# Tissue IL-6/LIF/LIFR and CXCL9 Expression Correlates with High-Risk NBI Patterns and Squamous Cell Carcinoma in Vocal Fold Lesions

## TL;DR

This study finds that specific tissue markers correlate with high-risk NBI patterns and SCC in vocal fold lesions, potentially improving preoperative risk assessment.

## Contribution

The study identifies novel associations between IL-6/LIF/LIFR and CXCL9 expression and high-risk NBI patterns in vocal fold lesions.

## Key findings

- Ni ≥ 4 was the strongest independent predictor of SCC with high diagnostic accuracy.
- LIF and LIFR expression decreased with higher histopathological severity and NBI risk categories.
- CXCL9 increased with more suspicious NBI patterns, suggesting a complementary role in SCC risk stratification.

## Abstract

Laryngeal squamous cell carcinoma (SCC) remains a major clinical challenge due to substantial mortality and limited preoperative risk stratification. Narrow-Band Imaging (NBI) enables real-time visualization of mucosal microvasculature, yet the molecular correlates of high-risk NBI phenotypes in vocal fold lesions are incompletely defined. In a prospective cohort of 145 patients with vocal fold lesions, NBI microvascular patterns were graded using the Ni classification and dichotomized using a pre-specified high-risk threshold (Ni ≥ 4 vs. Ni ≤ 3). Histopathology was classified according to WHO 2017. Epithelial expression of IL-6, LIF, LIFR and CXCL9 was quantified by immunohistochemistry using the immunoreactive score (IRS). Associations were tested using non-parametric methods and logistic regression, and diagnostic performance was assessed by ROC analysis. SCC was diagnosed in 63/145 cases. The Ni category showed a strong stepwise association with WHO 2017 histopathological severity. Using Ni ≥ 4, diagnostic performance for SCC was balanced (sensitivity 82.5%, specificity 82.9%; accuracy 82.8%). LIF and LIFR expression decreased with increasing histopathological severity and higher-NBI-risk categories, whereas CXCL9 increased with more suspicious NBI patterns; epithelial IL-6 did not differ across lesion categories. In multivariable logistic regression, Ni ≥ 4 was the strongest independent predictor of SCC (adjusted OR 8.90), while higher LIF (adjusted OR 0.73) and LIFR (adjusted OR 0.78) were independently associated with lower odds of SCC (model AUC 0.943). Multivariable analysis confirmed NBI as the strongest independent predictor of carcinoma, while epithelial LIF and LIFR expression showed inverse associations with histological malignancy and high-risk NBI vascular patterns. LIF/LIFR and CXCL9 show distinct, biologically plausible associations with NBI risk phenotypes, suggesting that selected tissue markers may complement NBI for refined SCC risk stratification.