N. Zendehdel, S. Massarrat, A. Sheykholeslami, et al. Original Article Topography of Gastritis and its Severity in 864 First Degree Relatives of Gastric Cancer Patients SI D Nasrin Zendehdel MD2, Sadegh Massarrat MD•1, Arghavan Sheykholeslami MD1, Naser Rakhshani MD1,3, Sandra Saeidi MD4, Reza Raee MD5, Hosein Nobakht MD1, Seyed Masoud Tabib MD1, Mehrdad Saliminejhad MD1, Masoud Dooghaie Moghadam MD1, Jafar Nasiri MD1, Kourosh Azimi MD1, Reza Fakhar MD1, Mehdi Babaei MD1, Reza Didehvar MD1, Nosratollah Mohammadi MD1, Mehdi Tavazoee MD1, Reza Malekzadeh MD1 ch ive of Abstract Objectives: Studies on gastric mucosal histological ndings among rst degree relatives (FDR) of gastric cancer (GC) patients are scarce. The aim is to evaluate the topography and the severity of gastritis among FDR of GC patients. Design: A total of 989 subjects who were FDR of GC patients, ages 40 – 65 years underwent gastroscopies. When no gross lesion was found, ve specimens were evaluated according to the Sydney Classication and one for urease testing in order to determine the type of gastritis and its severity. Results: Of the 989 subjects, 107 had signicant lesions, including two with GC and one with esophageal cancer. The 864 subjects who had complete morphological data taken from ve gastric areas (two from the antrum and three from the corpus) comprised 419 males (mean age 48.5±7 years) and 445 females (mean age 47±6.4 years). The H. pylori rate was 76.6%. Normal mucosa was seen in 6.9%, antrum-restricted gastritis in 7.4%, antrum-predominant gastritis in 63.5% and corpus-predominant gastritis in 20% (both had >80% H. pylori infection) and corpus-restricted gastritis in 2%. More atrophy was seen in the antrum and corpus of FDR females than males. The severity did not differ between those with one or more GC patients’ relatives. Forty-nine percent of FDR had atrophy and 9.4% intestinal metaplasia (IM) in the corpus. After the age of 40, there was progression of intestinal metaplasia from 12.2 to 27.3% in the antrum and from 6.7% to 26.2% in the corpus during two decades. No high grade dysplasia was found in this mid-age population. Conclusion: Only one-fth of FDR have H. pylori-induced corpus-predominant gastritis who are at risk for cancer and suitable for eradication. Corpus-restricted gastritis is a rare disease in this area. Ar Key words: familial, gastric cancer, gastritis, H. pylori Authors’ afliations: 1Digestive Diseases Research Center, Tehran University of Medical Sciences, Tehran, 2Department of Internal Medicine, Shohada Hospital Shahid Beheshti University of Medical Sciences, Tehran, 3Gastroenterology and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, 4 Gastroenterology Department, Artesh University of Medical Sciences, Tehran, 5 Department of Pathology, Shohada Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. •Corresponding author and reprints: Sadegh Massarrat MD, Digestive Diseases Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran. P.O. Box 19615-654, Tel: +98-218-822-0026, Fax: +98-218-241-5400, E-mail: massarrat@ams.ac.ir Accepted for publication: 19 May 2010 Introduction G astric cancer (GC) is the leading cause of cancer deaths among males in some Latin American, Asian countries, and in Iran.1,2 The detection of early GC by routine endoscopic screening of those at risk can improve the survival of patients.2,3 As H. pylori-induced atrophic gastritis is a precursor of distal GC, its eradication provides the best way for prevention of GC. Among Archives of Iranian Medicine, Volume 13, Number 6, November 2010 469 www.SID.ir Gastritis Severity in Relatives of GC Patients intestinal metaplasia (IM) was categorized according to four grades (none=0, slight=1, moderate=2, and severe=3). The mean scores of mononuclear and neutrophil cell inltration were calculated separately for two areas of the antrum and