Hypoxia-inducible factor 1α expression as an intrinsic marker of hypoxia: Correlation with tumor oxygen, pimonidazole measurements, and outcome in locally advanced carcinoma of the cervix

Purpose: Hyposia-inducible factor (HIF)-1α expression was studied retrospectively in locally advanced carcinoma of the cervix in relation to other methods for measuring/assessing tumor hypoxia and outcome after radiotherapy. Experimental Design: HIF-1α expression was examined in formalin-fixed tamor biopsies using a semiquantitative scoring system and correlated with measurements of hypoxia obtained using oxygen electrodes, pimonidazole staining, and carbonic anhydrase 9. Results: High HIF-1α expression showed a weak correlation with low pO2 (r = -0.26; P = 0.030; n = 72). Weak significant correlations were found between HIF-1α and pimonidazole staining (r = 0.34; P = 0.040; n = 36) and carbonic anhydrase IX (r = 0.27; P = 0.001; n = 160). There was no relationship with surviving fraction at 2 Gy. The relationship between HIF-1α expression and radiotherapy outcome was examined in 99 patients. HIF-1α expression did not correlate with disease stage, grade, tumor size, and patient age. HIF-1α alone was not a significant prognostic factor for disease-free survival, metastasis-free survival, or local recurrence-free survival. High HIF-1α expression tended to be associated with poor outcome in small tumors but good outcome in large tumors, with statistically significant interactions between HIF-1α and tumor size for survival (P = 0.046) and local control (P = 0.009). Conclusions: In this study, HIF-1α had no prognostic significance in locally advanced carcinoma of the cervix. The possible switch in large tumors for an association between high HIF-1α expression and good outcome might relate to tumor size-related changes in the balance of genes up-regulated by HIF-1α. Whereas angiogenesis-promoting genes might be preferentially up-regulated in small tumors, pro-apoptotic genes might be induced in large tumors. This hypothesis needs testing in future work.