Alteration in Urinary Matrix Metalloproteinase-9 to Tissue Inhibitor of Metalloproteinase-1 Ratio Predicts Recurrence in Nonmuscle-invasive Bladder Cancer

Purpose: The purpose is to assess the prognostic significance of matrix metalloproteinase (MMP)-9 in patients with bladder cancer using a combination of ELISA (to measure MMP-9 in voided urine) and immunohistochemistry (to study MMP-9 in bladder tumors). The relationship between MMP-9 and its principal inhibitor, tissue inhibitor of metalloproteinase (TIMP)-1 (in voided urine samples) was also studied. Experimental Design: A total of 134 patients with bladder tumors (7 cis, 76 T a , 27 T 1 , 24 T 2 -T 4 ; 40 G1, 43 G2, and 44 G3), 33 patients with benign urological conditions, and 36 healthy volunteers was studied. Samples from 106 patients with bladder cancer and 12 controls were stained for MMP-9. Clinical follow-up data were available on 116 patients (median: 25 months; range: 4–36 months). Results: MMP-9 was present in all urine samples analyzed. There were no differences between patients with cancer and patients with benign disorders. However, patients had significantly higher urinary MMP-9 than normal volunteers ( P = 0.0167). Urinary MMP-9 was associated with bladder tumors of advanced stage ( P = 0.0065) and large size ( P P = 0.14), multiplicity ( P = 0.31), recurrence ( P = 0.55), progression ( P = 0.83), or survival ( P = 0.55). Low MMP-9:TIMP-1 ratios in patients with nonmuscle-invasive tumors were associated with higher recurrence rates ( P = 0.0035). Sixty percent (64 of 106) of bladder tumor specimens expressed MMP-9 compared with none of 12 normal urothelial biopsies ( P P = 0.014), disease progression ( P = 0.005), and poor disease-specific survival ( P = 0.022) but was unrelated to tumor stage ( P = 0.46), grade ( P = 0.26), multiplicity ( P = 0.85), or recurrence rate ( P = 0.62). Conclusions: High urinary MMP-9 levels are associated with large bladder tumors. A low urinary MMP-9:TIMP-1 ratio may indicate a higher risk of intraluminal nonmuscle-invasive tumor recurrence and may assist in planning follow-up surveillance protocols.