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Value of Immunohistochemical Markers in Preinvasive Bronchial Lesions in Risk Assessment of Lung Cancer¹

Centre Hospitalier Universitaire Albert Michallon, Département de Médecine Aiguë Spécialisée [M. J., F. F., D. M., C. B.] and Laboratoire de Pathologie Cellulaire, 38043 Grenoble Cedex 09 [S. L., N. S., E. B.], and INSERM EMI 9924, Institut Albert Bonniot, Domaine de la Merci, 38700 La Tronche [M. J., S. L., D. M., C. B., E. B.], France

Purpose: Bronchial carcinogenesis is a multistep process characterized by accumulation of genetic and molecular abnormalities, which precedes and accompanies the preinvasive lesions known as dysplasia and carcinoma in situ (CIS). We hypothesized that the level of accumulated molecular abnormalities in dysplasia assessed by immunohistochemical markers might reflect the severity of the carcinogenic process, thus allowing for risk assessment in smokers.

Experimental Design: We performed a prospective analysis of bronchial biopsies in 48 former smokers who had at least one area of metaplasia. Twenty-two of the patients had a previous history of lung cancer. Eighty bronchial lesions were recorded at baseline, including 31 metaplasia, 12 mild dysplasia, 9 moderate dysplasia, 9 severe dysplasia, and 19 CISs. Forty-one percent of the patients had multiple preinvasive lesions. Immunohistochemical analysis of P53, cyclin D1, cyclin E, Bax, and Bcl2 was performed. Aberrant expression of one of these proteins as compared with normal bronchi was recorded as one molecular alteration.

Results: After 18 months, 17 patients were diagnosed with lung cancer. No isolated parameter, including dysplastic grade or any isolated molecular alteration, was significantly associated with cancer occurrence at 18 months follow-up, using a logistic regression statistical analysis. In contrast, considering CIS and cancer as end point, more than two immunohistochemical abnormalities were associated with cancer or CIS occurrence (P = 0.02).

Conclusions: We concluded that the cumulative index of immunohistochemical abnormalities in a random dysplasia is associated with CIS or lung cancer in the cancerization field of symptomatic smokers, independently of the histopathological grade of dysplasia. This set of histopathological biomarkers might be useful in risk assessment and provide intermediate end points for chemopreventive trials.

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