, México

Communication with: Pablo Ramírez-Mendoza

Telephone: (55) 5724 5900, extensión 23053

Email: drpabloramirezm@gmail.com

Background: Gastric carcinoma causes about 700 000 deaths worldwide per year. Is feasible detect it in earlier stages. The aim of this article is to assess the atrophy in the mucosa neighboring an intestinal-type gastric adenocarcinoma by comparing the Sydney vs. OLGA systems.

Methods: Twenty-eight individuals with intestinal-type gastric adenocarcinoma (Lauren) were compared with 32 non-neoplastic cases. Both groups had undergone total gastrectomy. Two pathologists made a consensus-based assessment of the atrophy in non-neoplastic corpus and antral epithelium using the Sydney and OLGA Systems. The mean, median, and distribution of the frequencies were obtained using the measuring and distribution scales of the study variables. The sensitivity, specificity, and predictive values, both positive and negative, for gastric cancer were calculated through the dichotomy of advanced atrophy-positive and advanced atrophy-negative scales.

Results: Twenty-four of the 28 cases with intestinal-type gastric carcinoma showed an advanced atrophy with the OLGA system, with a sensitivity and specificity of 77 and 85 %, respectively. Conversely, 4 of the 28 individuals showed an advanced atrophy with the Sydney system, with a sensitivity and specificity of 14 and 100 %, respectively.

Conclusions: The OLGA system has a high sensitivity and specificity (77 y 85 % respectively) for the recognition of preneoplastic changes in the mucosa neighboring a gastric carcinoma.

Keywords: Stomach neoplasms, Gastrectomy, Adenocarcinoma, Atrophy

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Although the frequency of gastric cancer has decreased in recent years, it remains the second leading cause of cancer death worldwide, causing 700,000 deaths a year.^1,2 This tumor has a secondary place in the United States, however, the American Cancer Society found that in 2008, 21,850 new cases occurred, with 10,880 deaths from this disease.³ In Mexico we do not even have approximate figures, part of the problem appears only expressed in the Registro Histopatológico de Neoplasias in Mexico 2002,⁴ where 3,395 deaths from gastric cancer were reported, slightly more prevalent in men. For both sexes it is among the four most common cancers.

The Pelayo Correa cascade,^5-7 (indicating the possible sequence of development of gastric cancer) noted the changes in the gastric mucosa culminating in intestinal type gastric adenocarcinoma (IGA). This theory holds that a segment of subjects with gastritis develops gastric atrophy that can be early or advanced. The latter is what carries greater risk of malignant transformation. Consequently, the mucosa surrounding the IGA contains preneoplastic changes. Several authors^8-16 have ratified these data.

There are two systems that evaluate atrophy with different histopathological criteria: the modified Sydney classification system¹⁷ for gastritis was created, among other purposes, to separate the atrophic changes from non-atrophic, according to the topography and intensity, related to varying degrees of cancer risk; on the other hand, an international group of pathologists, originally called Club Atrophy and then later calling themselves Operative Link on Gastritis Assessment (OLGA), analyzed the Sydney system and proposed modifications.^18-20 There is expressed a stage (step) of atrophy, which links the presence, extent, and topography of lesions to the likelihood of developing cancer.²⁰

In this study we assessed the presence of atrophy for this specific type of tumor in the mucosa surrounding IGA, qualified according to the criteria in Sydney and OLGA systems.

Methods

In the period from July 1, 2007 to December 31, 2011, in the Servicio de Oncología at the Centro Médico Nacional Siglo XXI of the Instituto Mexicano del Seguro Social we identified 40 patients, ages 18 and up, diagnosed with intestinal type primary gastric carcinoma, according to Lauren criteria.²¹ All of them underwent total gastrectomy. We included those cases that had histological samples of the tumor and the mucosa surrounding the tumor, of body and antrum. The following information was collected from clinical records: age, sex, diagnosis of surgical specimen, and anatomic site of tumor. During the review we eliminated a total of 5 cases, three for lack of histological preparations of body or antrum, and two more for being histological types other than intestinal type adenocarcinoma, for a total of 35 cases included in the study. 

