A 68-year-old man with a 50-pack-year history of smoking had been followed since 1992 at our hospital. The patient's first cancer occurred in the ascending colon and was surgically resected in 1992. His second and third cancers occurred in the sigmoid colon and rectum, respectively, and were resected in 2012. The pathological diagnosis of both cancers was pStage I. His fourth cancer was squamous cell carcinoma in the lower lobe of the left lung (pT2bN0M0, pStage IIA); this tumor was resected in 2012. His fifth and sixth cancers occurred in the sigmoid colon and the rectum, respectively, and were endoscopically resected in 2013. The pathological diagnosis of both cancers was carcinoma in situ. His seventh cancer occurred in the prostate and was treated via retropubic radical prostatectomy in 2014 (pT3aN1M0, pStage IV).
The patient's mother had had uterine cancer, and his brother had been diagnosed with stomach cancer at a young age (Fig. 1). Given this history, familial cancer syndrome was suspected. We provided counseling to him and his family according to the ethical guidelines of the Division of Clinical Genetic Oncology of our hospital; we then examined him for microsatellite instability (MSI). The loss of MSH2 and MSH6 was detected via immunohistochemistry (IHC) in the colon cancer resected in 2013, and two of five microsatellite markers (BAT25 and BAT26) showed replication error (Fig. 2A-E). Therefore, the patient's colon cancer was considered to be a high-frequency MSI (MSI-H) tumor. In addition, rearrangement in the MSH2 germline gene, which has previously been described in Lynch syndrome, was identified using a multiplex ligation-dependent probe amplification assay (Fig. 2F).
In April 2015, a consolidation shadow with a thick-walled cavity in the upper lobe of the left lung was identified on computed tomography. A transbronchial lung biopsy (TBLB) revealed organizing pneumonia. The shadow gradually expanded, and new lesions emerged in the right upper and lower lobes. Another TBLB performed in April 2016, revealed adenocarcinoma without epidermal growth factor receptor mutation or anaplastic lymphoma kinase rearrangements in the left upper lobe. We used IHC to confirm that the tumor was a primary lung cancer and not a metastatic tumor from known colorectal cancers (Fig. 3A-H). Furthermore, the results of additional IHC staining indicated that programmed death ligand-1 (PD-L1) expression was observed in about 3% of the tumor cells of lung biopsy tissue (Fig. 3I), and PD-L1 was not expressed in colorectal tumor cells (Fig. 3J).
Examinations of MSI in lung biopsy tissue were performed via IHC and MSI analyses. IHC revealed the loss of MSH2 and MSH6 in the lung cancer (Fig. 4). However, MSI-H was not detected in the MSI analysis.
In summary, the patient was diagnosed with primary lung cancer of the left upper lobe, which was pathologically proven to be adenocarcinoma, as well as MSI with radiologically multiple pulmonary metastases of the right upper and lower lobes (cT3N0M1a, cStage IV). He began receiving cisplatin and pemetrexed therapy in June 2016 and was subsequently treated with maintenance pemetrexed. The lung tumors exhibited a partial response, but the bilateral lung tumors progressed after five months (Fig. 5A). The patient began receiving nivolumab (3 mg/kg intravenously every 2 weeks) in November 2016. The lung tumors dramatically decreased in size within 2 months. However, the patient discontinued nivolumab due to drug-induced interstitial lung disease and started treatment with corticosteroids in March 2017. Surprisingly, tumor shrinkage continues to be obtained without anti-cancer treatment as of September 2018, when we drafted this report (Fig. 5B).