Increased expression of matrix metalloproteinase‐2 and tissue inhibitor of metalloproteinase‐2 is correlated with poor prognostic variables in patients with thymic epithelial tumors

Abstract

BACKGROUND A distinction between noninvasive, invasive, and metastatic thymoma on the basis of the cytologic features is difficult. The current study investigated whether the expression of MMP and TIMP was correlated with tumor invasiveness and prognosis in patients with thymoma. METHODS Tumor tissue samples were obtained from 42 patients with thymic epithelial tumors between 1974 and 2001 at Tokushima University Hospital. Three‐micrometer‐thick, formalin‐fixed, paraffin‐embedded tissue sections were immunostained using specific antibodies against MMP‐2, MMP‐9, TIMP‐1, and TIMP‐2. RESULTS MMP‐2 expression was detected in 30 tumors (71%), and TIMP‐2 expression was detected in 31 tumors (74%). MMP‐9 expression was detected in 22 of 36 tumors (61%), and TIMP‐1 expression was detected in only 7 tumors (19%). MMP‐2 and TIMP‐2 expression levels were very low (10% and 0%, respectively) in noninvasive tumors but were very high (91% and 97%, respectively) in invasive tumors. In thymic epithelial tumors, the more progressive the clinical stage of tumor, the higher the strongly positive rate of MMP‐2 and TIMP‐2 expression. There was no correlation between positivity for MMP‐9 and stage. Twenty‐five percent of Type AB thymomas and 50% of Type B1 thymomas expressed MMP‐2 and TIMP‐2. Most of Type A, Type B2, Type B3, and Type C thymomas expressed MMP‐2 and TIMP‐2. There were significant differences in disease‐free survival at 5 years between patients without and with MMP‐2 expression (91% vs. 55%, respectively) and patients without and with TIMP‐2 expression (100% vs. 53%, respectively). CONCLUSIONS MMP‐2 and TIMP‐2 are key enzymes for invasiveness of thymic epithelial tumors. The expression of these proteins can predict a poor outcome in patients with thymoma. Cancer 2003. © 2003 American Cancer Society.

Serum Tissue Inhibitors of Metalloproteinase-1 and -2 in Patients with Non-Small Cell Lung Cancer

“…11 An immunohistochemical reaction for TIMP-2 was also observed in the basal cell hyperplasia or squamous metaplasia. 11 Sogawa et al 13 reported that immunostained TIMP-2 expression levels were very low in patients with noninvasive thymic epithelial tumors, but very high in those with invasive tumors. Therefore, we considered that SCC contained more of an epithelium component than adenocarcinoma, resulting in greater overexpression of TIMP-2.…”

Clinical and pathological aspects of thymic epithelial tumors

“…Matrix metalloproteinase and tissue inhibitor of metalloproteinase were suggested to be involved in invasiveness. 36,37 Comparisons of gene expression between early and late stages by DNA microarray analysis revealed differences in c-Jun and AL050002 (unknown gene), and these genes were expressed in type B3 at a higher level than in type AB, B1, and B2 thymomas. 38 Results from the analysis of chromosomal imbalances are compatible with the indolent behavior of type A and AB thymomas and the aggressive nature of type B3.…”

Aberrant methylation of tumour-related genes in thymic epithelial tumours

“…As distinguishing between non-invasive, invasive, and metastatic thymomas on the basis of the cytologic features is difficult, several studies have assessed factors associated with the invasiveness of thymoma [3,[6][7][8][9][10][11]; however, few studies have addressed the genetic alterations that occur in the tumourigenesis of thymoma [10,[12][13][14][15][16].…”

“…Distinguishing non-invasive, invasive, and metastatic thymomas on the basis of their cytologic features is difficult; however, thymic carcinoma and thymoma can be distinguished histologically in most cases [1,2,4,5]. Several studies have assessed factors associated with the invasiveness of thymoma, such as the nuclear areas of epithelial cells, the nuclear DNA content, proliferative activity (proliferating cell nuclear antigen, Ki-67, mitotic figures), the argyrophilic nucleolar organizer region, p53 expression and metalloproteinases [6][7][8][9][10][11]; however, few studies have addressed the genetic alterations that occur in the tumourigenesis of thymoma [10][11][12][13][14][15][16].…”