Expression of LEKTI correlates with perineural invasion in oral cavity carcinoma

Abstract

6036 Background: Invasion may result from imbalance of proteinase enzymes and their inhibitors that favors degradation of extracellular matrix (ECM). Lymphoepithelial kazal-type inhibitor (LEKTI) is a serine proteinases inhibitor we identified by constitutive expression in normal oral mucosa and lost or downregulated expression in 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 OSC- 19 cells compared to those derived from clones expressing LEKTI. We hypothesized that loss of LEKTI expression in primary tumors correlates with aggressive biologic behavior in patients with HNSCC. 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. Primary tumor specimens were recut and stained with a purified mouse anti-LEKTI monoclonal antibody. Slides were reviewed and scored by two independent investigators. Surgical pathology reports were reviewed for covariate and clinical follow-up data. Time-to-event analysis was performed by 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). 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: 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 aid in the selection of therapeutic approaches. No significant financial relationships to disclose.