Morphology and development of experimental bronchiolar lung
tumors were studied in Syrian hamsters, using light and electron microscopic techniques. At the age of 9 weeks, 46 hamsters were each given one weekly gavage of 6.8 mg
N-nitrosomethyl-n-heptylamine for 35 weeks, and hamsters were examined at intervals from 2 to 46 weeks. The present report describes the progression of
adenocarcinomas of bronchiolar cell origin to adenosquamous and
squamous cell carcinomas. Squamous
metaplasia was commonly noted at the
tumor periphery, i.e., zone of growth. In 20 hamsters, 22 adenosquamous and two
squamous cell carcinomas (one a
large cell carcinoma) were diagnosed by light microscopy. Overt keratinization was infrequent. Squamous cell
metaplasia was not a feature of papillary
neoplasms but was seen mainly with acinar structures. Ultrastructurally, squamous differentiation (
metaplasia) appeared to develop along two different pathways. First, secretory cells were observed with large numbers of intermediate filaments and tonofilaments, with concurrent loss of organelles such as secretory granules and microvilli. Second, squamous
metaplasia also appeared to develop from a progeny of
tumor cells that failed to mature into secretory cells. Such cells were often present within the basal layer of secretory acini and resembled basal cells of the tracheobronchial tree. These observations were supported by increased expression of cytokeratins, as revealed by immunohistochemical procedures. Immunoelectron microscopic examination localized hamster
Clara cell antigen in secretory granules of neoplastic Clara cells, in the cytoplasm between granules, and at the microvillous border. With the onset of squamous differentiation,
Clara cell antigen was progressively lost from secretory cells and was only rarely seen in cells with tonofilaments. No labeling was present in squamous cells arising at the base of
tumor acini. These results suggest that pulmonary
squamous cell carcinomas may develop by direct squamous differentiation of secretory cells or may proceed from undifferentiated
tumor cells.