Squamous cell carcinomas of the lung were induced in female Sprague Dawley rats by oral administration of N-Nitrosoheptamethyleneimine (NHMI) for 14 weeks, and their ultrastructure and immunohistochemical nature were investigated in special reference to their histogenesis and cellular origin. 1) The major pathologic changes during the administration of NHMI were bronchial basal cell hyperplasia, subsequent development of squamous metaplasia and bronchioloalveolar hyperplasia. 2) The pulmonary tumors at eight weeks after tapering NHMI were exclusively squamous cell carcinoma. 3) Ultrastructure of the peripheral squamous cell carcinomas presented characteristice of bronchiolar epithelium such as electron dense or lucent granules, many degenerated mitochondria and well developed Golgi apparatus. Presence of thin filaments or bundles of intracytoplasmic keratin and transformation of microvilli to interdigitating cytoplasmic processes with desmosomes represented a squamous metaplastic process through the carcinogenesis of NHMI-induced squamous cell carcinoma. 4) Bidirectional differentiation to squamous and mucus secreting cells within the keratinizing squamous cell carcinomas was identified with ultrastructural examination, which was assumed an expression of phenotypic heterageneity of lung tumors and suggested the importance of electron microscopic evaluation in lung tumor classification. 5) Pulmonary epithelial cells in rats were all negative on immunohistochemical staining for three types of cytokeratin. However, metaplastic bronchial or bronchiolar epithelial cells were positive for polycfonal cytokeratin (56-64 kd). All squamous cell carcinomas showed strong stainability for polyclonal cytokeratin, and weak and focal positivity for high molecular weight cytokeratin (68 kd). The above pathologic findings suggest that NHMI-induced pulmanary squamous cell carcinomas be assumed to develop through a squamous metaplasia of bronchial and/or bronchioloalveolar epithelial cells. A similarity in histogenesis and histopathologic characteristics between this animal model and human squamous cell careinoma supports this model being expected to be suitable for the study of biological nature of squamous cell carcinoma.
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