Effects of localized chemical carcinogenesis and immunosuppression upon bronchial preneoplasia in the dog

Abstract

Early detection of lung cancer is becoming increasingly more common in clinical practice, but serial studies in patients are rarely possible. To permit serial observations during the preneoplastic stages of carcinogenesis, we employed bronchoscopy to expose 54 dogs recurrently to carcinogens at the orifice of the right accessory (intermediate) lobe bronchus. Benzo(a)pyrene (BP) and N-methyl-N-nitrosourea (NMU), either alone or sequentially, were injected into the bronchial submucosa or were topically applied to the mucosa in three groups of mongrels and two groups of beagles. Long-term immunosuppression with azathioprine and methylprednisolone was used in one group of beagles. Weekly injections of 45 mg. of NMU were found to be excessively toxic. However, weekly submucosal injections of up to 45 mg. of BP and topical application of 5 mg. of NMU were well tolerated. The gross bronchoscopic and histologic changes induced by these carcinogens used singly or in sequence were essentially the same. Marked mucosal irregularity and stenosis were routinely noted by the third month. Serial monthly biopsies of the sites of carcinogen exposure regularly revealed columnar hyperplasia within the first month. Squamous metaplasia occurred as early as 4 weeks after the first chemical exposure, and it became a persistent and progressive feature by the third month. Atypical structure with increased mitotic activity was recurrently seen, and 76 percent of all dogs have squamous metaplasia with atypia. Chronic immunosuppression did not alter the pattern of gross and histologic changes. Recurrent trauma alone did not cause squamous metaplasia or any other preneoplastic change. We conclude that the sequential use of BP-NMU has proved safest and most effective of the methods used in producing bronchial preneoplasia in the dog. The use of adjuvant immunosuppression has not proved worth while. A predictable, reproducible means of producing localized endobronchial preneoplasia in the dog has been developed.