Species: Rat Strain/breeder: Wistar (Hsd/Cpb:WU) Sex: Male Age: 2 years Study type: 24-month-carcinogenicity study Treatment: po (gavage), control Animal status: Intercurrent death Clinical findings: Emaciation, pododermatitis hindlegs Organ(s): Adrenal gland Macroscopic finding(s): Adrenals enlarged Staining: H&E

Fig. 1 (107k)

Abstract

M. HEINRICHS¹ A. BUBE¹ H. ERNST² G. TROSCHAU¹ and S. FRIDERICHS-GROMOLL³

¹Drug Safety Evaluation, Aventis Pharma Deutschland GmbH, Hattersheim/M., Germany
²Fraunhofer-Institut für Toxikologie und Aerosolforschung, Hannover, Germany
³Covance GmbH, Münster/W., Germany

Key words: rat, pituitary tumour, pituitary carcinoma, pars intermedia; adrenocortical hyperplasia, Cushing's disease, adrenocorticotropic hormone, ACTH, POMC

An emaciated control male Wistar rat (Hsd/Cpb:Wu) from an oral gavage carcinogenicity study died on study day 637 and was found at necropsy to have a pituitary mass, extremely large adrenal glands, a swollen, mottled brown-yellow liver, extremely small testes and pododermatitis of the hindlegs. Histopathology revealed an adenoma of the pars intermedia of the pituitary gland, diffuse bilateral adrenocortical hyperplasia, hepatic lipidosis and necrosis, lymphoid atrophy, and atrophy of testes and seminal vesicles. The pituitary adenoma was immunoreactive for adrenocorticotropic hormone (ACTH), α-melanocyte-stimulating hormone, ß-endorphin, and pro-opiomelanocortin (POMC).

Similar findings were noted in three additional cases from two different dietary carcinogenicity studies. All three were aged males and belonged to either mid or high dose-groups. One case was a Wistar (Hoe:WISKf[SPF71]) rat and two cases were Sprague-Dawley (SD-CR) rats. In the Wistar rat, the pituitary tumour had markedly infiltrated the brain and meninges and had metastasized to a mandibular lymph node. This was confirmed by positive ACTH immunohistochemistry and was consistent with the diagnosis of a carcinoma of the pituitary, pars intermedia.

Histopathologic and immunocytochemical findings in these four rats suggest that functional ACTH-secreting tumours of the pars intermedia with secondary adrenal cortical hyperplasia are a distinct clinico-pathologic entity and have some features in common with Cushing's disease.