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

Abstract

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. 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 coalterations 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.

Clinicopathologic and Imaging Features of Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations

“…While there was no primary tumor imaging feature unique to METex14-mutated NSCLC in our cohort, there was an increased frequency of multifocality, with more than one in five patients having multifocal adenocarcinoma at the time of initial presentation ( Figure 2). This incidence was higher than the prevalence of ALK and concomitant ALK and EGFR alterations in multifocal lung adenocarcinomas [52]. It is possible that the multifocality reflects multiple synchronous adenocarcinomas with distinct splice site mutations, a finding which has been previously described in the literature for METex14-mutated primary lung adenocarcinomas [53].…”

“…Multifocal adenocarcinomas at presentation may help indicate the possibility of METex14-mutated NSCLC and lead to more rapid triaging for molecular screening. These synchronous lung adenocarcinomas are increasingly being recognized and can be a diagnostic and management challenge [52]. Detection of these potentially targetable mutations in multifocal NSCLC may prove to be beneficial when these malignancies progress and metastasize.…”

Concomitant EGFR mutation and ALK rearrangement in multifocal lung adenocarcinoma: a case report

“…Interestingly, there were more lymph node metastasis in patients with multiple ALK gene fusion-positive lesions and more patients with N2 stage tumors. Furthermore, in our retrospective study, metastatic lesions in lymph node were driven by ALK rearrangement rather than EGFR mutation in four cases [6,8]. All these results suggested that ALK probably played a key role in tumor metastasis of multifocal Lung Adenocarcinoma Harboring EGFR/ALK co-alteration.…”

“…The prevalence and clinical relevance of EGFR/ALK co-alterations in multifocal adenocarcinomas required detailed investigation as well. Our previous study showed that concomitant EGFR mutation and ALKrearrangement in synchronous multifocal lung adenocarcinomas was more frequent [8]. Here, we reported a case of patient who diagnosed with multifocal lung adenocarcinomas exhibiting both EGFR mutation and EML4-ALK rearrangement, in order to give some helpful advices for the clinical practice.…”

Morphological and Genetic Heterogeneity of Synchronous Multifocal Lung Adenocarcinoma in a Chinese Cohort

“…Recently, several studies have emerged which use different molecular biology techniques to analyze SMLC. These include comparative genomic hybridization (CGH), DNA microsatellite analysis, and next-generation sequencing (NGS) [12][13][14] . Generally, tumors with similar molecular characteristics are believed to be IM with a monoclonal origin.…”