Objective: Invasion may result from imbalance of proteinase enzymes and their inhibitors in the microenvironment that favors degradation of extracellular matrix (ECM). Lymphoepithelial kazal-type inhibitor (LEKTI) is an endogenous inhibitor of serine proteinases we identified by constitutive expression in normal oral mucosa and lost or downregulated expression patients with head and neck squamous cell carcinoma(HNSCC). Previously, we found that expression of LEKTI in HNSCC cell lines regulates the expression and secretion of matrix metalloproteinases critical to ECM degradation. Furthermore, using an orthotopic mouse model, we found increased perineural invasion (PNI) in tongue tumors derived from parental or vector OSC-19 cells compared to those derived from clones expressing LEKTI. Accordingly, we hypothesized that loss of LEKTI expression in primary tumors correlates with aggressive biologic behavior in patients with HNSCC. To determine the significance for the loss of LEKTI expression, we investigated the expression of LEKTI in primary tumor specimens of patients with tongue cancer.
Methods: We assembled a retrospective, inception cohort of 81 consecutive, previously untreated patients who underwent surgery as initial treatment for SCC of the oral tongue with at least 18 months of follow-up. The primary tumor specimens were recut and stained with a purified mouse anti-LEKTI monoclonal antibody. Slides were reviewed and scored by two independent investigators. The surgical pathology reports were reviewed for histopathologic features of the primary tumor. Medical records were reviewed for covariate and clinical follow-up data. Time-to-event analysis was performed with the Kaplan-Meier method for patients stratified by LEKTI-staining pattern. >Results: LEKTI expression was negative in 31, intermediate in 44, and strong in 6 patients. PNI was present in 12 of 31 patients with LEKTI-negative tumors, in contrast to 6 of 50 patients with LEKTI-positive tumors. Therefore, the relative risk of PNI was 3.2 (95% CI from 1.2 to 8.9) in patients with LEKTI-negative tumors compared to those LEKTI-positive tumors (p = 0.007 by Chi Square Test). Analysis of the covariates for disease recurrence and death found no significant differences in age, gender, T-stage, grade, N-stage, and postoperative treatment between patients with LEKTI-negative and LEKTI-positive tumors. Patients with LEKTI-negative expression had a 20% increased risk of disease recurrence (HR 1.2 and 95% CI 0.61 to 2.33, p = 0.23 by Logrank test) and an 80% increased risk of death from all causes (HR 1.8 and 95% CI 0.34 to 9.41, p = 0.48). >Conclusions: These data confirm our previous in vitro and in vivo findings that loss of LEKTI expression in HNSCC results in a cellular phenotype with locally aggressive behavior. Our findings shed new light on mechanisms of PNI, offer prognostic value, and may bring insight into patient selection for therapeutic approaches.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA