Histological characteristics of lung adenocarcinoma with uncommon actionable alterations: special emphasis on MET exon 14 skipping alterations

Abstract

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 characterised cancers. Methods and results To more clearly 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 elderly 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, three cases (23%) had tumour 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 in only one case with lepidic adenocarcinoma. Immunohistochemically, all METex14, ERBB2 and BRAF‐positive tumours, except for invasive mucinous adenocarcinoma, were positive for thyroid transcription factor 1 (TTF‐1). Conclusions Our data from Japanese patients showed that lung adenocarcinoma with METex14 had unique clinicopathological characteristics: tumour cells with marked nuclear pleomorphism, hyaline globules and expression of TTF‐1 in elderly women who never or lightly smoked.

Characteristic computed tomography features in mesenchymal-epithelial transition exon14 skipping-positive non-small cell lung cancer

“…Approximately 20%–30% of pulmonary sarcomatoid carcinomas harbor METex14 alterations, although METex14 alterations are found in 2%–3% of adenocarcinomas [ 4 ]. In contrast, adenocarcinomas with METex14 skipping frequently contain giant cells with nuclear pleomorphisms [ 25 ]. These data suggest that sarcomatoid carcinoma components such as highly pleomorphic tumor cells with multiple large, irregularly lobulated nuclei may be characteristic of METex14 skipping [ 25 ].…”

“…In contrast, adenocarcinomas with METex14 skipping frequently contain giant cells with nuclear pleomorphisms [ 25 ]. These data suggest that sarcomatoid carcinoma components such as highly pleomorphic tumor cells with multiple large, irregularly lobulated nuclei may be characteristic of METex14 skipping [ 25 ]. Thus, the CT findings of METex14 skipping-positive NSCLC may resemble those of pleomorphic carcinoma represented by invasion into surrounding tissue and the presence of internal low-density areas.…”

Molecular pathology of non‐small cell carcinoma

“…105,106 In addition, this molecule biologically plays a crucial role in maintaining the function and development of peripheral lung parenchyma; TTF-1 regulates most of the surfactant proteins and club cell antigens and TTF-1-deficient transgenic mice are lacking lung parenchyma formation, despite maintaining intact bronchial trees. 107 Among lung adenocarcinomas, TTF-1-positive ones are enriched in EGFR mutations 105,106,108 and the majority of other driver mutation-positive adenocarcinomas express TTF-1, [109][110][111][112] although such expression is less frequent in KRAS-mutated tumours.…”