Stromal Fibroblast Activation Protein-α (FAP) as a Potential Adjunctive Biomarker of Invasion in the Transition From Laryngeal High-grade Dysplasia to Squamous Cell Carcinoma.

The transition from squamous epithelial dysplasia to invasive laryngeal squamous cell carcinoma (LSCC) is a critical biological and diagnostic step that is difficult to define using morphology alone. Cancer-associated fibroblasts (CAFs) are key mediators of stromal activation during malignant progression, and fibroblast activation protein (FAP) has emerged as a candidate marker of tumor-stroma interaction and invasiveness. We evaluated stromal FAP immunohistochemical expression in laryngeal squamous lesions (n=83), focusing primarily on the diagnostically relevant transition from high-grade dysplasia (HGD, n=23) to invasive LSCC (n=57). The study also included 3 low-grade dysplasias (LGD) to extend the analysis to an earlier stage of noninvasive squamous disease. FAP expression was absent in all LGDs and in 91.3% of HGDs, whereas 93% of LSCCs showed stromal FAP positivity (χ2 test, P=2.3×10-13). Receiver operating characteristic analysis demonstrated high diagnostic accuracy for identifying invasive disease, with a sensitivity of 93%, specificity of 92.3%, and an area under the curve of 0.926 (95% confidence interval: 0.856-0.997). In a subset of HPV-associated carcinomas, focal epithelial FAP expression was also observed. These findings suggest that stromal FAP expression may serve as an adjunctive biomarker to support conventional histopathologic assessment in the recognition of stromal invasion, particularly in the distinction between HGD and invasive LSCC.