Abstract: Background and purpose: As the incidence of multifocal lung cancer (MLC) is increasing in the world, differentiation between multiple primary lung adenocarcinoma (MPLA) and intrapulmonary metastases (IM) has been a problem. This study was designed to analyze the clinicopathological features of multifocal lung adenocarcinoma (MLA) and distinguish MPLA from IM. Methods: We systematically reviewed 83 patients with MLA at Zhongshan Hospital of Fudan University from January 2016 to December 2017. Pathologic histological analysis combined with gene mutation analysis was employed to distinguish MPLA from IM. Chi-square or Fisher exact test was applied to compare variables between MPLA and IM groups. Kaplan-Meier plots and COX regression were applied for survival analysis. Results: According to the results of histological analysis, there were 50 MPLA cases and 33 IM cases, while there were 41 MPLA cases and 42 IM cases combined with the results of gene mutation analysis. The histological results of 18 cases were contradicted with gene mutation analysis. The 3-year overall survival (OS) rate of 83 patients was 93.98%, and the 3-year disease-free survival (DFS) rate was 77.11%. Survival analysis revealed that there was no statistically significant difference in OS rate between MPLA and IM groups, while patients diagnosed with IM were statistically associated with worse DFS rate. Univariate analysis showed that male, lymphatic/vascular invasion and wild-type epidermal growth factor receptor (EGFR) were significantly correlated with OS rate. Lymphatic/vascular invasion and comprehensive MLA classification were significantly correlated with DFS rate. Wild-type EGFR was an independent predictor for OS. Comprehensive MLA classification was an independent predictor for DFS rate. Conclusion: Pathological histological analysis was an important way of distinguishing MPLA from IM, and gene mutation analysis could provide important clues. MLA classified as IM was significantly correlated with worse DFS rate. MLA patients diagnosed with IM should be reviewed periodically for better survival.

Key words: Multiple primary lung adenocarcinoma, Intrapulmonary metastases, Pathologic histology, Gene mutation, Prognosis