Case B (Case 10 in Table 1 and Table S2)

A 59-year-old woman presented with 0.7-cm nodules in the right lower lobe 1.5 years after undergoing right upper lobectomy for cancer. The tumors were round and had a smooth surface. Because of their morphology, they were suspected of being metastatic lesions. After 4 months of follow-up, there was no increase in the number of lung lesions, suggesting solitary intrapulmonary metastasis. Subsequently, wedge resection was performed. Although both tumors were pathologically papillary-predominant adenocarcinoma (Figure 4C,D), a lepidic pattern was observed in the periphery of the smaller nodule (Figure 4E), leading to a diagnosis of double primary lung cancers. However, the genetic mutation profile was consistent between the two tumors, suggesting them to be metastases (Figure 4F). The patient was positive for a mutation in the epidermal growth factor receptor (EGFR) gene (exon 19 deletion); hence, oral administration of an EGFR-tyrosine kinase inhibitor (gefitinib) was continued. The patient has remained alive without recurrence for 4 years after the second surgery.

**Figure 4.** Radiological, histopathological and genomic findings in case B. (**A**) Lung cancer in the right upper lobe. (**B**) A small nodule in the right lower lobe. (**C**) Histology of the lung cancer in the right upper lobe. (**D**,**E**) Histology of the nodule in the right lower lobe. A lepidic pattern was observed in the periphery of the small nodule. Each scale bar indicates 100 μm. (**F**) Heatmap of the gene mutations of the two lung tumors. The significant mutations identified in the right upper lobe tumor were homologous with those detected in the right lower lobe tumor. RU, right upper lobe; RL, right lower lobe; AF, allele fraction

Case C (Case 18 in Table 1 and Table S2)

A 74-year-old man presented with tumors measuring 4.0 cm and 1.8 cm in the left upper lobe, so left upper lobectomy was performed (Figure 5A,B). As both tumors were closely located and pathologically similar squamous cell carcinomas, they were assumed to be single origin pulmonary metastases (Figure 5C,D). However, the mutation profile was completely different between the two tumors genetically, suggesting double primary cancers (Figure 5E).

**Figure 5.** Radiological, histopathological and genomic findings in case C. (**A**,**B**) Two tumors, a large one (T1) and a small one (T2), were located in the left upper lobe in proximity to each other. (**C**,**D**) The tumors exhibited a similar histology of squamous cell carcinoma. Each scale bar indicates 100 μm. (**E**) Heatmap of the gene mutations of the two lung tumors. The mutation profiles of T1 and T2 were completely different. (**F**,**G**) Postoperatively, tracheobronchial lymph node enlargement was observed and the tumor was identified as a squamous cell carcinoma. Each scale bar indicates 100 μm. AF, allele fraction.