For comparison, during the period from January 1, 2010 and March 31, 2012 in the Hospital de Especialidades Centro Médico Nacional La Raza of the Instituto Mexicano del Seguro Social, we identified 35 patients who underwent total gastrectomy and whose definitive histopathological diagnosis was other than IGA (Table I). In subjects of both sexes, age was comparable to the cancer group. For this reason we eliminated three cases, all of them for being under 18.

In all cases, with or without neoplasia, we recovered histological preparations of tumor of body and non-neoplastic antrum, each one stained with hematoxylin-eosin. We applied Sydney and OLGA systems by consensus. The histological type of tumor and the presence, or not, of dysplasia were recorded.

The time periods studied for each hospital were different due to problems related to the file. As beneficiaries of the same institution we assume that patients have comparable profiles because they share similar socioeconomic and occupational characteristics.

The Sydney system17 distinguishes between: atrophic and non-atrophic stomach. It is considered atrophy when there is glandular loss and consequent thinning of the mucosa. It assumes that metaplasia is a phenomenon independent of atrophy. In the visual analogue scale published there, three grades are reported: mild, moderate, and severe, without considering percentage of mucosa affected. It is proposed that in case of moderate to severe atrophy, which predominantly affects one or both anatomical sites, body and antrum, there is implied a higher risk of developing gastric carcinoma.

The OLGA system19,20 corresponds to a specific staging system of atrophy according to histopathological parameters. It is based on the interpretation of 5 gastric biopsies, as suggested by the modified Sydney system.17 Atrophy can be of three types: non-metaplastic (equivalent to that of Sydney) consisting of contraction and loss of glandular units with surrounding expansion of the lamina itself; a second called metaplastic is based on metaplastic, intestinal or pseudopyloric replacement that replaces native glands in at least one compartment of the mucosa; and the third, which is mixed with the presence of both criteria. Importantly, when we found the mixed form is was preferred to designate it as metaplastic. This system assumes that mucosal damage is distributed over time (between chronic gastritis and atrophy itself), with varying degrees, and that advanced atrophy is closer to gastric carcinoma.^19,20,22-24 The stage of atrophy by the OLGA system results from combining the "antrum qualification" with "body qualification". Stages 3 and 4 are considered positive for precancerous lesions, and stages 1 and 2 negative.^22-24

We compared the two classifications regarding atrophy. The key fact: glandular loss for Sydney, unlike the OLGA system, which uses the metaplastic change to define atrophy. Moreover, both systems employ the extent of damage to determine increased risk for developing IGA, with the difference that OLGA expresses it in stages and Sydney does not establish what percentage of the condition is a cohort point.

For the purposes of our study, we assumed that only the intense atrophy of body or antrum, or the simultaneous change of both regions, predicted increased risk for gastric carcinoma with the Sydney system. For OLGA only stages 3 and 4 have increased risk for developing cancer. Therefore, all qualifications other than those stated have no increased risk for gastric cancer in both systems. Arbitrarily we called them positive and negative cases.

We defined intraepithelial neoplasia (IEN) according to the criteria proposed in the Padua meeting.²⁵

Statistic analysis

The descriptive analysis was performed using mean, median, and frequency distribution according to the measuring range and type of distribution of the study variables. The sensitivity, specificity, and positive and negative predictive values ​​for gastric cancer were calculated according to each system. We dichotomized the parameters into positive tests (advanced atrophy) and negative (no atrophy or mild atrophy) for atrophy respectively.

Results

Among the 35 cases of cancer we identified 28 patients with intestinal type gastric adenocarcinoma (IGA) and seven with intestinal type gastric adenocarcinoma with a secondary histological component. As in the Pelayo Correa cascade, also known as gastric carcinogenesis sequence, specifically applies to intestinal type carcinoma,^5-7 we used only the 28 cases of intestinal carcinoma for our analysis (Table II). 

