Expression of p63 Protein and Its Variants Switches MCPyV- Positive Merkel Cell Carcinoma towards a More Aggressive Tumor

Background: Prediction of clinical evolution in Merkel cell carcinoma (MCC), a rare and potentially aggressive tumor, is notoriously uncertain. In our previous experience, p63 expression in MCC represented an independent predictor of poor prognosis. In addition, recently it has been suggested that the presence of Merkel cell polyomavirus (MCPyV) is an indicator of adverse prognosis. Thus, to investigate on significance of the co-expression of p63 and MCPyV, we examined a series of MCC from different Institutions. Design: We collected data on 72 MCCs; 27 cases were tested for p63 expression by immunohistochemistry (IHC) alone, while the remaining 45 were studied for p63 status by IHC, RT-PCR and FISH and for the presence of MCPyV by PCR. Results: p63 expression, detected in 52.7% of cases by IHC, was associated with decreased OS (p=0.041) and DFS (p<0.001). In the 45 MCCs investigated with both IHC and RT-PCR a variable expression pattern of the different p63 isoforms was found in 25 out of 26 IHC-positive MCCs. In these same lesions at least one of the N terminal p63 isoforms was detected in the primary MCC. Accordingly, TAp63α was the most frequently expressed isoform. No p63 isoform was found in the 19 cases negative for p63 at IHC. P63 gene amplification was observed in only one case. Clonal integration of MCPyV DNA sequences was evidenced in 84.4% of MCCs. Expression of p63 protein in MCPyV-positive MCC cases was associated with an increased risk of death (p=.001) whereas p63 negativity indicated a less aggressive behaviour. Conclusions: The present data indicate that clonal integration of MCPyV DNA sequences was not per se related to prognosis in our series while the expression of p63 protein and its variants in MCPyV-positive MCC cases related to a significant risk of death of disease, higher that staging or any other factor.