Multivariate analysis of immunohistochemical evaluation of protein expression in pancreatic ductal adenocarcinoma reveals prognostic significance for persistent Smad4 expression only

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a 5-year survival rate of <5% and an average survival of only 6 months. Although advances have been made in understanding the pathogenesis of PDAC in the last decades, overall survival has not changed. Various clinicopathological and immunohistological variables have been associated with survival time but the exact role that these variables play in relation to survival is not clear.

Methods and results: To examine how the variables affected survival independently, multivariate analysis was conducted in a study group of 78 pancreatic ductal adenocarcinomas. The analysis included clinicopathological parameters and protein expression examined by immunohistochemistry of p53, Smad4, Axl, ALDH, MSH2, MSH6, MLH1 and PMS2. Lymph node ratio <0.2 (p = 0.004), tumor free resection margins (p = 0.044) and Smad4 expression (p = 0.004) were the only independent prognostic variables in the multivariate analysis. Expression of the other proteins examined was not significantly related to survival.

Conclusions: Discrepancies with other studies in this regard are likely due to differences in quantification of immunohistochemical staining and the lack of multivariate analysis. It underscores the importance to standardize the methods used for the application of immunohistochemistry in prognostic studies.

Fig. 1

Immunohistochemical evaluation of both negative (a,c,e,g) and positive (b,d,f,h) expression of ALDH (a/b), Axl (c/d), Smad4 (e/f) and p53 (g/h). Arrows intense staining of ALDH in the basally located neoplastic cells

Fig. 2

Kaplan-meier plots of overall survival of 78 PDAC patients in relation to node status (log-rank p = 0.066), resection margin (log-rank p = 0.056), lymph node ratio (log-rank p = 0.002), Smad4 expression (log-rank p = 0.008) and tumor Stage (log-rank p = 0.02)