Table III shows the general data of the subjects. The average age was 63.5 years. We found a predominance of women with gastric cancer. Advanced atrophy, according to the OLGA criteria, was observed in 24 of the 28 cases with IGA, compared with 28 as evaluated with Sydney. According to the binary system previously defined (positive and negative tests), sensitivity and specificity was 77 and 85% respectively with the OLGA system, compared to 14.3 and 100% in Sydney.

Four cases stand out without neoplasia, in whom we saw advanced stages, 3 and 4 per OLGA. These cases were: a patient who received surgery for margin expansion, with a history of previous gastric carcinoma resection; two patients with endoscopic and histopathological diagnosis of gastric carcinoma that was not supported by gastrectomy, and one that was the case of a 59 year old man with a history of alcoholism and hypertension who showed extensive metaplastic atrophy, OLGA stage 3. 

Discussion

Our data confirm that the OLGA system can consistently recognize predicted changes in mucosa surrounding intestinal gastric carcinoma. In this series, with the OLGA system most cases 24/28 (85.7%) had advanced stages 3 and 4 of atrophy, versus the Sydney system which found it in 4/28 cases (14.3%) Successful classification lies in the inclusion of metaplasia as a phenomenon of the atrophy itself. Several authors had already recognized metaplasia as part of atrophy.^26-28 Genta28 envisioned that the key datum is not glandular loss alone, as proposed by the modified Sydney system, but the loss of adequate glands, which brought the leap in quality that lets us reliably define advanced atrophy.

Arista et al.²⁹ studied surrounding mucosa in cases of primary gastric carcinomas and lymphomas in the Mexican population. Among the 30 cases with intestinal gastric adenocarcinoma they recognized atrophy, by Sydney criteria, in 76.6% and intestinal metaplasia in 86.6%. This draws attention to the high prevalence of atrophy when the Sydney system criteria were used. In our opinion, in the Sydney system, the mucosa surrounding the gastric cancer does not show glandular loss, i.e. atrophy. By contrast, glandular density, a critical datum for the system, can appear intact when we observe metaplastic change. Moreover, we agree on the high prevalence of intestinal metaplasia that determines atrophy according to the OLGA system criteria.  

Satoh et al.³⁰ studied the surrounding mucosa in 18 cases of early gastric carcinoma of whom 15 were endoscopically resected and three treated with surgery, assessed with the OLGA system. They found figures almost identical to ours: a high frequency of atrophy (56% in stage 4 and 28% in stage 3 OLGA, for a total of 84% of cases with advanced atrophy) in the adjacent mucosa. Also, they included subjects with atrophic gastritis, gastric ulcer and duodenal ulcer and in none of these groups of patients did they find a link with advanced stages of atrophy according to the OLGA system. In our case-controls without neoplasia, 4 patients had advanced atrophy. One had surgery to expand margins, with a history of gastrectomy because of gastric carcinoma; two with endoscopic and histopathological diagnosis of early gastric carcinoma not demonstrated in gastrectomy, and finally a man with a history of alcoholism and hypertension, with OLGA stage 3. Subjects without cancer included here were selected according to the final histopathological diagnosis. Their background was: previous resection of gastric carcinoma, probable dysplastic changes, and a subject with hepatic impairment related to alcoholism not contrary to the finding of advanced atrophy.

A cohort study in a Western population³¹ showed that metaplasia alone did not significantly increase the risk of gastric cancer. In contrast, the presence of IEN, particularly in older men, significantly increased the risk of developing gastric cancer. In our study we found high frequency of IEN in cases with advanced atrophy (20/24). In everyday practice, the main difficulty of demonstrating the presence of IEN depends on its multifocal nature and size of the dysplastic nests in the mucosa. Hence their recognition would be proportional to the depth of endoscopic sampling, endoscopic resolution or auxiliary techniques during the study. It is understood that their presence corresponds to a stage close to gastric cancer. At present, the OLGA system does not emphasize the presence of IEN. We propose emphasizing this fact in the biopsy report. This simple guideline could recognize patients at greatest risk. However, it has been shown that the presence of stages 3 and 4 are sufficient to undertake follow-up.²³

In Vanoy valley, a region of Italy with high prevalence of gastric cancer, gastric biopsies were gotten from 100 patients with dyspepsia according to Sydney protocol.²³ Of these subjects, 10 were found with OLGA stage 3 and 4. In a second biopsy, among the 93 subjects who attended, (done twelve years later, on average) six neoplastic events were detected: three with low-grade intraepithelial neoplasia, one more with high-grade intraepithelial neoplasia and two invasive elements. None of the remaining 83 subjects with original biopsies in stage 1 and 2 of the disease, developed IEN.

