**1. Introduction**

In patients with synchronous or metachronous multiple cancers, individual tumors may appear as either a primary lung cancer or both primary and metastatic lung cancers. The selection of treatment in such cases is dependent on the resulting characteristics. In patients with multiple lung cancers, the nature of a tumor (i.e., whether it is metastatic or primary) can usually be judged on the basis of diagnostic imaging findings, clinical course, and/or pathology. If individual tumors composing multiple lung cancers are histologically inconsistent in terms of histological morphology and/or cellular atypism, the multiple onset of primary cancers is highly likely. However, there are no specific radiological, clinical or histological features that can be utilized to unambiguously distinguish intrapulmonary metastases from multiple primary cancers and the cut diagnosis can be perplexing in the clinical setting. The differing biological activities of tumors allow for prognostic distinctions to be drawn and patients with intrapulmonary metastasis are supposed to have a poorer prognosis. Therefore, it is critically important to develop improved methods for the identification of tumors by exploring new, practical techniques and markers. We have previously demonstrated that as a more precise and clinically applicable method, a comparison of the driver mutation profiles enables elucidation of the clonal origin of tumors and thus facilitates an accurate discrimination between primary and metastatic tumors [1]. However, this finding was based on only 12 multiple lung cancer cases; hence, validation through a study involving a larger number of such cases was needed. Moreover, the significance of these findings in the clinical setting remained to be determined. In view of this, we extended the case accrual period to 5 years and included 37 patients with multiple lung cancers in the present study. In addition, we analyzed the clinical course in individual patients in detail to examine the use of mutation data for the diagnosis of multiple lung cancers in clinical practice and to determine the actual contribution of this approach to an improvement of clinical practice. Furthermore, we analyzed gene mutations in primary lung cancers as well as metastatic lymph nodes and genetically examined the pathology of the metastatic lymph nodes to accurately understand the pathology of lymphatic metastasis and thus enhance the postoperative treatment outcome.
