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High dietary salt increases severity of gastritis and gastric epitheial cell proliferation in the Helico-bacter mustelae-infected ferret
Gastrointestinal Oncology A639
April 1998 • G2631 PREVALENCE OF GASTRIC CARCINOID AND ENTEROCHROMAFFIN-LIKE (ECL) DYSPLASTIC LESIONS IN ATROPHIC BODY GASTRITIS (ABG) PATIENTS. M Mafi~nani, MR Aprile*, G D'Ambra, C Mancino, P Caruana*, R Caprilli, C Bordi*,G.Delle Fave,B Annibale. Gastroenterology Dept. University "La Sapienza" Rome and Department of Pathology, University of Parma*, Italy. In hypergastrinemic ABG patients, the ECL calls of the oxyntic mucosa show different patterns of growth. These patterns have been classified and arranged in a sequence of morphological lesions with increasing oncological potential in a supposed order of progression from normal, to hyperplasia to dysplasia and, finally, to neoplasia [1]. In fact, in ABG patients ECL cells can give origin to type I gastric carcinoid, a neoplasia characterized by a remarkably low malignant potential, with a reported prevalence ranging from 2 to 9% in pts with both ABG and pernicious anemia (PA). However, little is known on the dysplastic lesion, regarded as the true precursors of ECL cell carcinoid. These are usually considered to be an exceptional finding in ABG patients but their true prevalence as single, non-carcinoid associated lesions has never been ascertained in prospective studies. Also, there are no data available concerning their biological behavious. Aim: To determine the prevalence of gastric carcinoid and dysplastic ECL lesions in a newly diagnosed population of ABG pts and to assess the behavious of these latter lesions during an adequate follow-up period. Patients: 130 hypergastrinemic, histologicallyproven ABG pts [38M, 92F; median age 56.5 yrs, range (22-83); 43% with PAl found in a screening study aimed to detect ABG in dyspeptic and anemic individuals. All pts underwent fasting gastrin determination (nv= <40 pg/ml) and gastroscopy with antral (n=3) and body (n=4) biopsy for conventional histology and immunostalning. Glandular atrophy of the body mucosa was defined as replacement of oxyntic glands by metaplastic and/or intestinal glands. ECL cell were identified by chromogranin A immunostaining and their pattern of growth classified according the previously cited classification. Histological evaluation was performed by two histopathologists unaware of the patients' clinical date. Pts with ECL cell dysplasia were further followedup for a median time of 24 months (range 12-36) performing at least two gastroscopies with multiple biopsies (2 antral and 8 from the body). Results: Patients ECL cell growth pattern Prevalence (% of total) 1 Carcinoid 0.7 5 Dysplasia 3.8
M/F 1/0 2/3
Age (range) 67 65 (47-72)
The patient with carcinoid and 4 (3F, 1M) out of the five with microfocal dysplasia had PA. During follow-up no carcinoid lesion developed in the 5 pts with ECL microfocal dysplasia. Presence of dysplastic lesion was reconfirmed at histology in only one pt. Accordingly, median fasting gastrin levels did not show any increasing trend in these pts, ranging from 375-1325 at entry to 80-2050 at last follow-up evaluation. Conclusion: In our study we find a markedly low prevalence of carcinoid tumors in newly diagnosed ABG pts. Microfocal dysplastic lesions were instead a relatively more frequent finding, however these lesion do not seem to show any progression during a median time of 24 months. [1] Solcia E, Bordi C, et al. Digestion 1988; 41: 185-200. • G2632 HIGH DIETARY SALT INCREASES SEVERITY OF GASTRITIS AND GASTRIC EPITHELIAL CELL PROLIFERATION IN THE HELICOBACTER MUSTELAE-INFECTED FERRET. R.P. Marini,*, C.A. Dangler,* LG. Fox,* N.S. Taylor,* S. Kirchain,* X-D. Wang,t R.M. Russell.i" *Massachusetts Institute of Technology, Cambridge, MA; "~Boston, MA. Both Helicobacter py[ori infection and the consumption of high salt diets have been associated independently with gastric cancer, the second most common cause of cancer-related deaths in the world. In this study, the Helicobacter mustelae-infected ferret model was used to