Clinicopathologic and prognostic significance of matrix metalloproteinases in rectal cancer

Abstract

The aim of this study was to determine the prognostic role of matrix metalloproteinases in rectal cancer. Formalin-fixed and paraffin-embedded tissue sections of 94 rectal carcinomas were used for the immunohistochemical analysis of matrix metalloproteinases (MMP)-2, MMP-7, MT1-MMP, and tissue inhibitor of metalloproteinases (TIMP)-2. Inclusion criteria were sporadic rectal adenocarcinoma resected curatively (including total mesorectal excision), adjuvant radiochemotherapy in UICC stages II and III, and complete intra-institutional follow-up. Results of immunohistochemistry were correlated with clinical and histopathologic data from the prospective rectal cancer registry and prognosis. End points of the prognostic analysis were tumor progression caused by local and/or distant recurrence and 5-year survival (disease-free and overall). To assess prognostic significance, statistics included univariate and multivariate analysis (p<0.05 statistically significant). Of the 94 rectal carcinomas, 35% (33/94) showed an epithelial MMP-2 expression, 77% (72/94) were MMP-2 positive in the stroma. Fifty-four percent (51/94) were MMP-7 positive, and 47% (46/94) were positive for both MT1-MMP and TIMP-2. The stromal MMP-2 staining pattern was correlated with the depth of invasion (pT status, p=0.006) with MMP-7 (p=0.016) and TIMP-2 expression (p=0.036). Positive expression of MMP-2 in tumor epithelium was correlated with MMP-7 (p=0.027), MT1-MMP (p=0.036), and TIMP-2 expression (p<0.0001). A positive staining pattern of MMP-7 was significantly correlated with depth of invasion and TIMP-2 (p<0.01). The positive staining pattern of MT1-MMP was correlated with epithelial MMP-2 (p=0.036), MMP-7 (p=0.004), and TIMP-2 expression (p=0.002). TIMP-2 immunoreactivity correlated with depth of invasion (p=0.013), epithelial MMP-2 (p<0.001), stromal MMP-2 (p=0.036), MMP-7 (p<0.001), and MT1-MMP (p=0.002). Neither pattern correlated with age, gender, tumor stage (UICC), grading, preoperative serum carcinoembryonic antigen (CEA) level, or nodal status (p>0.05). Within a mean follow-up of 46 months, tumor progression, caused by either local recurrence or distant metastasis, occurred in 14 patients (15.4%). There was no significant association between the MMP expression and the incidence of local and/or distant recurrence. In terms of survival, preoperative CEA level (disease-free 5-year survival 46% with increased CEA vs 70% with normal CEA, p=0.01; overall 5-year survival 43 vs 74%, p<0.01) and UICC stage were the only factors to be significantly related to 5-year survival by univariate analysis, whereas the metalloproteinases failed to show a significant association. In multivariate analysis, CEA and UICC stage were not identified as independent factors predictive of survival. MMP-2, MMP-7, MT1-MMP, and TIMP-2 do not appear to be significant predictors of prognosis in a homogenous collective of curatively resected rectal adenocarcinomas.