title: RITA/Registry of Industrial Toxicology Animal data: a comparative immunohistochemical study of 77 islet cell carcinomas in Sprague-Dawley and Wistar rats using antibodies against insulin, glucagon, somatostatin and gastrin.
abstract: The objective of this study was to investigate spontaneous islet cell carcinomas with particular reference to possible existing strain differences between Sprague Dawley (SD) and Wistar (W) rats in incidence and immunohistochemical staining pattern. Secondly the occurrence of somatostatin and/or gastrin-positive islet cell tumors should be tested. Islet cell adenocarcinomas (34 from SD, 43 from W-rats) were selected from the RITA-data base and company in-house data base out of an animal pool of 3915 (1681 SD, 2234 W-rats). They were untreated or sham-treated (vehicle) control animals from carcinogenicity studies and whole life-span experiments. Islet cell carcinomas occurred in a higher incidence in male rats (2.98% for SD, 3.23% for W) than in female rats (1.07% for SD, 0.63% for W). All specimens were immunohistologically stained with antibodies against insulin, glucagon, somatostatin and gastrin and, selected specimens with additional antibodies (pancreatic polypeptide, lipase, chymotrypsin, S100-protein, actin and cytokeratin). 94% (SD) and 93% (W), respectively, were insulin-positive and the mean staining intensity (on a scale ranging from 0-4) for insulin was 3.58 (SD) versus 3.37 (W). This high insulin staining incidence and intensity characterized most islet cell carcinomas as malignant insulinomas. 24% (SD) and 37% (W), respectively, were glucagon-positive. Except two tumors in W-rats with a focal strong glucagon expression, the mean staining intensity for glucagon was low (0.38 SD, 0.72 W). 38% (SD) and 44% (W), respectively, were somatostatin-positive, but except for five cases having a focal to multifocal, moderate to marked staining, only a few tumor cells were positive for somatostatin in the other cases and the mean staining intensity for somatostatin was low (0.50 SD, 0.84 W). 6% (SD) and 23% (W), respectively, were gastrin-positive, but only one case of a male Wistar rat exhibited a focal strong staining in parts of the tumor. The other cases showed only a few tumor cells which were positive for gastrin. The mean staining intensity for gastrin was low (0.06 SD, 0.35 W). In all tumors with marked glucagon, somatostatin or gastrin expression, the immunostaining for insulin was still predominating. Thus, insulin was the major hormone produced by most of the tumor cells. Five out of 77 tumors evaluated were immunohistologically negative with all applied antibodies.
  
  
  CONCLUSIONS
  This study presents the first immunohistochemical survey on spontaneous islet cell carcinomas in SD and Wistar rats stained with antibodies against the endocrine pancreas hormones insulin, glucagon, somatostatin and gastrin. No major differences in incidence or immunohistochemical staining pattern between SD and W-rats could be detected. In contrast to SD rats, Wistar rats had multihormonal coexpression in 16.3%. The multihormonal appearance of the neoplasms is well comparable with the findings in other animal species and human insulinomas. Moreover, this is the first study in rats which reports five cases with a marked co-expression of somatostatin and one case with marked focal co-expression of gastrin in malignant islet cell adenocarcinomas.
authors.affiliation: Institute of Pathology and Toxicology, Byk Gulden Pharmaceuticals, Hamburg, Germany.
authors.forename: P G
authors.initials: PG
authors.lastname: Germann
authors.forename: M
authors.initials: M
authors.lastname: Heinrichs
authors.forename: H
authors.initials: H
authors.lastname: Püschner
authors.forename: J
authors.initials: J
authors.lastname: Hellmann
authors.forename: M
authors.initials: M
authors.lastname: Kohler
authors.forename: H
authors.initials: H
authors.lastname: Ernst
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis; D018273:Carcinoma, Islet Cell / Q000737:chemistry* / Q000503:physiopathology; D005260:Female; D005755:Gastrins / Q000276:immunology; D005934:Glucagon / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000276:immunology; D008297:Male; D010190:Pancreatic Neoplasms / Q000737:chemistry* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012042:Registries; D013004:Somatostatin / Q000276:immunology
chemical_list: D000912:Antibodies, Neoplasm; D014408:Biomarkers, Tumor; D005755:Gastrins; D007328:Insulin; D013004:Somatostatin; D005934:Glucagon