Comparative mutational analysis of pulmonary scar epithelium, bronchioloalveolar carcinomas, and invasive well-differentiated pulmonary adenocarcinomas: A molecular approach to diagnostically challenging cases

Discrimination of invasive well-differentiated adenocarcinoma (IAD) from reactive bronchioloalveolar epithelium entrapped in pulmonary scars (PSE) may be difficult on routine histology, especially on small biopsies. Ancillary studies to help in this regard are desirable. Whereas IADs have been shown to harbor cumulative mutational damage of tumor suppressor genes, little is known about molecular changes in PSEs. In this study, we compared cumulative loss of heterozygosity (LOH) of tumor suppressor genes in PSEs (N = 12), bronchioloalveolar carcinomas (BACs, N = 15) and stage 1 IADs (N = 7). Unstained serial sections were microdissected to obtain lesional and normal tissue DNA. PCR was performed for up to 16 polymorphic markers. An allelic ratio of <0.5 or >2.0 was designated as LOH. Fractional allelic loss (FAL) was calculated for each case as the number of markers with LOH divided by the total number of informative markers. Mean percentage of informative markers was 76.8%. PSEs showed significantly lower mean FAL compared with BACs and IADs (3.0% vs. 20.4% and 28.5%, respectively; P < 0.003). Only 1 case of PSE showed LOH of one marker in two different areas, whereas the majority of allelic losses in the neoplasms were present in two or more microdissected foci. Our study shows that PSEs harbor LOH of tumor suppressor genes at relatively low rates and in a random distribution compared with BACs and IADs, which show consistent allelic losses, and high FALs. These molecular differences may serve as an adjunct to histology in challenging glandular lesions of the lung.