[Reevaluation of preneoplastic lung lesions in lung carcinoma? In bronchial carcinoma?]

Since the genetic model for colorectal carcinogenesis was presented by Fearon and Vogelstein, carcinogenesis has been thought to occur based on the accumulation of gene-mutations. In this context, preneoplastic lesions may be morphological phenotypes of different steps during multistep carcinogenesis. Historically, autopsy findings reported by Auerbach and cytological findings by Nasiell and Saccomanno support the idea that bronchial squamous metaplasia (BSM) with atypia is a preneoplastic lesion in large bronchi. Thereafter, the de novo theory became prevalent, because BSM was almost never shown to appear immediately adjacent to tiny bronchial neoplasias on examinations of resected lung materials. However, advanced molecular biological analysis shows that BSM with various grades of atypia has been found to correlate with cellular and genetic alterations (e.g., hyperproliferation, genomic instability, deletion of 3p and p53 tumor-suppressor gene etc.). These findings suggested that BSM with atypia might be a preneoplastic lesion of bronchial squamous cell carcinoma. Recently, it was shown that similar kinds of sequential genetic changes occurred in atypical adenomatous hyperplasia (AAH). It was also suggested that AAH might be a preneoplastic lesion of adenocarcinoma in peripheral regions of the lung. Based on these ideas, chemopreventive effects on BSM of folate and vitamin B12 were evaluated. The therapeutic efficacy of these vitamins was assessed in terms of grades of histopathological atypia. Vitamins were administered (B12, 750 micrograms/day and folate 10 mg/day) to 24 persons in whom bronchoscopic biopsy had revealed BSM but no malignancy. Controls consisted of 20 subjects who received no medication. Evaluation of a second biopsy performed 12 months later showed a decrease in atypia score from 1.7 to 0.4 in the treatment group but no significant change (1.4, 1.2) in the controls. At present, reevaluation of the concept of preneoplastic lesions is extremely important from the stand-point of reduction of lung cancer mortality. It is necessary to establish the criteria and therapeutic strategy for lung preneoplastic lesions.