ATOH1, TFAP2B, and CEACAM6 as Immunohistochemical Markers to Distinguish Merkel Cell Carcinoma and Small Cell Lung Cancer

Simple Summary Merkel cell carcinoma (MCC) and small cell lung cancer (SCLC) are both neuroendocrine cancers that can resemble each other under the microscope. Immunostaining with diagnostic markers such as cytokeratin 20 (CK20) and thyroid transcription factor 1 (TTF-1) can help differentiate these two cancers, but their sensitivity and specificity are limited. We compared the gene expression of MCC and SCLC tumors to identify highly differentially expressed genes for potential use as diagnostic markers. Two candidate markers for MCC, atonal BHLH transcription factor 1 (ATOH1) and transcription factor AP-2 beta (TFAP2B), and one candidate marker for SCLC, carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6), were tested using immunostaining. Combined use of CEACAM6 with TTF-1 increased SCLC diagnostic sensitivity to 93% and specificity to 98%. A panel of CK20, ATOH1, and TFAP2B was 100% sensitive and specific for MCC, suggesting the potential utility of these new markers in differentiating MCC and SCLC.Abstract Merkel cell carcinoma (MCC) and small cell lung cancer (SCLC) can be histologically similar. Immunohistochemistry (IHC) for cytokeratin 20 (CK20) and thyroid transcription factor 1 (TTF-1) are commonly used to differentiate MCC from SCLC; however, these markers have limited sensitivity and specificity. To identify new diagnostic markers, we performed differential gene expression analysis on transcriptome data from MCC and SCLC tumors. Candidate markers included atonal BHLH transcription factor 1 (ATOH1) and transcription factor AP-2 beta (TFAP2B) for MCC, as well as carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) for SCLC. Immunostaining for CK20, TTF-1, and new candidate markers was performed on 43 MCC and 59 SCLC samples. All three MCC markers were sensitive and specific, with CK20 and ATOH1 staining 43/43 (100%) MCC and 0/59 (0%) SCLC cases and TFAP2B staining 40/43 (93%) MCC and 0/59 (0%) SCLC cases. TTF-1 stained 47/59 (80%) SCLC and 1/43 (2%) MCC cases. CEACAM6 stained 49/59 (83%) SCLC and 0/43 (0%) MCC cases. Combining CEACAM6 and TTF-1 increased SCLC detection sensitivity to 93% and specificity to 98%. These data suggest that ATOH1, TFAP2B, and CEACAM6 should be explored as markers to differentiate MCC and SCLC.