Concomitant EGFR Mutation and EML4-ALK Rearrangement in Lung Adenocarcinoma Is More Frequent in Multifocal Lesions

Background: The coexistence of epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement in patients with multifocal lung adenocarcinomas (LUAC) constitutes a rare molecular subtype of lung cancer. We aimed to investigate the intertumoral heterogeneity of pathologic and genetic characteristics of multifocal LUAC with EGFR/ALK co-alterations. Patients and Methods: A total of 1059 LUAC patients who underwent resection were investigated to screen for EGFR or ALK alterations using amplification refractory mutation system polymerase chain reaction and immunohistochemistry/fluorescence in situ hybridization. Molecular testing was extensively performed in patients with synchronous multifocal LUAC. Clonal evolution analysis was implemented using next-generation sequencing. Results: A total of 97 multiple synchronous lesions were observed among 1059 LUAC patients. Patients with at least 1 sample harboring EGFR mutation or ALK rearrangement were 62.89% (61/97) and 14.43% (14/97), respectively. Patients with concomitant EGFR and ALK alterations were 4.71% (4/97). Comparatively, patients with unifocal LUAC harboring EGFR mutation, ALK rearrangement, and EGFR/ALK co-alterations were 58.25% (570/962), 6.44% (62/962), and 0.83% (8/962), respectively. The prevalence of EGFR/ALK co-alterations in the multifocal LUAC was significantly higher than that in the unifocal LUAC (4.71% (4/97) vs. 0.83% (8/962)). Furthermore, we present 4 cases of EGFR/ALK co-altered multifocal LUAC with different morphological and molecular patterns. In addition to radiographic, pathological, and molecular testing results, clonal evolutional analysis could also be used to distinguish intertumoral heterogeneity. Conclusion: The results highlight the importance of distinguishing synchronous primary tumors from intrapulmonary metastases, and of assessing the relative abundance of EGFR mutation and ALK rearrangement in patients with multifocal adenocarcinomas with EGFR/ALK co-alterations. We retrospectively investigated the intertumoral heterogeneity of pathologic and genetic characteristics of multifocal lung adenocarcinomas (LUAC) with epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) co-alterations. The prevalence of EGFR/ALK co-alterations was higher in the multifocal LUAC than in the unifocal LUAC. To determine appropriate treatment strategies, extensive molecular profiling could give us more information to distinguish primary lesions from metastatic lesions.