A Comparative Immunohistochemical Study of Spontaneous and Chemically Induced Pheochromocytomas in B6C3F1 Mice

Abstract

Spontaneously occurring and chemically induced pheochromocytomas are rare in mice. That the mouse pheochromocytoma is a more appropriate animal model than that of the rat for study of human medullary adrenal tumors has been suggested. The expression of phenylethanolamine-N-methyltransferase (PNMT), the enzyme responsible for production of epinephrine from norepinephrine, is common to both mouse and human pheochromocytomas. This investigation assessed the expression of the immunohistochemical markers PNMT, tyrosine hydroxylase (TH), and chromogranin A (CGA) in spontaneously occurring and chemically induced pheochromocytomas in the B6C3F1 mouse. Spontaneous tumors were derived from control animals from 10 different studies and the pheochromocytomas from treated groups from 4 different studies. All tumors were positive for maximal TH expression. A highly significant difference in PNMT expression (p < 0.01) occurred between spontaneously occurring pheochromocytomas classified as benign or "malignant" by the criteria of toxicologic pathology. Chemically induced tumors showed intermediate PNMT staining. A marked reduction in CGA expression occurred in pheochromocytomas induced by technical grade pentachlorophenol, compared to the other three chemicals and the spontaneously occurring tumors. These findings suggest that immunohistochemistry is a reliable tool in investigating the functional capabilities of pheochromocytomas in mice. PNMT expression is a tightly regulated component of the chromaffin cell phenotype and appears to be readily lost in mouse pheochromocytomas, particularly those with aggressive characteristics.

Malignant pheochromocytoma: predictive factors of malignancy and clinical course in 16 patients at a single tertiary medical center

“…This may be explained by defective catecholamine synthetic enzymes with down-regulation of the phenylethanolamine N-methyltransferase (PNMT) in malignant pheochromocytoma, as observed in mice [11], which converts NE to E. Although controversial, a lower ratio of E/NE ? E may be a predictive marker of malignant pheochromocytoma [12].…”

Expression of the noradrenaline transporter and phenylethanolamine N-methyltransferase in normal human adrenal gland and phaeochromocytoma

“…that mouse phaeochromocytomas show high levels of TH expression but variable levels of PNMT expression (Hill et al 2003). Of great interest is that, in mice, PNMT expression levels are significantly different between spontaneously occurring benign and locally invasive "malignant" phaeochromocytoma.…”

“…Of great interest is that, in mice, PNMT expression levels are significantly different between spontaneously occurring benign and locally invasive "malignant" phaeochromocytoma. Hill et al (2003) have proposed the hypothesis that loss of PNMT regulatory mechanisms is a feature of aggressive phaeochromocytomas, associated with a less-mature phenotype or an inability to maintain PNMT expression during "malignant" transformation. This is relevant given that the pathologic distinction of benign and malignant phaeochromocytomas in humans remains a diagnostic challenge (Eisenhofer et al 2004).…”

“…These issues are countered, however, by our finding that PNMT could be readily detected in rat positive controls and in normal human adrenal sections. Furthermore, in the study of mouse spontaneous phaeochromocytoma, immunohistochemistry has been shown to be a reliable tool in investigating the functional capabilities of the phaeochromocytomas studied (Hill et al 2003).…”

Adrenal Gland Background Findings in CD-1 (Crl:CD-1(ICR)BR) Mice from 104-week Carcinogenicity Studies

“…Although they are commonly seen in different strains of rats (e.g., F344, Long-Evans, Wistar, and New England Deaconess Hospital rats) and hamsters as spontaneous lesions. In mice pheochromocytomas are less commonly seen as spontaneous lesions (Rosol et al 2013;Nyska and Maronpot 1999) and even less easily induced by xenobiotics (Greaves 2012;Haseman, Hailey, and Morris 1998;Hill et al 2003;Mahler et al 1996). In 1 report on tumor incidence in B6C3F1 mice, the overall incidence of benign pheochromocytoma was 0.43% in males and 1.37% in females, and that for the malignant counterpart was 0.21% in males and 0.53% in females (National Toxicology Program 2013).…”