Clinicopathological and Prognostic Value of Survivin Expression in Surgically Resected Pancreatic Ductal Adenocarcinoma

SIMPLE SUMMARY: In spite of recent optimisation of surgical therapy and multimodal treatment options, late diagnosis and devastating overall prognosis continue to characterise pancreatic cancer. The inhibitor of apoptosis protein survivin has been established as a relevant if not unambiguously understood factor in the formation and progression of pancreatic ductal adenocarcinoma (PDAC) being upregulated already in the early stages of tumourigenesis. Therefore, we analysed the expression of survivin in primary PDAC and lymph node metastases in an ample collective of 236 patients and demonstrated that cytoplasmic as nuclear overexpression of the protein correlated significantly with clinicopathological indicators of disease progression and, accordingly, showed prognostic relevance. The findings support the use of survivin as a biomarker to further explore the aggressiveness of PDAC subtypes and encourage its therapeutic approach as a molecular target to expand current chances for disease survival and potential cure. ABSTRACT: Background: Survival after surgery for pancreatic ductal adenocarcinoma (PDAC) remains poor. Thus, novel therapeutic concepts focus on the development of targeted therapies. In this context, inhibitor of apoptosis protein (IAP) survivin is regarded as a promising oncotherapeutic target. However, its expression and prognostic value in different tumour compartments of PDAC have not been studied. Methods: Immunohistochemical analysis of survivin in different PDAC tumour compartments from 236 consecutive patients was correlated with clinicopathological variables and survival. Results: In comparison to healthy pancreatic tissue high nuclear (p < 0.001) and high cytoplasmic (p < 0.01) survivin expression became evident in the tumour centre, along the invasion front and in lymph node metastases. Cytoplasmic overexpression of survivin in tumour centres was related to the presence of distant metastasis (p = 0.016) and UICC III/IV stages (p = 0.009), while high cytoplasmic expression at the invasion front grouped with venous infiltration (p = 0.022). Increased nuclear survivin along the invasion front correlated with perineural invasion (p = 0.035). High nuclear survivin in tumour centres represented an independent prognostic factor for overall survival of pancreatic tail carcinomas (HR 13.5 95%CI (1.4–129.7)) and correlated with a limited disease-free survival in PDAC (HR 1.80 95%CI (1.04–3.12)). Conclusion: Survivin is associated with advanced disease stages and poor prognosis. Therefore, survivin will help to identify patients with aggressive tumour phenotypes that could benefit from the inclusion in clinical trials incorporating survivin inhibitors in PDAC.