Value of immunohistochemical markers in preinvasive bronchial lesions in risk assessment of lung cancer.
OBJECTIVE
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.


METHODS
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.
Jeanmart
Michel
M
Centre Hospitalier Universitaire Albert Michallon, Département de Médecine Aiguë Spécialisée, 38043 Grenoble Cedex 09, France.
Lantuejoul
Sylvie
S
Fievet
Frédéric
F
Moro
Denis
D
Sturm
Nathalie
N
Brambilla
Christian
C
Brambilla
Elisabeth
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D001980:Bronchi / Q000473:pathology*; D001984:Bronchial Neoplasms / Q000473:pathology*; D002278:Carcinoma in Situ / Q000473:pathology; D019938:Cyclin D1 / Q000032:analysis; D019927:Cyclin E / Q000032:analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011230:Precancerous Conditions / Q000473:pathology*; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D018570:Risk Assessment; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D015415:Biomarkers; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019938:Cyclin D1