PMC6548921_01
Pedigree of the patient as of current. His mother had a uterine cancer, and his brother had a stomach cancer. His niece also had a uterine cancer at a young age.
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The patient's mother had had uterine cancer, and his brother had been diagnosed with stomach cancer at a young age (Fig. 1).
Results of microsatellite instability (MSI) analysis of colorectal cancer. MSI status was assessed by the results of electrophoresis of polymerase chain reaction of five markers [BAT25 (A), BAT26 (B), D2S123 (C), D5S346 (D), and D17S250 (E)]. Instability of two markers [BAT25 (A) and BAT26 (B)] was observed and the patient's colorectal cancer was identified as MSI-H cancer. Multiplex ligation-dependent probe amplification assay revealed increased copy number of exons 4-8 of the MSH2 gene in germline cells (F).
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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). 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).
Histological and immunohistochemical findings comparing lung tumor and colorectal tumor tissues. Hematoxylin and Eosin staining of the lung tumor (A) and colorectal tumor (E) are shown. Expression of cytokeratin (CK) 7, a marker of lung cancer, was observed in the tumor cells of lung biopsy tissue (B). The expression of CK 20 and caudal-type homeobox protein 2 (CDX-2), which are markers of colorectal cancer, was not observed in the tumor cells of lung biopsy tissue (C, D). In contrast, expression of CK 7 was not observed in the tumor cells of colorectal tissue (F). The expression of CK 20 and CDX-2 was observed in the tumor cells of colorectal tissue (G, H). Both lung cancer and colorectal cancer were considered as primary cancers because the IHC results were exclusive. PD-L1 expression was observed in the tumor cells of lung biopsy tissue (I). CK7 (clone OVTL12/30, DAKO), CK20 (clone IT-Ks20.8, POG), CDX-2 (clone DAK-CDX2, DAKO), PD-L1 (clone 28-8, abcam).
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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).
A comparison of histology and immunohistochemistry (IHC) findings for lung tumor and colorectal tumor tissues. MSH2 (A) and MSH6 (B) were not expressed in the nuclei of tumor cells (white arrows), whereas MLH1 (C) and PMS2 (D) were expressed in tumor cell nuclei (black arrows). MSH2 (clone G219-1129, BD Biosciences), MSH6 (clone EPR3945, Gene Tex), MLH1 (clone ES05, Leica), PMS2 (clone A16-4, BD Pharmingen).
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IHC and MSI analyses. IHC revealed the loss of MSH2 and MSH6 in the lung cancer (Fig. 4).
Computed tomography findings for the patient. Consolidation shadows with ground glass opacities were observed in the left upper and right lower lobes before nivolumab therapy (A). Tumor shadows were greatly reduced in size after 2 months of nivolumab therapy (B).
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The lung tumors exhibited a partial response, but the bilateral lung tumors progressed after five months (Fig. 5A). Surprisingly, tumor shrinkage continues to be obtained without anti-cancer treatment as of September 2018, when we drafted this report (Fig. 5B).