One of the refinements proposed for the OLGA system is to consider only the metaplasia and its extension to express the stage of atrophy.³² These authors stressed that atrophy with OLGA, in inter-observer comparison, had a substantial kappa (0.6), but it was excellent (0.9) for all cases with metaplastic atrophy. This was called Operative Link on Gastric Intestinal Metaplasia Assessment, or its acronym: OLGIM. Hence his proposal: just recognize the metaplastic atrophy, which has better inter-observer agreement.

Rugge et al.³³ compared 4552 gastric biopsies with OLGIM and OLGA systems. They found 243 cases with OLGA stage 3 and 4 against 229 with equivalent OLGIM stages. Similarly, in two of the 34 cases of intestinal gastric adenocarcinoma, the OLGIM system showed stage 2 atrophy. Therefore, considering only cases with metaplastic atrophy (OLGIM) could ignore a few cases deserving follow-up. In our opinion,³⁴ the main difficulty in recognizing non-metaplastic atrophy is related to the lack of interest in consistently reporting atrophy, and the oft-cited difficulty there may be in recognizing it in biopsies of gastric antrum. However this is not an insurmountable difficulty. 

In 22 of the 28 cases of IGA we saw metaplastic or partly metaplastic atrophy in the surrounding mucosa. We divided it into complete, incomplete, and mixed forms. We wonder whether the specific type of metaplasia has specific relationship with IGA, which is yet to be determined.^35-37 This material will be subject to further study.

Four of the 28 subjects with IGA had early atrophy, stages 0 to 2 with the OLGA system, i.e., without increased risk of cancer. Two cases showed wide, high-grade gastric foveolar adenoma and intraepithelial neoplasia in surrounding mucosa. The remaining two, totaling four, were found seated in the gastric fundus. These could be conditions of exception, not registered until now, for the OLGA system in its ability to recognize premalignant disease.

Foveolar adenomas are a very rare, causal condition of gastric adenocarcinoma. In Abraham³⁸ series of subjects with foveolar adenomas, metaplastic atrophy was not found, as happened in our two cases. Conversely, Youn Park³⁹ in their series of patients with foveolar adenomas found intestinal metaplasia and dysplasia. These differences could have genetic or epidemiological grounds. Undoubtedly, it requires further research to clarify this apparent discrepancy. 

With regard to the anatomic location, there are epidemiological differences regarding tumors proximal and distal to the stomach.^3,40,41 Perhaps the atrophy valued here, in body and antrum, it is not related to tumors of the cardia. However, our data are scarce and require further validation studies.

Finally, on the predominance of women in the study we believe that is a biased datum. At the cancer hospital where we got the data, we recovered only those cases that met our inclusion criteria. In no way is this an attempt to study the prevalence of gastric adenocarcinoma.

Conclusions

The OLGA system, not the Sydney, reliably recognizes and stages preneoplastic changes in surrounding mucosa in patients with intestinal gastric carcinoma. We found conditions that could be the exception by which OLGA recognizes premalignant lesions: 1) foveolar adenomas with IEN, and 2) the proximal stomach tumors. We propose that the presence of IEN should be emphasized as part of the diagnosis.

Acknowledgements

Thanks to Dr. Gabriela Medina who selflessly shared all her knowledge with us for the publication of the manuscript.

