Merkel cell polyomavirus and cutaneous Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine skin cancer of elderly patients. Generally, it originates from Merkel cells of the basal layer of the epidermis characterized by typical neuroendocrine granules (neuron-specific enolase; NSE+) and keratin filament (cytokeratin-20; CK20). Its incidence has been increasing in the last two decades, likely because of improved ability to diagnose it. However, its mortality is still too high owing to systemic metastases (20–30% of MCC) despite the early detection of locally advanced disease through sentinel node (SN) biopsy and standard therapies [1]. Common risk factors for developing MCC include advanced age and immunocompromised state (secondary neoplasm, organ transplantation, HIV infection, druginduced state and so on) and chronic UV exposure. Histopathologically, the most important prognostic indicators are represented by size, thickness, depth, mitotic rate, lymphovascular invasion and tumoral infiltrating CD8 T cells (tumoral infiltration of lymphocytes [TIL]) of the primary MCC as well as SN status. More recently, a human polyomavirus (MCPyV) has been discovered as an oncogenic agent of MCC [2]. It is a small, circular double-stranded DNA virus of the family Polyomaviridae. MCPyV sequences have revealed a very low genetic variability with the presence of five major variants corresponding to the different continents [3]. However, MCC is frequently reported in patients of Caucasian origin, mainly North America and Europe including Italy, while rarely in Asia and exceptionally in Africa. To date, there is a robust collection of scientific evidence supporting its classification as a causative agent of MCC according to the WHO’s International Agency for Research on Cancer; however, a combination of this potential oncogenic pathway with other clinical factors and particularly immunosuppression seems to be mandatory for the pathogenesis of this rare skin cancer. In fact, MCPyV infection is common in the human population and skin is the most frequent asymptomatic location. Moreover, up to 80% of the adult population contains serum antibodies to the major capsid protein, VP1. However, the clonal integration of its viral genome into Merkel cells, and most frequently on chromosome 5, can induce mutations of the early region that result in truncation of the large T antigen (LTAg) inactivating pRB tumor suppressor function, while the small T antigen (STAg) coding sequence remains generally intact but promotes translation, instead. These MCC tumor-specific mutations abrogate viral DNA replication capacity and subsequently cell death, but preserve its oncogenic function with induction of uncontrolled cellular proliferation [4]. MCPyV LTAg and DNA have been detected by immunohistochemistry and PCR, Merkel cell polyomavirus and cutaneous Merkel cell carcinoma Commentary