three areas of the corpus. H. pylori infection was considered absent when both the RUT and histology of H. pylori in at least four out of ve specimens were negative. H. pylori was conrmed by positive RUT and histological detection in at least one of the ve specimens. The type of gastritis was characterized as antral gastritis only or antrum-predominant gastritis when the mean score of neutrophil and mononuclear cell inltrations in both antral biopsies was higher than the mean score of the three corpus samples. Corpusrestricted gastritis was considered when the mean score of neutrophil and mononuclear cell inltration from all three areas of the corpus mucosa was greater than the mean score from both areas of the antrum. Corpus gastritis was only considered when neither neutrophil nor mononuclear cells were seen in either areas of the antrum. The biomarkers pepsinogen I, II, and gastrin 17 by ELISA (Biohit, Oslow, and Finland) were measured in the sera of those with corpus-restricted gastritis. Parietal cell antibody was measured in these sera by immunouorescence.16 Statistical analysis was done by SPSS (independent t-test and Chi-square t-test). The difference was considered signicant with a value P<0.05. The study was approved by Institutional Review Board of the “Digestive Diseases Research Center of Tehran University of Medical Sciences” in accordance with the Declaration of Helsinki. Informed consent was obtained for all participants according to the guidelines of the Institute. Materials and Methods Ar ch ive of The residential addresses of subjects who underwent surgery for GC in Tehran hospitals during 2002 – 2005 were obtained from various hospital databases and from the Tehran Cancer Institute. Contact was made with the patients’ FDR, including brothers, sisters, children, or parents of GC patients. All relatives between the ages of 40 to 65 years were invited to undergo a screening upper GI endoscopy in the hospital. Before the endoscopy, the patients’ characteristics and number of additional FDR diagnosed with GC were obtained. Participants with had no macroscopic ndings such as cancer or peptic ulcer in the duodenal bulb or stomach had biopsy specimens taken from ve areas of the stomach for histological examination; two from the antrum (one just below the incisura angularis from the lesser and one from the greater curvature), three from the corpus (one from the lesser curvature in the midarea between the cardia and incisura, one from the opposite side and one from the fornix, the superior most part of the stomach). One specimen was additionally taken from the incisura angularis for a rapid urease test (RUT). All specimens were xed in formalin, stained by Hematoxylin and Eosin (H&E) and/or giemsa and evaluated according to the updated Sydney Classication. In the initial part of the study, two pathologists who were blinded to all clinical and endoscopic data evaluated all biopsies and the rate of agreement was calculated. The severity of neutrophil or mononuclear cell inltration, atrophy, and SI D those with H. pylori infection, rst degree relatives (FDR) of GC patients are more prone to GC than the general population.4–8 Morphological changes, such as atrophy and intestinal metaplasia involving the corpus of the stomach are precancerous conditions for the development of GC.9,10 There are few studies concerning the morphological ndings of the stomach in FDR of GC.11–15 This study has aimed to determine the topography, severity and extent of the gastritis and other precancerous conditions in FDR of GC with advancing age, and when one or two family members have been diagnosed with GC. Results During a period of 4 years (2001 – 2004) a total of 989 FDR from 551 families with GC were recruited to participate in this study. Of these, 357 FDR were from one GC family and the remaining 632 from 194 families