investigate the interaction of Helicobacter infection and high salt diets on gastritis severity, H. mustelae colonization, and gastric epithelial cell proliferation as manifest by proliferating cell nuclear antigen (PCNA) expression. Twelve, adult, spayed female ferrets, naturally infected with H, mustelae, were randomized into two groups of six and fed a low salt (0.25% NaCI) or high salt (7.4% NaCI) diet. Gastric mucosal biopsy samples collected endoscopically at 12 weeks, and necropsy samples collected at 24 weeks, were assessed using histology and PCNA immunohistochemistry. Necropsy samples were additionally evaluated by quantitative urease test. After 12 weeks of treatment, ferrets fed the low salt diet had a mean antral PCNA index of 8.6%, while those fed the high salt diet had an index of 15.5% (p<0.002). Inflammation scores were significantly increased in the group fed the high salt diet (p=0.027). In the necropsy samples, chronic antral gastritis affecting the greater curvature was increased in intensity and distribution in ferrets fed the high salt diet. In this group, the quantitative urease assay demonstrated an increase in antral colonization by H. mustelae (p<0.035). These data indicate that exposure to a high salt diet results in significant exacerbation of gastritis, and increase in H. mustelae colonization and PCNA expression. The exacerbation of inflammation by high salt intake has been implicated as a factor in the severity and progression of H. pylori-gastritis in humans. These changes may promote and accelerate the development of chronic atrophic
gastritis, the entity which underlies the gastric ulcer and gastric carcinoma syndromes in humans. The ferret is an excellent model for evaluation of Helicobacter-associated gastritis and carcinogenesis. G2633
DOES THE RISK OF COLORECTAL NEOPLASIA INCREASE IN PROBANDS WHEN A SECOND PARENT IS AFFECTED WITH COLORECTAL CANCER? AJ Markowitz, TM Kuhn, A Hewlett, H Gerdes, AG Zauber, SJ Winawer, Memorial Sloan-Kettering Cancer Center, New York, New York. BACKGROUND: The risk for colorectal cancer has been shown to be increased for first degree relatives when one parent is affected with colorectal cancer, especially at an early age. Little information is available in the literature concerning the change in risk status when a second parent is affected with colorectal cancer. The purpose of this study was to determine if a second parent affected increases the risk of developing a colorectal neoplasia in the proband. METHODS: Patients referred for colonoscopy to the Colon Cancer Prevention Program (CCPP) at MSKCC completed an extended family history questionnaire. The CCPP is a multidisciplinary program providing patients and their families with a cancer history risk assessment and recommendations for prevention of colorectal cancer. Probands were stratified as average (no family history), intermediate (one or two close relatives with colorectal cancer), and high (HNPCC) risk. All families with two parents affected (2P) with colorectal cancer, and a random sample of families with one parent affected (1P) were identified. Probands were assessed for prior history and new findings of colorectal neoplasia. Patients with an HNPCC family history were excluded from this study. Patients with only one or two relatives with colorectal cancer, and who did not meet liberalized HNPCC criteria, were classified as intermediate risk and were eligible for this study. RESULTS: More than 200 close relatives in 41 families that fulfilled the criteria for increased risk, and did not have HNPCC were studied. Of the 41 probands in these families, 28 had two parents affected and 13 had one parent affected with colorectal cancer. Of the 28 probands in the 2P group, 18 had colorectal neoplasia (64%); and of the 13 probands in the 1P group, 4 had colorectal neoplasia (31%) (P<0.045). CONCLUSION: This preliminary study demonstrates that probands who do not fulfill the criteria for HNPCC, and have two parents affected with colorectal cancer, have approximately double the risk of colorectal neoplasia as probands with one parent having colorectal cancer. This study is being expanded within the framework of the ongoing Colorectal Cancer Prevention Program. This research was funded in part by the Tavel-Reznik Fund for Colon Cancer Research. • G2634