References

1. Pisani P, Parkin DM, Bray F, Ferlay J. Estimates of the worldwide mortality from 25 cancers in 1990. Int J Cancer 1999; 83(1):18-29.
2. Allum WH, Powell DJ, McConkey CC, Fielding JW. Gastric cancer: a 25 year review. Br J Surg 1989; 76 (6):535-540.
3. Wu H, Rusiecki JA, Zhu K, Potter J, Devesa SS. Stomach carcinoma incidence patterns in the United States by histologic type and anatomic site. Cancer Epid Biomarkers Prev 2009; 18(7):1945-1952.
4. Secretaría de Salud. Subsecretaría de prevención y promoción de la salud. Compendio de Cáncer 2002 Registro histopatológico de neoplasias malignas en la República Mexicana (CD ROM). Dirección general de epidemiología México. 2002.
5. Correa P, Haenszel W, Cuello C, Tannembaum S, Archer M. A model for gastric cancer epidemiology. Lancet 1975; 2(7924): 58-60.
6. Correa P. A human model of gastric carcinogenesis. Cancer Res1988; 48(13):3554-3360.
7. Correa P, Piazuelo MB. The gastric precancerous cascade. J Dig Dis 2012; 13(1): 2-9.
8. Zhang C, Yamada N, Wu YL, Wen M, Matsuhisa T, Matsukura N. Helicobacter pylori infection, glandular atrophy and intestinal metaplasia in superficial gastritis, gastric erosion, erosive gastritis, gastric ulcer and early gastric cancer. World J Gastroenterol 2005; 11(6):791-796.
9. Ho SB. Premalignant lesions of the stomach. Semin Gastrointest Dis 1996; 7(2): 61-73.
10. Komoto K, Haruma K, Kamada T, Tanaka S, Yoshikara M, Sumii K, et. al. Helicobacter pylori infection and gastric neoplasia: Correlations with histological gastritis and tumor histology. Am J Gastroenterol 1998; 93(8):1271-1276.
11. Uemura N, Okamoto S, Yamamoto S. Helicobacter pylori infection and the development of gastric cancer. N Eng J Med 2001; 345(11):784-789.
12. Villako K, Kekki M, Maaroos HI, Sipponen P, Uibo R, Tammur R, et. al. Chronic gastritis: progression of inflammation and atrophy in a six year endoscopic follow-up of a random sample of 142 Estonian urban subjects. Scand J Gastroenterol 1991; 186: 135-141.
13. Hackelrsberger A, Günther T, Schultze V, Peitz U, Malfertheiner P. Role of aging in the expression of helicobacter pylori gastritis in the antrum, corpus and cardia. Scand J Gastroenterol 1999; 34(2):138-143.
14. Sipponen P, Keikki M, Siurala M. Atrophic chronic gastritis and intestinal metaplasia in gastric carcinoma. Comparison with a representative population sample. Cancer 1983; 52(6):1062-1068.
15. Sipponen P, Keikki 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.
16. Sipponen P, Seppala K, Aärynen M, Helske T, Kettunen P. Chronic gastritis and gastroduodenal ulcer, a case control study on risk of coexisting duodenal or gastric ulcer in patients with gastritis. Gut 1989; 30(7):922-929.
17. 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(10):1161–1181.
18. Rugge M, Genta RM. Staging and grading of chronic gastritis. Hum Path 2005; 36(3): 228-233.
19. Rugge M, Correa P, Dixon MF, Fiocca R, Hattori T, Lechago J, et. al. Gastric mucosal atrophy: interobserver consistency using new criteria for classification and grading. Aliment Pharmacol Ther 2002; 16 (7):1249-1259.
20. Rugge M, Genta RM; OLGA Group. Staging gastritis: an international proposal. Gastroenterology 2005; 129(5):1807-1808.
21. Lauren P. The two histological main types of gastric carcinoma. Diffuse and so called intestinal type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 1965; 64:31-49.
22. Rugge M, Meggio A, Penneli G, Piscioli F, Giaconelli L, De Prettis G, et. al. Gastritis staging in clinical practice; the OLGA staging system. Gut 2007; 56 (5):631-636.
