Genetic Evolution of Epidermal Growth Factor Receptor in Adenocarcinoma With a Bronchioloalveolar Carcinoma Component

Background: Epidermal growth factor receptor (EGFR) mutations may accumulate during the multistage progression of bronchioloalveolar carcinoma (BAC), leading to heterogeneity within the tumor. This study sought to determine whether metachronous adenocarcinomas with a BAC component emerging in the lung field arise from a single or multiple clones in the same individual. Materials and Methods: Samples of adenocarcinomas exhibiting various degrees of BAC were obtained by thoracotomy. Sequential specimens were obtained upon detection of metachronous lesions in the lung field. Genomic DNA was extracted from specimens, and the presence of activating mutations in EGFR was determined via direct sequencing. Our pathologic findings, sequential image information, and genetic data were compared to track evidence of cancer evolution. Results: Based on EGFR gene analyses of tumor specimens from 431 patients, 17 cases of sequential BAC-related adenocarcinomas, obtained by thoracotomy, were noteworthy. Upon alteration of the BAC/adenocarcinoma components, the EGFR tyrosine kinase inhibitor-untreated series, which had at least one episode of an EGFR-activating mutation, represented 3 potential hypotheses: no significant EGFR evolution for a single clone, genetic alterations from mutant to wild-type EGFR for multifocal lesions, or a switch from wild-type to mutant EGFR, leading to indeterminable cancer progression. Conclusion: Genetic analysis, in conjunction with pathologic and radiologic diagnoses, can be used to explore the origin of multifocal BAC. The single-clone model indicates subsequent disease progression, whereas genetic alterations from mutations to wild-type EGFR are suggestive of second primary carcinoma. In cases when additional lesions emerge after the radical resection of BAC-related lung cancer, sequential tumor samples should be obtained for further evaluation.