*3.5. Genetic Diagnosis of Lymph Node Metastasis in Patients with Multiple Lung Cancers*

Lymph node metastasis was detected in five patients with double primary lung cancers (Table 2). It occurred approximately at the time of surgery in three patients and was identified as postoperative lymph node recurrence in two patients (Table 2). In some patients, the route of lymph node metastasis was apparent from the timing of the metastasis as well as the location and pathological findings of the metastatic lesions (cases 4 and 5 in Table 2). In contrast, it was difficult to identify the clonal origin of lymph node metastasis on the basis of the clinical and pathological findings in the other patients, especially in those in whom the primary lesions were both squamous cell carcinomas (cases 1–3 in Table 2). However, even in these patients, a comparison of the mutation profiles of the primary and lymph node metastatic lesions revealed the route of lymph node metastasis (Figure 6).

**Figure 6.** Schema of lymphatic metastasis and mutation profiles in multiple lung cancers. On the basis of the coincidence and differences in the mutation profiles, the clonality of each tumor and the pathway of lymphatic progression are clearly elucidated in each case. The arrows indicate the lymphatic routes of the cancer invasion. Tumor 1 is shown in black, tumor 2 in red and lymph node metastasis in blue. #4, tracheobronchial lymph node; #7, subcarinal lymph node; #11, interlobar lymph node; and #12, hilar lymph node. S, segment; LN, lymph node; AF, allele fraction


**Table 2.** LN metastasis in patients with multiple lung cancers.
