Overexpression of Hypoxia-inducible Factor-1alpha Predicts an Unfavorable Outcome in Urothelial Carcinoma of the Upper Urinary Tract

Objectives: Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays an important role in cell hypoxia adaptation. Overexpression of HIF-1alpha subunit has been reported to be involved in the carcinogenesis, progression and metastasis of many human cancers. We evaluated the clinical significance of HIF-1alpha expression in urothelial carcinoma (UC) of the upper urinary tract.

Methods: Ninety-eight cases (mean age = 63.5 +/- 11.7, range = 23-84 years) of renal pelvic or ureter UC were included in the present study. Those who had distant metastasis at diagnosis, other cancer, urolithiasis, incomplete clinical information or had received radiotherapy or chemotherapy before surgery were excluded. Nuclear HIF-1alpha expression were evaluated by immunohistochemistry staining on a paraffin-embedded section of the tumor and non-malignant upper urinary tract specimens and scored by two qualified pathologists. Clinical data were collected retrospectively.

Results: Positive HIF-1alpha expression was found in 65 (66.3%) of the cancer specimens. No HIF-1alpha expression was found in normal urothelial specimens. Tumor HIF-1alpha expression score was significantly correlated with tumor T stage (P < 0.001), N stage (P < 0.001) and grade (P = 0.004). Tumor necrosis was associated with high tumor T stage (P < 0.001), N stage (P = 0.002) and grade (P < 0.001). Higher HIF-1alpha score (negative vs 3-5 vs 6-7) was a significant predictor for cancer-specific survival (Cox regression hazard ratio = 2.23, P = 0.004), and tumor recurrence (Cox regression hazard ratio = 1.58, P = 0.036).

Conclusion: Our findings indicate that HIF-1alpha immunostaining may have an important role in predicting prognosis in upper urinary tract urothelial carcinoma.