COLORECTAL NEOPLASM IN PATIENTS WITH ACROMEGALY. Y.Matano, H.Iwane, N.Hamano, T.Okada, Y.Takeda, A.Nakagawa, H.Mabuchi. 2nd. Department of Internal Medicine, Kanazawa University, Ishikawa, Japan. Background and Aim: It has been reported that patients with acromegaly have an increased risk of colonic polyps and adenocarcinomas. To investigate the prevalence of colonic neoplasm, we performed a colonoscopic study on acromegalic patients over a period of seven years. Method: Twenty-five consecutive Japanese acromegalic patients with and without gastrointesinal symptoms and fecal occult blood who visited the department between January 1, 1990 and August 31, 1997 received a total colonoscopy. Thirteen were men(mean age 48.7) and twelve were women (mean age 55.0), with sixteen more than 50 years old. One patient had received a sigmoidectomy due to colon cancer in 1987 and two other patients had a family history of the malignant neoplasm(skin and larynx). Six patients repeated colonoscopy during the study. All elevated lesions found during colonoscopy were separately reocorded, biopsied and histologically examined. Result: Fourteen patients(56%) had a number of colorectal polypoid lesions. Ten(40%) had hyperplastic polyps, eight(32%) had adenomas, and three(12%) had adenocarcinomas. Carcinomas raised at the ascending colon and sigmoid colon, respectively. All three patients with carcinoma were more than fifty years old(52y, 53y and 73y) and also had a number of adenomas and/or hyperplastic polyps concurrently. Of the eight patients with documented adenomatous polyps, four had multiple adenomas ranging from two to at least eight in number. Of the patients repeating colonosopy, three had new hyperplastic polyps. Conclusion: In the present study, acromegalic patients had a high prevalence of colorectal polyps and colon carcinomas. We suggest that acromegalic patients, particularly those more than fifty years old, should undergo screening colonoscopy regardless of their symptoms.
April 1998 • G2631 PREVALENCE OF GASTRIC CARCINOID AND ENTEROCHROMAFFIN-LIKE (ECL) DYSPLASTIC LESIONS IN ATROPHIC BODY GASTRITIS (ABG) PATIENTS. M Mafi~nani, MR Aprile*, G D'Ambra, C Mancino, P Caruana*, R Caprilli, C Bordi*,G.Delle Fave,B Annibale. Gastroenterology Dept. University "La Sapienza" Rome and Department of Pathology, University of Parma*, Italy. In hypergastrinemic ABG patients, the ECL calls of the oxyntic mucosa show different patterns of growth. These patterns have been classified and arranged in a sequence of morphological lesions with increasing oncological potential in a supposed order of progression from normal, to hyperplasia to dysplasia and, finally, to neoplasia [1]. In fact, in ABG patients ECL cells can give origin to type I gastric carcinoid, a neoplasia characterized by a remarkably low malignant potential, with a reported prevalence ranging from 2 to 9% in pts with both ABG and pernicious anemia (PA). However, little is known on the dysplastic lesion, regarded as the true precursors of ECL cell carcinoid. These are usually considered to be an exceptional finding in ABG patients but their true prevalence as single, non-carcinoid associated lesions has never been ascertained in prospective studies. Also, there are no data available concerning their biological behavious. Aim: To determine the prevalence of gastric carcinoid and dysplastic ECL lesions in a newly diagnosed population of ABG pts and to assess the behavious of these latter lesions during an adequate follow-up period. Patients: 130 hypergastrinemic, histologicallyproven ABG pts [38M, 92F; median age 56.5 yrs, range (22-83); 43% with PAl found in a screening study aimed to detect ABG in dyspeptic and anemic individuals. All pts underwent fasting gastrin determination (nv= <40 pg/ml) and gastroscopy with antral (n=3) and body (n=4) biopsy for conventional histology and immunostalning. Glandular atrophy of the body mucosa was defined as replacement of oxyntic glands by metaplastic and/or intestinal glands. ECL cell were identified by chromogranin A immunostaining and their pattern of growth classified according the previously cited classification. Histological evaluation was performed by two histopathologists unaware of the patients' clinical date. Pts with ECL cell dysplasia were further followedup for a median time of 24 months (range 12-36) performing at least two gastroscopies with multiple biopsies (2 antral and 8 from the body). Results: Patients ECL cell growth pattern Prevalence (% of total) 1 Carcinoid 0.7 5 Dysplasia 3.8
