Angiogenic squamous dysplasia in bronchi of individuals at high risk for lung cancer

Lung carcinogenesis is assumed to be a multistep process, but detailed unde rstanding of the sequential morphological and molecular changes preceding i nvasive lung cancer remains elusive. To better understand early lung carcin ogenesis, we initiated a program of fluorescence bronchoscopy in smokers at high risk for lung cancer. in the bronchial biopsies from these subjects, we observed a unique lesion consisting of capillary blood vessels closely j uxtaposed to and projecting into metaplastic or dysplastic squamous bronchi al epithelium, angiogenic squamous dysplasia (ASD). Serial sections of the capillary projections confirmed that they represent intramucosal capillary loops. Microvessel density in ASD was elevated in comparison to normal muco sa (P = 0.0003) but not in comparison to other forms of hyperplasia or dysp lasia, ASD thus represents a qualitatively distinct form of angiogenesis in which there is architectural rearrangement of the capillary microvasculatu re. Genetic analysis of surface epithelium in a random subset of lesions re vealed toss of heterozygosity at chromosome 3p in 53% of ASD lesions. No co nfirmed p53 mutations were identified, Compared with normal epithelium, pro liferative activity was markedly elevated in ASD lesions. ASD occurred in 5 4 of 158 (34%) high-risk smokers without carcinoma and in 6 of 10 patients with squamous carcinoma who underwent fluorescence bronchoscopy, One early- stage invasive carcinoma was noteworthy fur the occurrence of ASD juxtapose d to invasive tumor. Seventy-seven (59%) of the ASD lesions mere detected b y abnormal fluorescence alone. Twenty: bronchial sites (11 patients) were r ebiopsied I year after the initial diagnosis. At nine (45%) of these sites, the lesion was found to persist. The Lesion was not present in biopsies fr om 16 normal nonsmoker control subjects. The presence of this lesion in hig h-risk smokers suggests that aberrant patterns of microvascularization mag occur at an early stage of bronchial carcinogenesis.