Expression of LEKTI Correlates With PNI and LVI In SCC of the Oral Tongue and Mechanism of LEKTI Loss in HNSCC

Abstract

Expression of Lympho-Epithelial Kazal-Type-Inhibitor (LEKTI), a broad spectrum protease inhibitor, is dysregulated in head and neck squamous cell carcinomas (HNSCC) and HNSCC cell lines. Here, we investigated expression of LEKTI in primary tumor specimens of 81 patients with SCC of the oral tongue in correlation with pathologic findings and clinical outcomes. IHC analyses have shown that LEKTI expression is negative in 31, intermediate in 44, and strong in 6 patients. Correlative analyses between LEKTI expression and perineural Invasion (PNI) and lymphovascular invasion (LVI) demonstrated that the relative risk of PNI and LVI were 3.2 (95% CI, 1.2 to 8.9, p = 0.007 by Chi Square Test) and 6.0 (95% CI 1.2 to 40.8, p = 0.01 by Fisher’s Exact Test) respectively in patients with LEKTI-negative tumors compared to those with LEKTI-positive tumors. Kaplan-Meier estimates showed that patients with LEKTI-negative expression had a 20% increased risk of disease recurrence (HR 1.19 and 95% CI 0.61 to 2.33, p = 0.23 by Log rank test) and an 80% increased risk of death from all causes (HR 1.78 and 95% CI 0.34 to 9.41, p = 0.48 by Log rank test). Analysis of the covariates for disease recurrence and death in tongue cohort found no significant differences in age, gender, T-stage, grade, N-stage, and postoperative treatment between patients with LEKTI-negative and LEKTI-positive tumors. Further, we present evidence that transcriptional regulation is a very likely mechanism accounting for loss of LEKTI mRNA and protein from HNSCC. These data confirm our previous in vitro and orthotopic model of tongue cancer findings and shed new light on mechanisms of PNI and LVI in HNSCC.