M/F 1/0 2/3
Age (range) 67 65 (47-72)
The patient with carcinoid and 4 (3F, 1M) out of the five with microfocal dysplasia had PA. During follow-up no carcinoid lesion developed in the 5 pts with ECL microfocal dysplasia. Presence of dysplastic lesion was reconfirmed at histology in only one pt. Accordingly, median fasting gastrin levels did not show any increasing trend in these pts, ranging from 375-1325 at entry to 80-2050 at last follow-up evaluation. Conclusion: In our study we find a markedly low prevalence of carcinoid tumors in newly diagnosed ABG pts. Microfocal dysplastic lesions were instead a relatively more frequent finding, however these lesion do not seem to show any progression during a median time of 24 months. [1] Solcia E, Bordi C, et al. Digestion 1988; 41: 185-200. • G2632 HIGH DIETARY SALT INCREASES SEVERITY OF GASTRITIS AND GASTRIC EPITHELIAL CELL PROLIFERATION IN THE HELICOBACTER MUSTELAE-INFECTED FERRET. R.P. Marini,*, C.A. Dangler,* LG. Fox,* N.S. Taylor,* S. Kirchain,* X-D. Wang,t R.M. Russell.i" *Massachusetts Institute of Technology, Cambridge, MA; "~Boston, MA. Both Helicobacter py[ori infection and the consumption of high salt diets have been associated independently with gastric cancer, the second most common cause of cancer-related deaths in the world. In this study, the Helicobacter mustelae-infected ferret model was used to investigate the interaction of Helicobacter infection and high salt diets on gastritis severity, H. mustelae colonization, and gastric epithelial cell proliferation as manifest by proliferating cell nuclear antigen (PCNA) expression. Twelve, adult, spayed female ferrets, naturally infected with H, mustelae, were randomized into two groups of six and fed a low salt (0.25% NaCI) or high salt (7.4% NaCI) diet. Gastric mucosal biopsy samples collected endoscopically at 12 weeks, and necropsy samples collected at 24 weeks, were assessed using histology and PCNA immunohistochemistry. Necropsy samples were additionally evaluated by quantitative urease test. After 12 weeks of treatment, ferrets fed the low salt diet had a mean antral PCNA index of 8.6%, while those fed the high salt diet had an index of 15.5% (p<0.002). Inflammation scores were significantly increased in the group fed the high salt diet (p=0.027). In the necropsy samples, chronic antral gastritis affecting the greater curvature was increased in intensity and distribution in ferrets fed the high salt diet. In this group, the quantitative urease assay demonstrated an increase in antral colonization by H. mustelae (p<0.035). These data indicate that exposure to a high salt diet results in significant exacerbation of gastritis, and increase in H. mustelae colonization and PCNA expression. The exacerbation of inflammation by high salt intake has been implicated as a factor in the severity and progression of H. pylori-gastritis in humans. These changes may promote and accelerate the development of chronic atrophic
gastritis, the entity which underlies the gastric ulcer and gastric carcinoma syndromes in humans. The ferret is an excellent model for evaluation of Helicobacter-associated gastritis and carcinogenesis. G2633
