Histological Characteristics of Lung Adenocarcinoma with Uncommon Actionable Alterations: Special Emphasis on MET exon 14 Skipping Alterations

AIMS In the evolving era of precision medicine, increasing emphasis is placed on detecting molecular alterations driving the development of specific cancers and targeting them with matched therapies that can yield the best outcomes for patients. Lung adenocarcinomas with uncommon actionable alterations, including MET exon 14 skipping (METex14), ERBB2 and BRAF mutations, are rare and poorly characterized cancers. METHODS AND RESULTS To better understand the histopathological features of lung adenocarcinoma with uncommon actionable alterations, we compared the histological features of 678 cases with mitogenic driver alterations from 996 surgically resected lung adenocarcinomas. Genomic data from our cohort revealed METex14, ERBB2, and BRAF mutations in 13, 16, and 15 cases, respectively. Patients who had lung adenocarcinoma with METex14 were often elder females. Histological features such as clear cell features (23%), hyaline globules (31%), and nuclear pleomorphism (39%) were the most frequently identified in METex14-positive cases; among those, 3 cases (23%) had tumor cells with bizarre giant or multilobulated nuclei. Additionally, the micropapillary pattern was the most frequently identified in ERBB2-mutated lung adenocarcinoma (31%). Lung adenocarcinoma with BRAF mutations tended to be less invasive, and the BRAF V600E mutation was identified only in one case with lepidic adenocarcinoma. Immunohistochemically, all METex14, ERBB2, and BRAF-positive tumors, except for invasive mucinous adenocarcinoma, were positive for TTF-1. CONCLUSIONS Our data from Japanese patients showed that lung adenocarcinoma with METex14 had unique clinicopathological characteristics: tumor cells with marked nuclear pleomorphism, hyaline globules, and expression of TTF-1 in elder women who never or lightly smoked.