Descriptions of two rare gastric neuroendocrine tumors (carcinoids) of enterochromaffin (ECL) cells in CD-1 mice (2/50) from a 104-week oncogenicity study of a serotonergic/dopaminergic compound are presented. These tumors were detected at necropsy and confirmed by histopathology in hematoxylin and eosin- and Chromogranin A-stained slides. ECL cell counts of the glandular stomachs were determined by quantitative image analysis and did not reveal any hyperplastic changes as possible predisposing lesions for carcinoid formation. To investigate the possibility of drug-induced hypergastrinemi a as the cause of tumor formation of ECL cells, gastrin blood levels were measured after treating mice for 7 days with the test substance. In this study, Omeprazole, the positive control, raised gastrin levels, while the test material did not. It was concluded that these two tumors were an example of “late-life”-occurring, spontaneous neuroendocrine tumors in the stomachs of aged CD-1 mice.
Belaiche J., Delwaide J., Louis E., Gast P. ( 1993). Enterochromaffin-like cells and their receptors: Physiological role and physiopathologica l significance. Acta Gastroenterol Belg56: 3— 4.
2.
Betton GR, Dormer CS, Wells T., Pert P., Price CA, Buckley P. (1987). Fundic mucosal ECL hyperplasia and carcinoids in rodents following chronic administration of the histamine H2-receptor antagonist SK&F 93479 and other antisecretory agents. Toxicol Pathol15: 365.
3.
Betton GR, Dormer CS, Wells T., PertP., Price CA, Buckley P. (1988). Gastric ECL-cell hyperplasia and carcinoids in rodents following chronic administration of H2-antagonists SK&F 93479 and oxmetidine and omeprazole. Toxicol Pathol16: 2—98.
4.
Colin-Jones DG, Langman MJS, Lawson DH, Vessey MP (1985). Post-marketing surveillance of the safety of cimetidine: Mortality during second, third and fourth years of follow-up. Br Med J291: 1084—1088.
5.
Delle Fave G. , Helander H., Holt S., Modlin IM, Powers R., Solcia E., Soll A., Tielemans Y., Wright NA (1994). Acid suppression and gastric mucosal cell biology. Dig Dis Sci39: 9—52.
6.
Eissele R., Arnold R. (1993). Risiko der Entwicklung von Tumoren unter der Therapie mit dem Protonenpumpen-Inhibito r Omeprazol (Risk for developing tumors in therapy with the proton pump inhibitor Omeprazole). Versicherungsmedizin45(4): 126—129.
7.
Ekman L., Hansson E., Havu N., Carlsson E., Lundberg C. (1985). Toxicological studies on omeprazole. Scand J Gastroenterol Suppl 108: 53.
8.
Emminger A., Mohr U. ( 1982). Tumours of the oral cavity, cheek pouch, salivary glands, oesophagus, stomach and intestines. In: Pathology of Tumours in Laboratory Animals—Tumours of the Hamster, Turusov V (ed). IARC scientifi cpublications, Lyon, pp 45—50.
9.
Greaves P. (1990). VII. Digestive system 1. In: Histopathology ofPreclinical Toxicity Studies—Interpretation and Relevance in Drug Safety Evaluation, Elsevier, Amsterdam , pp 321—325.
10.
Hakanson R. , Chen D., Andersson K., Monstein HJ, Zhao CM, Ryberg B., Sundler F., Mattsson H. (1994a). The biology and physiology of the ECL cell. Yale J Biol Med67: 3— 4.
11.
Hakanson R. , Chen D., Tielemans Y., Andersson K., Ryberg B., Sundler F., Mattsson H. (1994b). ECL cells: Biology and pathobiology. Digestion55 (suppl 3): 38— 45.
12.
Havu M., Mattson H., Ekman L., Carlsson E. (1990). Enterochromaffin-like cell carcinoids in the rat gastric mucosa following long-term administration of Ranitidine. Digestion45: 189—195.
13.
Head KW (1990). Tumours of the alimentary tract. In: Tumors in Domestic Animals, Moulton JE (ed). University of California Press, Berkeley , pp 45—50.
14.
Kokkola A., Sjoblom SM, Haapiainen R., Sipponen P., Puolakkainen P., Jarvinen H. (1998). The risk of gastric carcinoma and carcinoid tumours in patients with pernicious anaemia—A prospective follow-up study. Scand J Gastroentero l33: 88—92.
15.
Kolby L., Wangberg B., Ahlman H., Modlin IM, Granerus G., Theodorsson E., Nilsson O. (1996). Histidine decarboxylase expression and histamine metabolism in gastric oxyntic mucosa during hypergastrinemia and carcinoid tumor formation. Endocrinology137: 4435— 4442.
16.
Kolby L., Wangberg B., Ahlman H., Modlin IM, Nilsson O. (1998). Histamine metabolism of gastric carcinoids in Mastomys natalensis. Yale J Biol Med71: 207—215.
