Merkel cell carcinoma: an updated guide for pathologists

Merkel cell carcinoma (MCC) is an aggressive, poorly differentiated neuroendocrine cutaneous carcinoma that has rapidly increased in incidence over the past decades. Due to the significant risk of recurrence, metastasis and mortality, prompt diagnostic recognition of MCC is essential to guide timely management. Definitive diagnosis can be challenging, especially in the context of limited sampling, morphological variants, immunophenotypic aberrancy or metastatic disease of unknown primary. The differential diagnosis can include other small cell malignancies, especially extracutaneous small cell carcinoma. Small cell carcinoma of the vulva carries substantial risk for misdiagnosis due to immunohistochemical overlap with MCC. Cutaneous carcinomas may also enter the differential diagnosis, especially the recently described WNT/Beta-catenin-activated nonpilomatrical carcinoma that can also express CK20 and neuroendocrine markers. In certain contexts, there is risk of diagnostic confusion with basal cell carcinoma or squamous cell carcinoma. This review details pitfalls and nuances for MCC diagnosis, including an updated differential diagnosis. The utility of recently proposed markers SATB2, H3K27me3 and POU4F3 is described, alongside important caveats for more traditional markers such as CK20, TTF1, neurofilament and Merkel cell polyomavirus. Molecular analysis can assist in certain cases. These recent advances help to ensure more definitive diagnosis of MCC in most cases.