NeuroD1 is frequently expressed in Merkel cell polyomavirus-negative and keratin 20-negative Merkel cell carcinoma: A potential diagnostic pitfall.

Objective: Neurogenic differentiation factor 1 (NeuroD1) is a known marker of a subtype of small cell lung carcinoma (SCLC). In this study, we aim to assess whether there is an association between NeuroD1 with Merkel cell polyomavirus (MCPyV) status, keratin 20, thyroid transcription factor 1 (TTF1), and overall survival (OS) in 125 Merkel cell carcinomas (MCCs).

Methods: NeuroD1-positive MCC tumors were characterized by immunohistochemical stains and an external RNA sequencing data set.

Results: NeuroD1 positivity (10%-100%) was seen in 29 (23%) of 125 cases, with 60 (48%) of 126 and 113 (94%) of 120 tumors MCPyV positive and keratin 20 positive, respectively. Focal TTF1 expression was seen in 9 (7.5%) of 120 tumors. NeuroD1 expression was seen more frequently in MCPyV-negative than MCPyV-positive MCCs (P = .0002) and more frequently in keratin 20-negative tumors vs keratin 20-positive ones (P < .0001). Increased NEUROD1 expression in MCPyV-negative MCC (P < .005) was confirmed in an external RNA sequencing data set (GSE235092). Univariate analyses showed NeuroD1 positivity and MCPyV-negative status correlated with worse OS (P = .024 and P = .0076, respectively); however, only MCPyV status remained significant in multivariate analyses (P = .033).

Conclusions: NeuroD1-positive MCCs are significantly correlated with MCPyV-negative, keratin 20-negative expression, and focal TTF1 expression. NeuroD1 expression can pose a potential diagnostic pitfall in the distinction of MCC from SCLC, especially in a setting of a limited immunohistochemical panel.