Association of aromatase with bladder cancer stage and long-term survival: new insights into the hormonal paradigm in bladder cancer

BACKGROUND Hormonal factors may play a role in bladder cancer (BCa). We investigated the expression of aromatase and estrogen receptor (ER)β and its association with pathological variables and survival outcomes. PATIENTS AND METHODS BCa specimens from 40 patients were evaluated. Immunohistochemistry was performed for aromatase and ERβ. Descriptive statistics and univariate analyses assessed the association of these markers with pathologic variables and survival outcomes. RESULTS Aromatase expression was significantly associated with tumor stage; muscle-invasive disease was found in 15 of 19 (79%) patients with positive staining and in 7 of 18 (39%) patients with negative staining (P = .02). Node-positive disease was found in 8 of 19 (42%) patients with positive staining and 1 of 18 (6%) patients with negative staining (P = .01). After a median follow-up of 112 months, Cox regression analysis demonstrated that aromatase expression was associated with a more than 2-fold risk of cancer recurrence (hazard ratio, 2.37; confidence interval, 0.92-6.08; P = .07) and an almost 4-fold higher risk of cancer-specific death (hazard ratio, 3.66; 95% confidence interval, 1.19-12.06; P = .02). Muscle-invasive disease was found in 15 of 18 (83%) ERβ-positive specimens and 4 of 12 (33%) ERβ-negative specimens (P = .0009). Hierarchical clustering analysis demonstrated a 4-fold up-regulation of ERβ gene expression in tumor versus adjacent, non-tumor urothelium (P < .05). However, no significant association with survival outcomes was found. CONCLUSION Aromatase expression in BCa may be associated with advanced tumor stage and poorer survival outcomes. ERβ is upregulated in malignant tissue, and its expression is associated with muscle-invasive disease. These findings provide further evidence for the hormonal paradigm in BCa