Mong-Wei Lin1, Kang-Yi Su2, Te-Jen Su3, Chia-Ching Chang4, Jing-Wei Lin3, Yi-Hsuan Lee5, Sung-Liang Yu6, Jin-Shing Chen1, Min-Shu Hsieh7. 1. Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. 2. Department of Clinical Laboratory Science and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Center of Genomic and Precision Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan. 3. Center of Genomic and Precision Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. 4. Department of Clinical Laboratory Science and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan. 5. Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. 6. Department of Clinical Laboratory Science and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Center of Genomic and Precision Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan. 7. Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: mshsieh065@gmail.com.
Abstract
OBJECTIVE: Histologic transformation from adenocarcinoma to small cell lung cancer (SCLC) is one of the mechanisms of acquired resistance after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. Furthermore, de novo combined SCLC/non-small cell lung cancer (NSCLC) have occasionally been reported; however, their mutational statuses and clinicopathological features have not yet been elucidated. In this study, we aimed to profile the genetic backgrounds of these 2 different histologic components by investigating patients with de novo combined SCLC/NSCLC as well as those with lung adenocarcinoma who experienced SCLC transformation after TKI treatment. MATERIALS AND METHODS: Four patients with de novo combined SCLC/NSCLC were investigated, as were 4 other patients with lung adenocarcinoma who experienced SCLC transformation after TKI treatment. The different histologic components of the tumors in each patient were tested for thyroid transcription factor-1, p40, synaptophysin, chromogranin A, p53, retinoblastoma protein (Rb), and achaete-scute homolog 1 (ASCL1) via immunohistochemistry, and were macroscopically dissected for mutational analysis using next-generation sequencing with the Oncomine Focus Assay and Comprehensive Assay panel. RESULTS: The distinct histologic components in patients with de novo combined SCLC/NSCLC and those with adenocarcinoma exhibiting small cell transformation showed high consistency in EGFR/TP53/RB1 mutations, and expression patterns of p53 and Rb. A high frequency of activating mutations involving PI3K/AKT1 signaling pathway was observed in SCLC. Nuclear ASCL1 expression was present in SCLC but absent or barely present in adenocarcinoma in 7 cases. CONCLUSIONS: Our data imply that inactivation of TP53/RB1 function is a possible early event in the histogenesis of synchronous and metachronous SCLC/NSCLC. Moreover, the non-adenocarcinoma (SCLC) component might arise from the adenocarcinoma (NSCLC) component through a mechanism that involves the activation of the ASCL1 and PI3K/AKT1 signaling pathways.
OBJECTIVE: Histologic transformation from adenocarcinoma to small cell lung cancer (SCLC) is one of the mechanisms of acquired resistance after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. Furthermore, de novo combined SCLC/non-small cell lung cancer (NSCLC) have occasionally been reported; however, their mutational statuses and clinicopathological features have not yet been elucidated. In this study, we aimed to profile the genetic backgrounds of these 2 different histologic components by investigating patients with de novo combined SCLC/NSCLC as well as those with lung adenocarcinoma who experienced SCLC transformation after TKI treatment. MATERIALS AND METHODS: Four patients with de novo combined SCLC/NSCLC were investigated, as were 4 other patients with lung adenocarcinoma who experienced SCLC transformation after TKI treatment. The different histologic components of the tumors in each patient were tested for thyroid transcription factor-1, p40, synaptophysin, chromogranin A, p53, retinoblastoma protein (Rb), and achaete-scute homolog 1 (ASCL1) via immunohistochemistry, and were macroscopically dissected for mutational analysis using next-generation sequencing with the Oncomine Focus Assay and Comprehensive Assay panel. RESULTS: The distinct histologic components in patients with de novo combined SCLC/NSCLC and those with adenocarcinoma exhibiting small cell transformation showed high consistency in EGFR/TP53/RB1 mutations, and expression patterns of p53 and Rb. A high frequency of activating mutations involving PI3K/AKT1 signaling pathway was observed in SCLC. Nuclear ASCL1 expression was present in SCLC but absent or barely present in adenocarcinoma in 7 cases. CONCLUSIONS: Our data imply that inactivation of TP53/RB1 function is a possible early event in the histogenesis of synchronous and metachronous SCLC/NSCLC. Moreover, the non-adenocarcinoma (SCLC) component might arise from the adenocarcinoma (NSCLC) component through a mechanism that involves the activation of the ASCL1 and PI3K/AKT1 signaling pathways.