Review
Merkel cell carcinoma – Recent advances in the biology, diagnostics and treatment☆

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Abstract

Merkel cell carcinoma (MCC) is an uncommon primary cutaneous carcinoma with neuroendocrine differentiation. Since recent discovery of MCCs strong association with Merkel cell polyomavirus (MCPyV), there has been a rapid increase in the understanding of the carcinomas genetics, molecular biology and pathogenesis. In our study, we reviewed recent advances and controversies concerning MCC histogenesis, epidemiology, diagnostic and prognostic markers. We analyzed the association of MCPyV with MCC and the possible new targets for therapy. We also examined English-based literature regarding MCC pathogenesis published between 2008 and 2013, which lead to a deeper understanding of the topic. Our study showed that the association of MCPyV strongly influences the course of MCC. Additionally, it has been shown that a immunological response to MCPyV may in the future give hope to identify new therapeutic strategies in treatment of this fatal malignancy.

This article is part of a Directed Issue entitled: Rare Cancers.

Introduction

Merkel cell carcinoma is an uncommon primary neuroendocrine carcinoma of the skin which predominantly develops in the geriatric population. However, recently described correlation with polyomavirus (MCPyV) infection and frequent coexistence with cellular immunodeficiency shed a new light on MCCs pathogenesis and biology.

Section snippets

Cell of origin

The histogenesis of Merkel cell carcinoma (MCC) is not entirely clear. For a long time there had been a dogmatic belief which presented MCC as a derivative of a Merkel cell, a mechanoreceptor which was described for the first time in the skin by Friedrich Sigmund Merkel in 1875. The vast majority of Merkel cells are intimately associated with nerve terminals and functionally act as mechanoreceptors (Halata et al., 2003). Since 1875, the term Merkel cell was also used for cells with similar

Epidemiology

The age-adjusted ratio of MCC is 0.18–0.41 per 100.000 persons (Albores-Saavedra et al., 2010). A recent, well documented, population-based study showed lower frequency for both males (0.11) and females (0.12) (Kukko et al., 2012). On the other hand, the frequency in Western Australia is much higher: 1.0 and 0.63 per 100.000 for male and females, respectively (Girschik et al., 2011). This may result rather from high level of sun exposure than MCPyV infection, as the latter is less frequent in

Pathology

The term Merkel cell carcinoma, that replaced the original name “trabecular carcinoma of the skin” (Toker, 1972), was introduced in 1980 (De Wolff-Peeters et al., 1980). MCC is included into the group of small blue cell neoplasms, composed of monomorphous population of cells with round-to-oval nucleus and scant cytoplasm (Fig. 1). Nucleus contains primitive, diffusely dispersed chromatin and mitoses are usually numerous. Three morphological patterns were distinguished in MCC, i.e. solid,

Etiological factors

In 2008, Feng et al. (2008) identified an unknown polyomavirus in approximately 80% of MCCs. This finding was confirmed in many other studies (Amber et al., 2013) and the virus was named Merkel cell polyomavirus (MCPyV). The frequency of MCPyV in Australian MCC patients is 24% (Garneski et al., 2009). However, with more sophisticated and sensitive methods almost all analyzed MCCs showed presence of MCPyV (Rodig et al., 2012), but the dosage of viral genes per cell varies among MCPyV-positive

MCC and immune response

Pathogenesis of MCC is associated with immunosuppression. It is not only demonstrated in patients with known defects in cellular immunocompetence but also in elderly patients with MCC who seemingly may manifest discreet senile low performance of immunological system. Nonetheless, viral proteins influence immunological response of the host. Merkel cell polyomavirus small T antigen (ST) targets the NEMO adaptor inhibiting NF-κB-mediated transcription. MCPyV ST expression inhibits IKK α/β-mediated

Prognostic factors in MCC

Five-year disease-specific survival rate for MCC is largely stage-dependent (stage I: 81%; stage II: 67%; stage III: 52%; stage IV: 11%). In the majority of patients (ca. 70%), the neoplasm is limited to the skin (stage I and II); a fourth of patients presents with stage III, while 5% shows distant metastases at the time of diagnosis (Tai et al., 2000). Clinical estimation of the process usually is understaged (Allen et al., 2005) and after lymph node evaluation stage III is the most frequent

New points for therapy

In metastatic MCC the range of therapeutic options is very limited, therefore, search for new drugs is mandatory.

As majority of MCC cases are related to viral infection, therapy directed against MCPyV seems to be promising. Some patients with MCC show antibodies against LTA and STA in which their titers correlate with tumor burden, these antibodies are largely restricted to MCC patients and are not identifiable in the healthy ones (Paulson et al., 2010). Additionally, the MCPyV-specific

Conclusions

Merkel cell carcinoma is an uncommon cutaneous malignancy showing an important role of immunological and infective background. The recent advances in our understanding of its biology may directly modify the treatment and provide more successful results of this relentless skin cancer.

Acknowledgements

This paper was supported by the Grant No. ST-95 from the Medical University of Gdańsk.

We thank Claudia Wiewióra for language proof of the manuscript

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