Clinical significance of HIF-2α immunostaining area in radioresistant cervical cancer

Objective: Hypoxia has been established as a key factor influencing the pathophysiology of malignant growth. Hypoxia-induced changes in gene expression are coordinated primarily by hypoxia inducible factor-1 alpha (HIF-1α) and HIF-2α. The purpose of this study was to determine whether or not HIF-2α expression is associated with survival and response to radiation in patients with cervical cancer. Methods: After reviewing the medical records of 119 patients treated in our institution by primary therapy for stage IIB-IVA cervical cancer, we performed a case-control study. Cases (n=12) were selected from patients with local recurrence or radiation failure after primary radiation therapy with or without concurrent chemoradiation. For each case, we selected two controls from patients who had no evidence of local recurrence. Using pre-treatment paraffin-embedded tissues, we evaluated the expression of HIF-2α by immunohistochemistry. Staining was scored based on intensity (intensity score [IS], 0-3) and proportion (proportion score [PS], 0-100). The results were analyzed by the Student t-test, Mann-Whitney U test, Fisher's exact test, and Cox proportional hazards regression model. Results: Cytoplasmic expression of HIF-2α, representing the degree of hypoxia, had a relationship with poor response to radiotherapy. The hazard ratio of recurrence was 1.71 for the HIF-2α IS (p=0.110) and 1.04 for the HIF-2α PS (p<0.001), indicating that the HIF-2α staining area correlates weakly with the risk for recurrence. Conclusion: The HIF-2α expression area may have an important role in radioresistance in patients with locally advanced cervical cancer. We conclude that a wider area of hypoxia predicts an increased probability of radioresistance.