Metachronous primary lung adenocarcinomas harboring distinct KRAS mutations

To distinguish whether multiple lung nodules represent multiple primary lung cancers (MPLC) or intrapulmonary metastases (IPM) is crucial for staging and subsequent therapy. We herein present the first report of a patient with two simultaneously resected metachronous lung adenocarcinomas in the right upper lobe, each with a distinct driver mutation in the KRAS gene identified by targeted next generation sequencing (NGS). The nodules appeared chronologically metachronous, with a 3.7 year interval. Histopathology showed two histologically identical adenocarcinomas, without lymph node metastases. It was hard to decide whether they should be classified as either MPLC or IPM based only on the clinicopathological criteria. Sequencing further revealed distinct KRAS mutation in each tumor, with one tumor harboring the KRAS-G12C mutation, and the other tumor harboring the KRAS-Q61H mutation. Incorporation of the molecular data cleared the confusion with regard to staging and spared this patient from adjuvant therapy. This case highlights that molecular profiling allows for better differentiation between MPLC and IPM than histopathology alone. KEY POINTS: To the best of our knowledge, this is the first case of multiple primary lung cancers harboring distinct KRAS mutations. The case highlights the importance of incorporating molecular profiling using NGS along with the clinicopathological criteria in classifying multiple lung tumors.