with more than one GC were enrolled. The number of GC patients who underwent surgery in Tehran hospitals during the inclusion period was unknown. However, during 1998 – 2001, 1991 pa- 470 Archives of Iranian Medicine, Volume 13, Number 6, November 2010 www.SID.ir N. Zendehdel, S. Massarrat, A. Sheykholeslami, et al. Table 1. Types of gastritis, mean age and H. pylori infection rate among FDR of GC patients (n=808) Gastritis types n(%) Mean age (years)±SD H. pylori infection, n(%) Normal mucosa 56 (6.3) 46.4±6.1 3 (5.4) Isolated antral gastritis 60 (7.2) 46.8±6.7 27 (45) Antrum predominant gastritis 513 (63.5) 47.4±6.7 457 (89.1) Corpus predominant gastritis 162 (20) 48.7±6.9 135 (83.3) Isolated corpus gastritis 17 (2) 51±6.2 4 (23.5) FDR=rst degree relatives; GC=gastric cancer SI D of cell inltration of three areas of the corpus was the same as the mean score from two areas of the antrum. Thus, these cases were classied as having a corpus-predominant gastritis. The type of gastritis could not be veried in 56 individuals due to lack of optimal specimens for evaluation of inammatory cell inltration in one or more areas. The type of gastritis and H. pylori infection rate are given in Table 1. Normal mucosa in all areas was seen in 6.9% of subjects. Antrum-restricted gastritis was found in 7.4%, while 63.5% had antrum-predominant gastritis and 20% corpus-predominant gastritis. Corpusrestricted gastritis was found in 2%. The mean age of subjects with all types of gastritis was approximately the same within each type. Subjects with corpus-predominant gastritis and antrum-predominant gastritis had high H. pylori infection rates of more than 80%, while the H. pylori infection rate in corpus-restricted gastritis was low at 23.5%. The prevalence of precancerous conditions, atrophy and intestinal metaplasia as well as their severity are given in Table 2. Forty percent of subjects had atrophy of both the antrum and corpus, 9.4% only in the corpus, 4% had IM both in the antrum and corpus, and 5.1% in the corpus only. Therefore, half of the FDR subjects had precancerous lesions in upper part of stomach. Less than 6% of them had advanced precancerous conditions (4.1% severe atrophy in corpus and 1.3% severe IM in corpus). In table 3 we have shown the progression of precancerous conditions and their severity with advancing age. Atrophy in antrum and corpus persists after age 44, while IM progress in antrum from 12.2% to 19% in the rst and from 19 to 27.3% in the second decade and in corpus from 6.7% to 12.3% in the rst and from 12.3% to 26.2% in the second age decade. In Ar ch ive of tients with GC were registered in Tehran.17 Taking the same number of GC patients observed during the same time length for the inclusion period in Tehran, the rate of families from which we recruited the subjects would have been about 27.6% of the total families with GC. All invited FDR consented for endoscopy and study protocol. Ninety-two subjects had signicant gastric lesions (32 with gastric ulcer, 58 had duodenal ulcer or deformity due to ulcer disease, two had symptomatic ulcerated gastric cancer, 11 had severe erosive duodenal erosions, four had combined gastric and duodenal ulcers and one subject had an esophageal tumor). These patients were treated accordingly and no protocol biopsies were obtained. In 17 subjects, histological classication was not possible due to the lack of data from all areas. Biopsy specimens were evaluated in 864 subjects [419 males with a mean age of 48.5±7.1 and 445 females with a mean age of 47±6.4 years. (range: 39 to 67 years)]. Ten patients had low grade dysplasia, localized along the lesser curvature in the corpus and mostly associated with intestinal metaplasia (IM). High grade dysplasia was not detected in the areas where biopsy specimens were routinely obtained. The positivity rate of H. pylori infection