Expression and prognostic significance of matrix metalloproteinases and their tissue inhibitors in primary neuroendocrine carcinoma of the skin

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been implicated in the development and progression of many tumors, but data for primary neuroendocrine carcinoma (PNC) of the skin are lacking. The aim of the study was to assess the expression of MMPs and TIMPs in PNC and to evaluate their prognostic significance. Expression of MMP-1, MMP-2, MMP-3, MMP-9, MMP-11, MMP-13, and MMP-14 and TIMP-1, TIMP-2, and TIMP-3 was evaluated by immunohistochemistry on 23 samples of PNC of the skin. The results were matched with clinical features and patient survival. In the 23 specimens of PNC, high (>20% of positive neoplastic cells) MMP-1 expression was found in 13 (56.5%) cases. MMP-2 was evidenced in 12 (52.1%) cases, 8 (34.7%) of which showed high expression in neoplastic cells. MMP-3 was detected in 11 cases (47.8%), with high expression in 9 (39.1%) of them. High MMP-9 expression was observed in 3 (13%) cases, whereas high MMP-14 expression was detected in 11 (47.8%) specimens. Expression of TIMP-I by neoplastic cells was found in 8 (34.7%) cases, with high expression in 3 cases, whereas high TIMP-3 expression was detected in 21 (91.3%) cases. No immunoreactivity for MMP-11, MMP-13, or TIMP-2 was found. Statistical analysis failed to identify a significant correlation between MMP/TIMP expression and clinical parameters. By univariate analysis, stage >I (P = 0.01), high expression of MMP-1 (P = 0.04) and MMP-3 (P = 0.01) resulted significant negative prognostic factors, whereas by multivariate analysis, stage was the only factor that affected survival (P = 0.02). Our results suggest that MMP-1 and MMP-3 may influence the invasive and metastatic potential of PNCs. It is conceivable that future attempts to specifically block MMP-1 and MMP-3 activity may provide a novel means to inhibit invasiveness and distant spread in selected patients with PNC.