Premalignant lesions of the lung

Associations have been described between foods (especially vegetables and fruits) and a number of micronutrients and lung cancer. Principal among the potentially protective nutrients is beta-carotene, but there is also evidence that folic acid, vitamins C and E, and selenium may play a role in impeding bronchial carcinogenesis. Human and animal studies have documented a graded progression from normal bronchial mucosa to cancer, involving squamous metaplasia with mild, moderate, and severe atypia as intermediate stages. These classic cytopathologic features are the best established premalignant lesions of the lung and have been used as intermediate end points in most completed and ongoing human lung cancer chemoprevention trials. Attempts have been made to quantify them through computerized measurements and statistical constructs such as the Atypia Status Index. However, these morphologic changes are preceded by genetic and molecular events that could represent more sensitive, earlier markers. Measurements proposed for use in chemoprevention trials include genetic alterations expressed as ploidy (cellular DNA content), micronuclei, and DNA adducts, and cellular hormones, gene products, and enzymes such as epidermal growth factor, cytokeratins, involucrin, and transglutaminase. In using any of these putative intermediate end points and biomarkers in chemoprevention trials, investigators must be careful to avoid confounding due to regression to the mean. This is the phenomenon whereby persons selected for extreme values of a variable will tend to have less extreme values, closer to the population mean, on subsequent measurements. Several methods can be used to eliminate the regression effect in the design of clinical trials. Two chemoprevention trials completed to date (one published) have tested whether the retinoid etretinate can reeuce the severity of bronchial squamous metaplasia and atypia. Although one trial suggested a chemopreventive effect of etretinate and the other did not, both were probably confounded by regression to the mean, leaving the effects of the treatment unclear. A third completed trial, using a combination of folic acid and vitamin B12, showed a reduction in the severty of atypia after four months. Ongoing trials are using isotretinoin or beta-carotene alone or combined with retinol or alpha-tocopherol in smokers and/or asbestos workers. Some studies require the presence of premalignant lesions in sputum samples or bronchial brushings or biopsies. Most are using one or more of the intermediate end points described above, although some are using cancer itself as the end point.