was 76.6%, with a signicant difference in the age groups that were under and over 50 years (79% vs. 71.1%, P<0.05) but was not signicant difference between men and women (78.7% vs.74.6%). The measure of agreement (Kappa value) between the two pathologists in the evaluation of ve areas of gastric mucosa in 147 subjects was 0.49 for normal mucosa, 0.55 for antral predominant gastritis, 0.51 for corpus predominant gastritis , 0.37 for any atrophy in the corpus and 0.47 for any intestinal metaplasia in the corpus (over all P<0.001). There were 36 subjects in whom the mean score Archives of Iranian Medicine, Volume 13, Number 6, November 2010 471 www.SID.ir Gastritis Severity in Relatives of GC Patients Table 2. Precancerous conditions in FDR of patients with GC (n=808) n (%) 495 (61.2) 134 (16.5) 408 (50.4) 169 (20.9) 76 (9.4) 124 (15.3) 65 (8 ) 76 (9.4) 38 (4.7) 41 (5.1) 323 (40) 59 (7.3) 32 (4) 14 (1.7) D Precancerous conditions Atrophy in antrum Moderate to severe Atrophy in corpus Moderate to severe Atrophy in corpus only IM in antrum Moderate to severe IM in corpus Moderate to severe IM in corpus only Atrophy in antrum and corpus Moderate to severe IM in antrum and corpus Moderate to severe FDR=rst degree relatives; GC=gastric cancer Table 3. The percentage of precancerous conditions in FDR subjects by age 38–50 44 668 SI Age (yr) and number of FDR subjects Age group Mean age Number 51–60 54 152 >60 63.6 53 59.7 19.6 46.6 20.8 55.6 11.4 54.8 31 Precancerous conditions in FDR subjects (%) Atrophy In antrum Moderate to severe In corpus Moderate to severe of ive IM In antrum Moderate to severe In corpus Moderate to severe 57.7 14.7 49.1 19.4 12.2 6.6 6.7 3.2 19** 8.4 12.3** 6.1 27.3* 20.5* 26.2# 14.3#* ch FDR=rst degree relatives; IM= intestinal metaplasia *Compared to 38 – 50 years. P<0.01; **Compared to 38 – 50 years. P<0.05; #compared to 51 – 60 years. P<0.05 Table 4. Precancerous conditions in FDR of patients according to numbers of GC in families and gender of the GC patients Precancerous conditions FDR of one GC n=830(%) FDR of more than one GC n=45 (%) FDR of a male with GC n=555 (%) FDR of a female with GC n=285 (%) 471 (56.7) 24 (54.5) 303 (54.5) 171 (60)* Atrophy in corpus 387 (46.6) 21 (46.7) 245 (44.1) 146 (51.2)* IM in antrum 117 (14.1) 7 (15.5) 76 (13.6) 42 (14.7) 69 (8.3) 7 (15.5) 49 (8.8) 21 (7.3) 154 (18.5) 8 (17.7) 97 (17.4) 60 (21) Ar Atrophy in antrum IM in corpus Corpus predominant gastritis * P<0.05; GC=gastric cancer; FDR=rst degree relatives Table 4 we have shown precancerous lesion of FDR subjects according to the number of gastric cancer in family. The FDR subject with two GC members in their families had the same percentage and severity of precancerous conditions as those with only one af- fected member. FDR of female GC patients had more atrophy in the antrum and corpus than FDR of male GC patients (P<0.05). Parietal cell antibody was positive in 3 out of 17 subjects with corpus-restricted gastritis (titer>1:10). The mean level of pepsinogen I, pepsinogen II and 472 Archives of Iranian Medicine, Volume 13, Number 6, November 2010 www.SID.ir N. Zendehdel, S. Massarrat, A. Sheykholeslami, et al. Ar ch ive of Once gastritis develops in the antrum, it may progress under certain environmental, socioeconomic and genetic conditions with advancing age, from the antrum upward along the lesser curvature to the corpus and may nally lead to atrophic gastritis.18 Biopsy specimens taken during endoscopic from different areas of the gastric mucosa have revealed three topographic types of gastritis (antrum-predominant, corpus-predominant and autoimmune gastritis) aside from normal mucosa. The rst two types of gastritis are induced by H. pylori infection and the latter one is associated with multiple autoimmune reactions and the occurrence of various antibodies in sera.19 In 1938, the German surgeon