DOES THE RISK OF COLORECTAL NEOPLASIA INCREASE IN PROBANDS WHEN A SECOND PARENT IS AFFECTED WITH COLORECTAL CANCER? AJ Markowitz, TM Kuhn, A Hewlett, H Gerdes, AG Zauber, SJ Winawer, Memorial Sloan-Kettering Cancer Center, New York, New York. BACKGROUND: The risk for colorectal cancer has been shown to be increased for first degree relatives when one parent is affected with colorectal cancer, especially at an early age. Little information is available in the literature concerning the change in risk status when a second parent is affected with colorectal cancer. The purpose of this study was to determine if a second parent affected increases the risk of developing a colorectal neoplasia in the proband. METHODS: Patients referred for colonoscopy to the Colon Cancer Prevention Program (CCPP) at MSKCC completed an extended family history questionnaire. The CCPP is a multidisciplinary program providing patients and their families with a cancer history risk assessment and recommendations for prevention of colorectal cancer. Probands were stratified as average (no family history), intermediate (one or two close relatives with colorectal cancer), and high (HNPCC) risk. All families with two parents affected (2P) with colorectal cancer, and a random sample of families with one parent affected (1P) were identified. Probands were assessed for prior history and new findings of colorectal neoplasia. Patients with an HNPCC family history were excluded from this study. Patients with only one or two relatives with colorectal cancer, and who did not meet liberalized HNPCC criteria, were classified as intermediate risk and were eligible for this study. RESULTS: More than 200 close relatives in 41 families that fulfilled the criteria for increased risk, and did not have HNPCC were studied. Of the 41 probands in these families, 28 had two parents affected and 13 had one parent affected with colorectal cancer. Of the 28 probands in the 2P group, 18 had colorectal neoplasia (64%); and of the 13 probands in the 1P group, 4 had colorectal neoplasia (31%) (P<0.045). CONCLUSION: This preliminary study demonstrates that probands who do not fulfill the criteria for HNPCC, and have two parents affected with colorectal cancer, have approximately double the risk of colorectal neoplasia as probands with one parent having colorectal cancer. This study is being expanded within the framework of the ongoing Colorectal Cancer Prevention Program. This research was funded in part by the Tavel-Reznik Fund for Colon Cancer Research. • G2634
COLORECTAL NEOPLASM IN PATIENTS WITH ACROMEGALY. Y.Matano, H.Iwane, N.Hamano, T.Okada, Y.Takeda, A.Nakagawa, H.Mabuchi. 2nd. Department of Internal Medicine, Kanazawa University, Ishikawa, Japan. Background and Aim: It has been reported that patients with acromegaly have an increased risk of colonic polyps and adenocarcinomas. To investigate the prevalence of colonic neoplasm, we performed a colonoscopic study on acromegalic patients over a period of seven years. Method: Twenty-five consecutive Japanese acromegalic patients with and without gastrointesinal symptoms and fecal occult blood who visited the department between January 1, 1990 and August 31, 1997 received a total colonoscopy. Thirteen were men(mean age 48.7) and twelve were women (mean age 55.0), with sixteen more than 50 years old. One patient had received a sigmoidectomy due to colon cancer in 1987 and two other patients had a family history of the malignant neoplasm(skin and larynx). Six patients repeated colonoscopy during the study. All elevated lesions found during colonoscopy were separately reocorded, biopsied and histologically examined. Result: Fourteen patients(56%) had a number of colorectal polypoid lesions. Ten(40%) had hyperplastic polyps, eight(32%) had adenomas, and three(12%) had adenocarcinomas. Carcinomas raised at the ascending colon and sigmoid colon, respectively. All three patients with carcinoma were more than fifty years old(52y, 53y and 73y) and also had a number of adenomas and/or hyperplastic polyps concurrently. Of the eight patients with documented adenomatous polyps, four had multiple adenomas ranging from two to at least eight in number. Of the patients repeating colonosopy, three had new hyperplastic polyps. Conclusion: In the present study, acromegalic patients had a high prevalence of colorectal polyps and colon carcinomas. We suggest that acromegalic patients, particularly those more than fifty years old, should undergo screening colonoscopy regardless of their symptoms.