Necrosis related HIF-1α expression predicts prognosis in patients with endometrioid endometrial carcinoma

Background: Hypoxia inducible factor 1 alpha (HIF-1 alpha) plays an essential role in the adaptive response of cells to hypoxia and is associated with aggressive tumour behaviour. We have shown p27(kip1), which is generally reduced in endometrial cancer, to be re-expressed in hypoxic regions. This possibly contributes to survival of cancer cells. The aim of this study was to evaluate the prognostic value of HIF-1 alpha and p27(kip) expression in patients with endometrioid endometrial cancer. Methods: Expression levels of HIF-1 alpha, CAIX, Glut-1, and p27(kip1) were analyzed by immunohistochemistry. Percentage of positive cells, staining pattern (perinecrotic, diffuse, or mixed) and presence of necrosis were noted. Results: Necrosis was correlated with shortened disease free survival (DFS) (p = 0.008) and overall survival (OS) (p = 0.045). For DFS, perinecrotic HIF-1 alpha expression was also prognostic (p = 0.044). Moreover, high p27(kip1) expression was an additional prognostic factor for these patients with perinecrotic HIF-1 alpha expression. In multivariate Cox regression, perinecrotic HIF-expression emerged as an independent prognostic factor. Perinecrotic HIF-1 alpha expression was significantly associated with CAIX and Glut-1 expression, pointing towards functional HIF-1. Conclusions: In patients with endometrioid endometrial cancer, necrosis and necrosis-related expression of HIF-1 alpha are important prognostic factors. More aggressive adjuvant treatment might be necessary to improve the outcome of patients with these characteristics.