Konjetzny, morphologically examined all resected stomachs in GC patients and described atrophic gastritis with metaplastic changes (Becherzellen Metaplasie as goblet cells) in all areas of the stomachs, while gastritis of the peptic ulcer type was almost entirely restricted to the antral area.20 These metaplastic changes, known as IM, were conrmed with time by numerous other authors21–24, particularly when seen to occur in the upper part of stomach. Gastritis with atrophy and IM, occurring in each area or in upper part of the stomach, was therefore considered to be a precancerous condition.25 Mononuclear cell inammation localized more in the corpus rather than the antrum (corpus-predominant gastritis) with IM found in the antrum and corpus of stomach of patients with early GC.9 On follow-up examinations of patients with H. pylori infection, GC was observed mainly in those with corpus-predominant gastritis.10 This type of gastritis and its advanced form is frequent in FDR of GC patients compared with controls.11–15 The severity of atrophy and IM with advanced stage gastritis in FDR of GC patients in different studies is illustrated in Table 5. In these studies, FDR had more frequent atrophy and IM in the corpus or in the whole stomach when compared with controls. In two studies, the gastric acid output of subjects was measured and D Discussion found to be reduced in FDR when compared with controls as a sign of earlier progression of advanced gastritis in this group.11,13 In our population, due to the high rate of H. pylori infection, only a small number of subjects had normal mucosa. Antral-restricted gastritis was seen in only 7.4% of the subjects. The majority of subjects had antrum-predominant gastritis, mostly H. pylori infected. Corpus-predominant gastritis was found in 20% of the subjects. Among this group only a small number had atrophy and IM as precancerous conditions for developing GC. As with our population, corpus-predominant gastritis was found in 22% of Scandinavian FDR of GC patients, which was more than in controls (10%) of the same age (about 47 years).11 The prevalence of corpus-restricted gastritis is 2% and only a few had parietal cell antibodies. The normal mean of pepsinogen I, ratio of pepsinogen I to II and gastrin-17 without H. pylori infection is indicative of the presence of an early type of non-infectious autoimmune gastritis, which is quite rare in our population in comparison with the higher rate in European studies. One study conducted in Germany had 7% fundic gastritis among 513 dyspeptic subjects.26 In a study among the Estonian rural population, isolated fundic gastritis was found in 10% of patients27 and in a Swedish population with a mean age of 60 years isolated fundic gastritis was seen in 5.6% of cases.28 The severity of morphological changes and percentage of corpus-predominant gastritis in FDR of GC patients was unrelated to family members with one or more GC patients. However, the FDR of female GC patients had more atrophy in the antrum and corpus than FDR of male GC patients, which was similar to a study from Scandinavia.11 It was remarkable we had not nd any high grade dysplasia in the biopsies were obtained. While no progression of atrophy was documented after the fourth decade of life with increasing age, IM increased in the antrum as well as in the corpus. In the corpus the increase was less than 1% per year in the rst decade and increased to greater than 1% per year during the second decade (Table 5). A shortcoming of this study is the lack of a control group with no familial history of GC. Inclusion of healthy subjects for endoscopy purposes is ethically SI gastrin 17 were 108±47.3 (g/L), 11.7±10.8 g/L and 7.6±15 pmol/L, respectively. The mean Values of ratio of pepsinogen I to pepsinogen II was 13±7. Archives of Iranian Medicine, Volume 13, Number 6, November 2010 