Combined mutation pattern analyses of epidermal growth factor receptor and K-ras genes for the differential diagnosis of primary versus metastatic lung adenocarcinomas.

Abstract

e21010 Background: The differential diagnosis of multiple primary lung cancers (MPLCs) from pulmonary metastases (PMs) is sometimes difficult based solely on the Martini and Melamed's criteria. We investigated whether combined mutation pattern analyses of the epidermal growth factor receptor (EGFR) and K-ras genes were useful for differentiating between MPLCs and PMs. Methods: We conducted a retrospective review of 84 tumors (81 adenocarcinomas and three atypical adenomatous hyperplasias) in 36 patients with multifocal lung adenocarcinomas. Genomic DNA was extracted from paraffin-embedded tissue. The peptide nucleic acid (PNA)-locked nucleic acid polymerase chain reaction clamp method was used for EGFR mutation analysis. The PNA-mediated PCR clamping method was used for K-ras mutation analysis. We determined clonality status of secondary tumors based on the mutation patterns of EGFR and K-ras by comparing them with primary tumors. Correlations between the mutation status and the proportion of bronchioloalveolar carcinoma (BAC) component in a tumor were examined. Results: EGFR and K-ras mutations were detected in 38 (45%) and 24 (29%) of 84 tumors, respectively. Thirty-four (71%) of secondary tumors were diagnosed as a different clonality (MPLC). Seven (15%) of secondary tumors were classified into the same clonality (PM). Clonality status could not be determined for the seven (15%) remaining secondary tumors. A clonality assessment based on the EGFR and K-ras mutation status was possible in 41 (84%) of 48 secondary tumors, and it was consistent with the Martini and Melamed's criteria in 29 (71%) of 41 secondary tumors. The proportion of BAC component in a tumor did not correlate with the EGFR/K-ras mutation status. Conclusions: The combined mutation pattern analyses of EGFR and K-ras enabled a definite distinction between PMLCs and PMs in a large portion of multifocal lung adenocarcinomas. Mutations of EGFR and K-ras in multifocal lung adenocarcinomas frequently occurred randomly, which support the concept of “field cancerization.” No significant financial relationships to disclose.