Prognostic significance of cysteine proteinases cathepsins B and L and their endogenous inhibitors stefins A and B in patients with squamous cell carcinoma of the head and neck

Cysteine proteinases cathepsins (Cats) B and L and their endogenous inhibit ors stefins (Stefs) A and B are implicated in the processes of local and me tastatic tumor spread. They were identified as potential prognosticators in various malignant diseases, particularly in breast cancer. The aim of the present study was to determine the concentrations of Cats B and L and Stefs A and B in the tumor and adjacent normal tissue samples collected from 49 patients (the present group) with squamous cell carcinoma of the head and n eck (SCCHN), using quantitative immunosorbent assays (ELISA; KRKA d.d., Nov o mesto, Slovenia), Their clinical significance was compared with that from a previous study (the reference group, 45 patients; Budihna et al., Biol, Chem, Hoppe-Seyler, 377: 385-390, 1996), The follow-up of patients from the latter report was updated for this purpose. In the present group, signific antly higher concentrations of Cat B (P < 0.0001), Cat L (P < 0.0001) and S tef A (P = 0.006) were found in tumors compared with concentrations in thei r normal tissue counterparts. Cat concentrations in normal laryngeat tissue were significantly/marginally elevated compared with nonlaryngeal tissue ( Cat B, P = 0.02; Cat L, P = 0.06), The tumor concentration of Cat L was fou nd to correlate with pT classification (P = 0.005) and tumor-node-metastasi s stage (P = 0.05), whereas the concentrations of Stefs A and B correlated with pN classification (P = 0.007 and P = 0.03, respectively) and tumor-nod e-metastasis stage of the disease (P = 0.02 and P = 0.03, respectively). Th ere was no statistically significant difference between low and high Cat B or Cat L groups, regarding either disease-free survival or disease-specific survival, using a minimum P approach to determine cutoff concentrations. T he risk of disease recurrence and SCCHN-related death was significantly hig her in patients with low Stef A (P = 0.0006 and P = 0.0005, respectively) a nd Stef B (P = 0.0009 and P = 0.0007, respectively) tumors, compared with t hose with high-Stef A and Stef B tumors. These results remained significant even after Ps were adjusted for a possible bias in the estimated effect on survival. The survival analysis in the reference group also confirmed thes e findings (Stef A: P = 0.0009 and P = 0.002, respectively; Stef B: P = 0.0 3 and P = 0.009, respectively). To avoid any possible bias arising from the differences between the laboratories that performed the biochemical analys is, the concentrations of both Stefs in the present group and in the refere nce group were standardized and coupled together to form a uniform group. I n univariate survival analysis, standardized values of Stef A and Stef B co rrelated inversely with the rate of relapse (P = 0.0000) and mortality rate (P = 0.0000), Multivariate regression analysis showed that the standardize d value of Stef A is the strongest independent prognostic factor for both d isease-free survival and disease-specific survival, These findings show the specific role of Cats B and L and Stefs A and B in the invasive behavior o f SCCHN, Furthermore, Stef A proved to be a reliable prognosticator of the risk of relapse and death in patients with this type of cancer.