23. Rugge M, Boni M, Pennelli G, de Bona M, Giacoenelli L, Fasson M, et al. Gastritis OLGA-staging and gastric cancer risk: a twelve-year clinic-pathologic follow up study. Alimen Pharmacol Ther 2010; 31:1104-1111
24. Rugge M, Correa P, Di Mario F, El Omar E, Fiocca R, Geboes K, et.al. OLGA staging for gastritis; a tutorial. Dig and Liver Dis 2008; 40(8): 650-658.
25. Rugge M, Correa P, Dixon MF, Hattori T, Leandro G, Lewin K, et. al. Gastric dysplasia: The Padova international classification. Am J Surg Pathol 2000; 24(2):167-176.
26. Genta R. Recognizing atrophy: another step toward a classification of gastritis. Am J Surg Pathol 1996, 20 (Suppl 1): S23-30.
27. Annibale B, Lahner E. Assessing the severity of atrophic gastritis. Eur J Gastroenterol Hepatol 2007; 19(12): 1059-1063.
28. Genta RM. Helicobacter pylori, inflammation, mucosal damage, and apoptosis, pathogenesis and definition of gastric atrophy. Gastroenterology 1997; 113(6 Suppl): S51-55.
29. Arista-Nasr J, Jiménez-Rosas F, Uribe-Uribe N, Herrera-Goepfert R, Lazos-Ochoa M. Pathological disorders of the gastric mucosa surrounding carcinomas and primary lymphomas. Am J Gastroenterol 2001; 96(6):1746-1750.
30. Satoh K, Osawa H, Yoshizawa M, Nakano H, Hirosawa T, Kihira K, et.al. Assessment of atrophic gastritis using the OLGA system. Helicobacter 2008; 13 (3):225-229.
31. de Vries AC, van Grieken NC, Looman CW, Casparie MK, de Vries E, Meijer JA, et.al. Gastric cancer risk in patients with premalignant gastric lesions: a nationwide cohort study in the Netherlands. Gastroenterology 2008; 134(4): 945-952.
32. Capelle LG, de Vries AC, Haringsma J, Ter Borg F, de Vries RA, Bruno MJ, et. al. The staging of gastritis with the OLGA system by using intestinal metaplasia as an accurate alternative for atrophic gastritis. Gastrointestinal Endoscopy 2010; 71(7):1150-1158.
33. Rugge M, Fassan M, Pizzi M, Farinati F, Sturniolo GC, Plebani M, et. al. Operative link for gastritis assessment vs operative link on intestinal metaplasia assessment. World J Gastroenterology 2011; 17 (41):4596-4661.
34. Ramírez Mendoza P, González Angulo J, Ángeles Garay U, Segovia-Cuevas GA. Evaluación de la atrofia gástrica: Comparación entre los sistemas Sidney and OLGA. Rev Med Inst Mex Seguro Social 2008; 46(2):135-139.
35. Gutierrez-Gonzalez L, Wright NA. Biology of intestinal metaplasia in 2008; more than a simple phenotypic alteration. Dig Liver Dis 2008; 40(7):510-522.
36. Silva E, Teixeira A, David L, Carneiro F, Reis CA, Sobrinho-Simoes SJ, et. al. Mucin as key molecules for the classification of intestinal metaplasia of the stomach. Virchows Arch 2002; 440(3):311-317.
37. Leung WK, Lin SR, Ching JY, To KF, Ng EK, Chang FK, et. al. Factors predicting progression of gastric intestinal metaplasia: results of a randomized trial on Helicobacter pylori eradication. Gut 2004; 53(9): 1244-1249.
38. Abraham SC, Montgomery EA, Sing 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(10):1276-1285.
39. Park do Y, Srisvastava A, Kim GH, Mino -Kenudson M, Desphande V, Zukerberg LR, et. al. Adenomatous and foveolar gastric dysplasia: distinct patterns of mucin expression and background intestinal metaplasia. Am J Surg Pathol. 2008; 32(4): 524-533.
40. Kelley JR, Duggan JM. Gastric cancer epidemiology and risk factors. J Clin Epidemiol 2003; 56(1): 1-9.
41. Ji BT, Chow WH, Yang G, Mc Laughlin JK, Gao RN, Zheng W, et. al. The influence of cigarrette smoking, alcohol, and green tea consumption of the risk of carcinoma of the cardia and distal stomach in Shanghai, China. Cancer 1996; 77(12): 2449-2457.

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