Abstract
Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy that is associated with a poor prognosis. The pathogenesis of MCC is not well understood, and despite a recent plethora of mutational analyses, we have yet to find a set of signature mutations implicated in the majority of cases. Mutations, including TP53, Retinoblastoma and PIK3CA, have been documented in subsets of patients. Other mechanisms are also likely at play, including infection with the Merkel cell polyomavirus in a subset of patients, dysregulated immune surveillance, epigenetic alterations, aberrant protein expression, posttranslational modifications and microRNAs. In this review, we summarize what is known about MCC genetic mutations and chromosomal abnormalities, and their clinical significance. We also examine aberrant protein function and microRNA expression, and discuss the therapeutic and prognostic implications of these findings. Multiple clinical trials designed to selectively target overexpressed oncogenes in MCC are currently underway, though most are still in early phases. As we accumulate more molecular data on MCC, we will be better able to understand its pathogenic mechanisms, develop libraries of targeted therapies, and define molecular prognostic signatures to enhance our clinicopathologic knowledge.
Highlights
Merkel Cell Carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine tumor
The relationship between immunosuppression and MCC is not entirely understood, the discovery of the Merkel cell polyomavirus (MCPyV) infection in up to 80% of cases offers a potential mechanism for malignant transformation, and may provide more insight in this regard [4]
The mechanisms of oncogenesis underlying MCPyV-negative MCC are less well understood, but are thought to involve somatic mutations in tumor suppressors including RB1 and TP53, as well epigenetic alterations resulting in aberrant expression and activity of oncogenes [5,6]
Summary
Merkel Cell Carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine tumor. MCC is most often found in elderly Caucasians approximately 60–80 years old, with an annual incidence in the United States of approximately three cases per million persons per year, though this number has nearly tripled in the last 20 years with an aging populace, increased UV exposure and greater frequency of immunosuppression in the population [1]. The relationship between immunosuppression and MCC is not entirely understood, the discovery of the Merkel cell polyomavirus (MCPyV) infection in up to 80% of cases offers a potential mechanism for malignant transformation, and may provide more insight in this regard [4]. Hematoxylin and eosin staining of MCC presents as round blue tumor cells, indicative of large basophilic nuclei with minimal cytoplasm, located in the dermis or subcutaneous tissue. They may have a trabecular pattern, scant eosinophilic cytoplasmic rims, multiple nucleoli and paranuclear staining of cytokeratin-20 (CK-20) in a dot-like pattern. Normal merkel cells are located within the stratum basale and rete ridges of epidermis, as well as in mucosa [10,11]. Consensus guidelines for management of MCC exist, there are still unanswered fundamental clinical questions regarding the best use of surgery, chemotherapy and radiation for this condition
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