Relationship between non-TRU lung adenocarcinomas and bronchiolar metaplasia - potential implication in their histogenesis.

Lung adenocarcinomas (ADCs) have been roughly divided into two groups: the terminal respiratory unit (TRU) type and non-TRU type. These ADCs appear to develop through exclusive carcinogenetic pathways because of differences in their cellular morphologies and the profiles of protein expression and genetic alterations. The TRU type develops from atypical adenomatous hyperplasia as a precursor. On the other hand, the histogenesis of the non-TRU type has not yet been defined in detail. We herein investigated histopathological changes in the non-tumor lung tissues of patients with non-TRU-type ADCs in order to define their potential histogenesis. The non-TRU type preferentially occurs in patients with interstitial pneumonia, in whom tumors are located in honeycomb lesions and are associated with bronchiolar metaplasia (BM). Among patients without interstitial pneumonia, non-tumor lung tissues from non-TRU-type ADCs were often affected by multiple BM. In these cases, tumors often were associated with BM. Metaplastic cells adjacent to non-TRU-type ADCs ectopically expressed HNF-4α, a marker for non-TRU-type ADCs. These results suggest that the non-TRU type develops through distinct histogenesis, in which BM is implicated.