17.
Larsson H., Hakanson R., Mattsson H., Ryberg B., Sundler F., Carlsson E. (1988). Omeprazole: Its infl uence on gastric acid secretion, gastrin and ECL cells. Toxicol Pathol16: 2—72.
18.
Leininger JR, Jokinen MP (1994). Tumours of the oral cavity, pharynx, oesophagu s and stomach. In: Pathology of Tumours in Laboratory Animals— Tumours of the Mouse, Turusov V, Mohr U (eds). IARC Scientifi c Publications , Lyon, pp 167—194.
19.
Leininger JR, Jokinen MP, Dangler CA, Whiteley LO (1999). Oral cavity, esophagus, and stomach. In: Pathology of the Mouse, Maronpot RR , Boorman GA, Gaul BW (eds). Cache River Press, Vienna, IL, pp 42— 45.
20.
Levene H. (1960). Robust tests for equality of variances. In: Contributions to Probability and Statistics, Olkin et al. (eds). Stanford University Press, Stanford, CA, pp 278—292.
21.
LIoyd RV (1999). Immunohistochemical markers of endocrine/ neuroendocrin e tumors. J Histotechnol22(3): 231—237.
22.
Maekawa A., Enomoto M., Hirouchi Y., Yamakawa S. (1996). Changes in the upper digestive tract and stomach . In: Pathobiology of the Aging Mouse, Mohr U, Dungworth DL, Capen CC, Carlton WW, Sundberg JP, Ward JM (eds). ILSI Press, Washington, DC, pp 267—286.
23.
Mattsson H. , Andersson K., Hakanson R., Larssson H., Sundler F., Wallmark B. (1988). Sex and species differences in plasma gastrin and gastrin-dependent variables. Studies in rats and mice during Omeprazole treatment. Gastroenterology94(5): 2.
24.
Nilsson O., Wangberg B., Johansson L., Modlin IM, Ahlman H. (1992). Praomys (Mastomys) natalensis : A model for gastric carcinoid formation. Yale J Biol Med65: 741 —751.
25.
Oberg K., Janson ET, Eriksson B. (1999). Tumour markers in neuroendocrine tumours. Ital J Gastroenterol Hepatol31(2): 160—162.
26.
Oh SW, Chae C., Jang D. ( 1997). Spontaneous gastric carcinoids tumors in the striped fi eld mouse (apodemus agrarius). J Vet Med Sci59: 703—706.
27.
Poynter D., Selway Sam, Papworth SA, Riches SR (1986). Changes in the gastric mucosa of the mouse associated with long-lasting insurmountable histamine H2 blockade. Gut27: 1338—1346.
28.
Rubin E., Farber JL (1994). The gastrointestinal tract. In: Pathology. J. B. Lippincott, Philadelphia , pp 668—670.
29.
SAS Institute, Inc. (1990). SAS/STAT User's Guide. Version 6, 4th ed. SAS Institute, Inc., Cary, NC.
30.
Spencer AJ, Barbolt TA, Henry DC, Eason CT, Sauerschell RJ, Bonner FW (1989). Gastric morphological changes including carcinoid tumors in animals treated with a potent hypolipidemic agent, ciprofi brate . Toxicol Pathol17(1): 1—15.
31.
Streett CP, Robertson JL, Crissman JW (1988). Morphologic stomach fi ndings in rats and mice treated with the H2 receptor antagonists, ICI 125,211 and ICI 162,846. Toxicol Pathol16: 299—304.
32.
Takahashi M., Hasegawa R. (1990). Tumours of the stomach. In: Pathology of Tumours in Laboratory Animals—Tumours of the Rat, Turusov V, Mohr U (eds). IARC Scientifi c Publications, Lyon , pp 129— 135.
33.
Waldum HL, Brenna E., Sandvik AK (1998). Relationship of ECL cells and gastric neoplasia . Yale J Biol Med71: 325—335.
34.
Waldum HL, Kvetnoi IM, Sylte R., Schulze B., Martinsen TC, Sandvik AK (1998). The effect of the peroxisome proliferator ciprofi brate on the gastric mucosa and particularly the gastrin cell. J Mol Endocrin20: 111— 117.
35.
Waldum HL, Sandvik AK, Idle JR ( 1998). Gastrin is the most important factor in ECL tumorigenesis . Gastroenterology114: 1113— 1114.
36.
Williams DA (1971). A test for differences between treatment means when several dose levels are compared with a zero dose control. Biometrics27: 103—117.
37.
Williams DA (1972). The comparison of several dose levels with a zero dose control. Biometrics28: 519—531.
38.
Zhao CM, Chen D., Lintunen M., Paula P., Hakanson R. (1999). Secretory organelles in ECL cells of the rat stomach: An immunohistochemical and electron-microscopic study. Cell Tissue Res298(3): 457—470.
