Prognostic significance of HIF-2alpha expression on tumor infiltrating macrophages in patients with uterine cervical cancer undergoing radiotherapy

Hypoxia-inducible factor (HIF)-2alpha, a basic helix-loop-helix (bHLH)-PAS protein, is the principal regulator of the hypoxic transcriptional response. An immunohistochemical study reported strong HIF-2alpha expression in the cytoplasm of tumor infiltrative macrophages (TIMs). Thus we assessed the expression of HIF-2alpha in human cervical cancer tissue before radiation therapy and its relationship to the clinical outcome. Seventy three patients with histologically proven primary advanced squamous cell carcinoma of the uterine cervix underwent radiotherapy in Tokushima University Hospital after biopsy specimens were taken. Among 73 specimens stained for HIF-2alpha, 53 (72.6%) exhibited HIF-2alpha immunoreactivity in the TIMs. In only 5 of 73 cases, HIF-2alpha immunoreactivity was observed in the nuclei of tumor cells. The HIF-2alpha positive cell count ratio in TIMs was associated with disease-free survival (DFS) with the worst DFS (p=0.024) being in cases in the group with a high positive cell count ratio. A high HIF-2alpha positive cell count ratio in TIMs increased the risk of local recurrence (p=0.0142). These findings might suggest that the ratio of the HIF-2alpha positive cell in TIMs may be a new predictive indicator for prognosis before radiation therapy for uterine cervical cancer.