SPONTANEOUS PROLIFERATIVE LESIONS IN THE NASOPHARYNGEAL MEATUS OF F344 RATS

Spontaneous proliferative lesions in the nasopharyngeal meatus were id entified as the cause of death in 12 of 1,600 male and 5 of 1,600 fema le Fischer 344 (F344) rats used in 2-yr carcinogenicity studies; none of the lesions were considered treatment related. All the rats showed dyspnea, abdominal distension, and clinical deterioration. Gross featu res were characterized by simultaneous occurrence of conspicuous gaseo us distension of the intestinal tract, especially in the ileum and cec um, and focal nodular lesions in the nasopharyngeal meatus. Histopatho logically, the nasopharyngeal meatus was partially obstructed by the f ollowing proliferative lesions: 3 areas of hyperplasia of the ectopic sebaceous glands in the soft and hard palate, 4 areas of squamous meta plasia (SM) with massive hyperkeratosis, 5 squamous cell papillomas (S CPs), and 5 squamous cell carcinomas (SCCs). No pathological changes w ere found in the distended portion of the intestinal tract. Formalin-f ixed, paraffin-embedded samples of the proliferative lesions from the nasopharyngeal meatus were examined for the presence of mutations in t he c-H-ras and c-K-rns genes. In vitro amplification of DNA using a po lymerase chain reaction was combined with a nonisotopic method for sel ective oligonucleotide hybridization. Two of the 4 SM lesions, 3 of th e 5 SCPs, and 5 of the 5 SCCs contained 1-3 point mutations in the c-H -ras and/or c-K-ms gene. Immunohistochemically, overexpression of p53 protein was found in 1 area of SM with a dysplastic lesion and 2 SCCs. These findings indicate that detailed examination of the upper respir atory system, including the nasopharyngeal meatus, may be particularly helpful for identifying primary occult lesions in F344 rats that show only gut distension at necropsy in long-term toxicity studies. In add ition, mutations of the ms genes may be an important step in the early stages of carcinogenesis in the rat nasopharyngeal meatus, whereas p5 3 mutations could occur relatively late.