Expression of Mismatch Repair Proteins in Merkel Cell Carcinoma

Simple Summary Merkel cell carcinoma (MCC) is a rare and highly malignant skin cancer with neuroendocrine differentiation. About 80% are Merkel cell polyomavirus (MCPyV) positive. The aim of this work was to immunohistochemically investigate the expression of mismatch repair proteins (MSH2, MSH6, MLH1, and PMS2) in MCC (n = 56). In a second step, tumors with a low expression were tested for microsatellite instability. Microsatellite instability in MCC could have an impact on immune checkpoint inhibitor therapy (ICI) outcome. This study showed a significant association between low expression of mismatch repair proteins and a negative MCPyV status. Microsatellite instability was detected in only one case. Future studies will establish whether this subset of MCC patients respond better to ICI. We aimed to assess for the first time the mismatch repair (MMR) protein expression in Merkel cell carcinoma (MCC). Immunohistochemistry was performed for MLH1, MSH2, MSH6, and PMS2 on patients' tumor tissue (n = 56), including neighbored healthy control tissue. In cases with low-level MMR expression (<10th percentile), we performed multiplex PCR in combination with high-resolution capillary electrophoresis in order to confirm microsatellite instability (MSI). Microscopic evaluation revealed a high median expression for all MMR proteins studied (91.6-96.3%). However, six patients (56/10.7%) had low-level MLH1 expression, six (55/10.9%) had low-level MSH2 expression, five (56/8.9%) had low-level MSH6 expression, and six (54/11.1%) had low-level PMS2 expression. Together, we observed nine (56/16.1%) patients who had low-level MMR expression of at least one protein. Of the patients with low-level MMR expression, MSI evaluation was possible in five cases, revealing one case with high-level MSI. In all MMR proteins assessed, low-level expression was significantly (p = 0.0004 to p < 0.0001) associated with a negative Merkel cell polyomavirus (MCPyV) status. However, the expression profiles of the MMR proteins did not correlate with clinical outcome measures such as disease relapse or death (p > 0.05). MCC appears to be a malignancy characterized by low-level MMR rather than completely deficient MMR in a subset of cases, predominantly affecting MCPyV-negative tumors. Future studies will establish whether this subset of MCC patients respond better to immune checkpoint inhibitor therapy.