Viral Etiology of Merkel Cell Carcinoma:Implications in Diagnosis, Prognosis, Therapy and Prevention

Merkel cell carcinoma (MCC) is a rare and a highly aggressive skin cancer of neuroendocrine origin that is frequently associated with a poor prognosis, a clonal integration of a polyomavirus (MCPyV), and a high propensy for recurrence and metastasis; its incidence increases with age, immunodeficiency and sun exposure. Importantly, cytokeratin 20 (CK20) is expressed in approximately 95% of MCC cases, MCPyV in about 80% of cases, and MCPyV is less common in CK20-negative MCC. The disease progression could be evaluated by means of high numbers of mitoses, proliferation and survival of tumour cells as marked by Ki-67- and Bcl-2-staining, and infiltration of lymphatic vessels. Moreover, a recent meta-analysis using random effects model revealed that there is an increased risk for second malignancies due to MCC (e.g. malignant melanoma). In fact, the origin of MCC is rather controversial, its pathogenesis (e.g. the molecular mechanisms underlying MCC development after MCPyV infection) remains unclear, and MCC seems to be a heterogenous entity with distinct subtypes. Indeed, while the presence of neurosecretory granules and expression of specific biomarkers (i.e. PGP 9.5, chromogranin A and several neuropeptides) has suggested that MCCs originate from one of the neurocrest derivatives, most probably Merkel cells, zurHausen et al. hypothesized that they could originate from early B cells since they commonly express. Terminal deoxynucleotidyl Transferase (TdT) and Paired Box Protein-5 (PAX5), which are restricted to pro/pre-B cells and pre-B cells when co-expressed under certain physiologic circumstances.