LABORATORY RESULTS: (clinical pathology, microbiology, etc…)
Tumor induced by exposure to pharmaceutical compound (Compound XX).
COMPOUND XX is a novel Type IV phosphodiesterase inhibitor that was being developed for the clinical indications of asthma and rheumatoid arthritis. During routine safety assessment studies, COMPOUND XX was found to be toxic to the nasal olfactory mucosa of Sprague Dawley rats (Pino, 1999). Toxicity occurred with either inhalation or oral exposure, and the distribution of the lesions was similar by either route. In addition, a 2-year inhalation carcinogenicity study resulted in a high incidence of malignant olfactory tumors in rats treated with COMPOUND XX. Electron microscopy revealed that the primary target cells of COMPOUND XX in the olfactory region were sustentacular cells and epithelial cells lining Bowman’s glands. Sustentacular cells and epithelial cells lining Bowman’s glands are among the most metabolically active cells in the nasal cavity, and it is likely that activation by drug metabolizing enzymes (i.e. cytochrome P450) was important in the observed olfactory toxicity caused by COMPOUND XX.
The classification of nasal olfactory tumors is somewhat controversial. Investigators have used a variety of terms to refer to tumors of the olfactory epithelium including (esthesio)neuroepithelioma, (esthesio)neuroblastoma, esthesioneuromas, or esthesioneurocytomas (Feron, 1986). The Society of Toxicologic Pathologists (STP) and Armed Forces Institute of Pathology classify all tumors of the olfactory neuroepithelium as olfactory neuroblastomas (Schwartz, 1994), while tumors of Bowman’s glands (adenomas or adenocarcinomas) are classified separately. In another classification scheme, tumors of the olfactory epithelium are categorized as neuroepithelial carcinomas, with subclassifications based upon the major morphologic pattern (i.e. sustentacular cell, basal cell/neuroblastoma, solid, or neuroendocrine) (Morgan, 1996). For the rat carcinogenicity study with COMPOUND XX, the classification scheme used was the one proposed by the STP with some modification as noted by Brown, 1991. There was often a continuum from areas of atypical hyperplastic basal cells to areas of malignancy, which suggested that several of the tumors were arising from basal cells.
1. Pino, MV, Valerio MG, Miller GK, Larson JL, Rosolia DL, Jayyosi Z, Crouch CN, Trajanowski JQ, and Geiger LE. (1999). Toxicologic and Carcinogenic Effects of the Type IV Phosphodiesterase Inhibitor RP 73401 on the Nasal Olfactory Tissue in Rats. Toxicol Pathol, 27:383-394.
Brown HR, Monticello TM, Maronpot RR, Randall HW, Hotchkiss JR, Morgan KT (1991). Proliferative and neoplastic lesions in the rodent nasal cavity. Toxicol. Pathol. 19: 358-72.
Feron VJ, Woutersen RA, Spit BJ (1986). Pathology of chronic nasal toxic responses including cancer. In: Toxicology of the Nasal Passages, CS Barrow, (ed). Hemisphere Pub. Corp. Washington, Chapter 5, pp. 67-89.
Morgan KT, Harkema JR (1996). Nasal neoplasia. In: Respiratory System, TC Jones, DL Dungworth, U Mohr, (eds). Second ed. Springer-Verlag Berlin Heidelberg, New York, pp. 87-104.
Schwartz LW, Hahn FF, Keenan KP, Keenan CM, Brown HR, Mann PC (1994). Proliferative lesions of the rat respiratory tract. In: Guides for Toxicologic Pathology, STP/SRP/AFIP, Washington, DC, pp. 1-24.
Legend: (Objective of the microscope or the magnification of the Electron Microscope when each photograph is taken, type of stain used, and descriptive legend you would suggest for the submitted image.)
1X. H&E stain. Section of posterior nasal cavity from rat on 2-year carcinogenicity study. A large cellular mass (M) occupies the left olfactory bulb region. S = nasal septum; DM = dorsal meatus; ET = ethmoturbinate; NP = nasopharynx; OB = right olfactory bulb.
4X. H&E stain. Higher magnification of previous photomicrograph from section of posterior nasal cavity. The olfactory mucosa lining the left dorsal meatus (DM) and septum (S) is lined by dysplastic, thickened epithelium. Atypical neoplastic olfactory epithelial cells are also present in the lamina propria/submucosa (arrows), and a large, space-occupying mass (M) is located in the left olfactory bulb region. OB = right olfactory bulb.