473 www.SID.ir Gastritis Severity in Relatives of GC Patients Table 5. The percentage of precancerous conditions (atrophy or intestinal metaplasia) in FDR of GC patients and controls Authors Ihamaeki (1979) FDR (n) Mean age (yr) Controls (n) Mean age (yr) Atrophy (%) Cases (controls) Intestinal metaplasia (%) Cases (controls) 301 (47) 358 (46) 9 (3) 12 (7) 300 (46) 426 (45.8) 23 (11.4) 15 (2) El-Omar (2002) 100 (43.7) 60 (44) 25 (3.3) in body 6 (1.6) in body Sepulveda (2002) 111 (39.1) 77 (49.6) — — Meining (1998) 237 (52.6) 237 (53.6) — 7.7 (3) in body Our study 881 (47.7) — 49 in body 9.4 in body Chang (2002) FDR=rst degree relatives; GC=gastric cancer Sadjadi A, Malekzadeh R, Derakhshan MH, Sepehr A, Nouraie M, Sotoudeh M, et al. Cancer occurrence in Ardabil: results of a population-based cancer registry from Iran. Int J Cancer. 2003; 107: 113 – 118. Malekzadeh R, Derakhshan MH, Malekzadeh Z. Gastric cancer in Iran: epidemiology and risk factors. Arch Iran Med. 2009; 12: 576 – 583. Sano T, Sasako M, Kinoshita T, Maruyama K. Recurrence of early gastric cancer: follow-up of 1475 patients and review of the Japanese literature. Cancer. 1993; 72: 3174 – 3178. Lehtola J. Family study of gastric carcinoma with special references to histological types Scand. J Gastroenterol Suppl. 1978; 50: 3 – 54. La Vecchia C, Negri E, Franceschi S, Gentile A. Family history and the risk of stomach and colorectal cancer. Cancer. 1992; 70: 50 – 55. Zanghieri G, Di Gregorio C, Sacchetti C, Fante R, Sassatelli R, Cannizzo G, et al. Familial occurrence of gastric cancer in the 2-year experience of a population-based registry. Cancer. 1990; 66: 2047 – 2051. Ogawa H, Kato I, Tominaga S. Family history of cancer among cancer patients. Jpn J Cancer Res. 1985; 76: 113 – 118. Lissowska J, Groves FD, Sobin LH, Fraumeni JF Jr, Nasierowska-Guttmejer A, Radziszewski J, et al. Family history and risk of stomach cancer in Warsaw, Poland. Eur J Cancer Prev. 1999; 8: 223 – 227. Meining A, Bayerdoerffer E, Mueller P, Miehlke S, Lehn N, et al. Gastric carcinoma risk index in patients infected with H. pylori. Virchows Arch. 1998; 432: 311 – 314. Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, et al. Helicobacter pylori infection and the development of gastric SI 1. D References 2. Ar ch ive of not justiable and practically not possible in such a large sample size. In the three studies mentioned in Table 5, dyspeptic subjects or those at risk for organic diseases without a history of GC in their families were selected as controls.12,14,15 In one study, the number of subjects was too small to determine the localization type of gastritis.13 In a study from Finland that had a large sample size of FDR and healthy controls, the case group whose mean age was similar to our population had the same rate of corpus-predominant gastritis as our study (22% in cases and 10% in controls).11 In all these studies, the possibility of decline in prevalence of gastritis and IM during the last decades of life must be taken into consideration.29 In conclusion, endoscopic screening in FDR of GC patients with a mean age of 48 years and a high H. pylori infection rate in endemic areas for GC is not justied. Only a fth of this population have predominant corpus gastritis, mostly H. pylori infected, who are at risk for the development of GC and available for its eradication. Screening subjects with serum biomarkers in this high risk group may spare the number of endoscopies in those with no morphological changes.30 The autoimmune type of gastritis is a rare disease in this geographic area. 3. 4. 5. 6. 7. 8. Acknowledgment I am sincerely indebted to Dr. M. Stolte (Professor, Institute of Pathology, Bayreuth, Germany) for his advice and evaluation of some of the histological ¿ndings and to Dr. F. Djavadi (Liver Unit, University of Southern California, Los Angeles, CA) for correction of this manuscript. 