To determine the role of the
cysteine proteinase inhibitor cystatin C in the invasive behavior of
squamous cell carcinoma of the head and neck (SCCHN),
Cystatin C protein level was measured in 82 pairs of primary tumour tissue and adjacent noncancerous mucosa, using the
enzyme-linked
immunosorbent assay. The median level of
cystatin C in tumour tissue was 1.18 times lower than that in corresponding mucosa (P=0.031). In normal mucosa samples, the
cystatin C level was influenced by the site of sampling: it was lower in nonlaryngeal tissue samples (oral cavity, oro- or hypopharynx) than in laryngeal samples (P=0.004). The tumour
cystatin C level correlated inversely with pN-stage (P=0.047), whereas a trend of lower
cystatin C levels was observed in the group with extranodal tumour extension compared to those with no extranodal spread (P=0.069). In univariate analysis, the patients with low tumour
cystatin C levels exhibited poor disease-free survival (DFS, P=0.013) and disease-specific survival (DSS, P=0.013). In multivariate analysis, the most powerful predictor of survival was pN-stage (DFS: P=0.040, HR 2.78; DSS: P=0.011, HR 4.36,), followed by the
cystatin C level (DFS: P=0.043, HR 0.22; DSS: P=0.067, HR 0.25). When comparing the prognostic strength of
cystatin C to that of
stefin A, another
cysteine proteinase inhibitor, which emerged as the most significant prognosticator for survival in our previous study analysing the same cohort of patients,
stefin A proved to be significantly more reliable predictor for both DFS and DSS than
cystatin C. Our results indicate that
cystatin C is implicated in the invasive behavior of SCCHN, and that there are variations in regulation of proteolytic pathways under nonmalignant conditions, inherent to individual subsites inside the upper aerodigestive tract. The correlation between high
cystatin C levels and improved survival concurs with the concept of the protective role of high levels of
cysteine proteinase inhibitors in tissue homogenates that has been previously suggested by the survival results in breast and lung
carcinoma as well as SCCHN.