Nuclear expression of survivin portends a poor prognosis in Merkel cell carcinoma

Abstract

Inhibition of apoptosis is a critical step in tumorigenesis in many cancers, including Merkel cell carcinoma; however, the exact regulatory mechanisms are not fully understood. Survivin is an inhibitor of apoptosis that is undetectable in most terminally differentiated normal human tissues, strongly expressed in embryonic and fetal organs and is strongly expressed in many different human cancers. In this study, we investigated the expression of survivin in cutaneous Merkel cell carcinoma using immunohistochemistry and correlated the findings with long-term clinical follow-up. We collected and immunostained 19 cases of Merkel cell carcinoma with antibodies to survivin. The median patient age was 79 years, with an average follow-up of 17 months, and a male/female ratio of 7:11. All but one sample represented primary lesions and two cases were obtained from one patient. Clinical follow-up was obtained in 15 cases (79%). All 19 cases of Merkel cell carcinoma demonstrated strong immunoreactivity for survivin. Survivin protein was localized and classified into predominately nuclear (N=8) or cytoplasmic (N=4) compartments. A mixed pattern of survivin expression was also seen in three cases. Cases with a nuclear staining pattern were distinguished by an aggressive clinical course, with seven of eight patients developing metastases or dead of disease on follow-up. Furthermore, all of the cases with predominately cytoplasmic survivin localization (N=4) were free of disease on follow-up. Merkel cell carcinomas represent aggressive malignancies regulated by apoptotic pathways. We demonstrate that survivin, a protein with a dual role in inhibition of apoptosis and regulation of cellular proliferation is expressed in Merkel cell carcinoma. Moreover, nuclear subcellular localization of survivin in Merkel cell carcinomas may portend a poor prognosis and identification of these cases may assist clinical management.