9. 10. 474 Archives of Iranian Medicine, Volume 13, Number 6, November 2010 www.SID.ir N. Zendehdel, S. Massarrat, A. Sheykholeslami, et al. 16. 17. 18. 19. 23. 24. 25. 26. 27. D 22. SI 15. 21. Houston 1996. Am J Surg Path. 1996; 20: 1161 – 1181. Konjetzny EG. Der Magenkrebs, Ferdinand Enke Verlag, Stuttgart, 1938: 136. Morson BC. Intestinal metaplasia of gastric mucosa. Br J Cancer. 1955; 9: 365 – 376. Du Plessis DJ. The distribution of gastritis in carcinoma of stomach. Br J Surg. 1974; 61: 521 – 524. Skinner JM, Heenan P, Whitehead R. Atrophic gastritis in gastrectomy specimens. Br J Surg. 1975; 62: 23 – 32. Reynolds KW, Johnson AG, Fox B. Is intestinal metaplasia of the gastric mucosa a premalignant lesion? Clin Oncol. 1975; 1: 101 – 109. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process. Cancer Res. 1992; 52: 6735 – 6740. Massarrat S, Paidlik A, Pittner P, Scmitz-Moorman P, Wurbs M. The role of certain habits and various diseases in the occurrence of gastritis. Hepatogastroenterology. 1983; 30: 249 – 253. Villako K, Tamm A, Savisaar E, Ruttas M. Is intestinal metaplasia of the gastric mucosa a premalignant lesion? Scand J Gastroenterol. 1976; 11: 817 – 822. Petersson F, Borch K, Franzén LE. Prevalence of subtypes of intestinal metaplasia in the general population and in patients with autoimmune chronic atrophic gastritis. Scand J Gastroenterol. 2002; 37: 262 – 266. De Vries AC, Meijer GA, Looman CW, Casparie MK, Hansen BE, van Grieken NC, et al. Epidemiological trends of pre-malignant gastric lesions: a long-term nationwide study in the Netherlands. Gut. 2007; 56: 1665 – 1670. Haj-Sheykholeslami A, Rakhshani N, Amirzargar A, Raee R, Shahidi SM, Nikbin B, et al. Serum pepsinogen I, pepsinogen II, and gastrin 17 in relatives of gastric cancer patients: comparative study with type and severity of gastritis. Clin Gastroenterol Hepatol. 2008; 6: 174 – 179. of 14. 20. 28. ive 13. ch 12. cancer. N Engl J Med. 2001; 345: 784 – 789. Ihamaeki TT, Varis K, Siurala M. Morphological, functional and immunological state of the gastric mucosa in gastric carcinoma families. Scand J Gastroenterol. 1979; 14: 801 – 812. Meining A, Bayerdoerfer E, Stolte M. Helicobacter pylori gastritis of gastric cancer phenotype in relatives of gastric carcinoma patients. Eur J Gastroenterol Hepatol. 1999; 11: 717 – 720. El-Omar EM, Oien K, Murray LS, El-Nujumi A, Wirz A, Gillen D, et al. Increased prevalence of precancerous changes of gastric cancer patients: critical role of H. pylori. Gastroenterology. 2000; 118: 22 – 30. Chang YW, Han YS, Lee DK, Kim HJ, Lim HS, Moon JS, et al. Role of Helicobacter pylori infection among offspring or siblings of gastric cancer patients. Int J Cancer. 2002; 101: 469 – 474. Sepulveda A, Peterson LE, Shelton J, Gutierrez O, Graham DY. Histological patterns of gastritis in H. pylori-infected individuals with a family history of gastric cancer. Am J Gastroenterol. 2002; 97: 1365 – 1370. Rose NR, Burek CL. Autoimmune diseases, antibodies to tissue specic endocrine gastrointestinal and surface receptors. In: Rose NR, ed. Manual of Clinical Laboratory Immunology. 4th ed. Washington DC: ASM; 1992: 723 – 785. Mohagheghi MA, Mosavi-Jarrahi A, Malekzadeh R, Parkin M. Cancer incidence in Tehran metropolis: the rst report from the Tehran populationbased cancer registry, 1998 – 2001. Arch Iran Med. 2009; 12: 15 – 23. Kimura K. Chronological transition of fundic-pyloric border determined by stepwise biopsy of the lesser and greater curvatures of the stomach. Gastroenterology. 1972; 63: 584 – 592. Dixon FM, Genta RM, Yardley JH, Correa P. Classication and Grading of Gastritis. The updated Sydney System and the participants in the International Workshop on the Histopathology of gastritis, Ar 11. 29. 30. Archives of Iranian Medicine, Volume 13, Number 6, November 2010 475 www.SID.ir