Etiology

Risk factors include chronic ultraviolet (UV) radiation exposure, immunosuppression, advancing age, male sex, and white skin.[14]

MCC is strongly associated with lower latitudes and high UV radiation indexes, as evidenced by MCC tumors often arising on sun-exposed skin.[7][13]​​

Immunosuppression due to hematologic malignancy, organ transplantation, immunosuppressive medication (e.g., for autoimmune disease), decreased immune function associated with advancing age, or HIV infection is associated with an increased risk of MCC.[15][16][17]​​​​​ MCC patients who are immunocompromised also have an increased risk of disease recurrence.[18]

Oncogenic transformation by Merkel cell polyomavirus (MCPyV) is associated with up to 70% to 80% of MCC tumors in the US and Europe, with lower associations in Australia.[7]​​[12][14]​​​ It is an oncogenic process that requires viral integration into the host genome, resulting in inactivation of a viral replication protein.

Pathophysiology

​MCC is a highly aggressive primary cutaneous neuroendocrine carcinoma with epithelial and endocrine features. Its origin is disputed, with epidermal Merkel cell precursors, pre-B cells, pro-B cells, or dermal fibroblasts all suggested.[7]

MCC tumorigenesis is attributed to two main etiologies with distinct molecular pathogenetic pathways: integration of MCPyV into the host genome, or exposure to UV radiation.[7][19]

MCPyV is a ubiquitous polyomavirus with 60% to 80% seropositivity in the US adult population.[20]​ MCPyV infection is typically asymptomatic.[20] While viral infection is common, oncogenic transformation by MCPyV is rare as it requires integration into the host genome.[20][21]​​ MCPyV-positive MCCs have a low tumor mutational burden but harbor clonal integration of the virus.[7]

UV-associated MCCs, which usually occur on sun-exposed parts of the body, are characterized by a high tumor mutational burden, with enrichment of the UV-DNA damage signature seen in MCPyV-negative MCC tumors.[7][22][23][24][25][26]​​​​​​​​​​ Retinoblastoma protein and p53 are among the most significantly mutated genes.[7]

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