Association of SOX2 Expression with Progression of Cervical Intraepithelial Neoplasia in Females: Whole-Slide Spatial Analysis of 135 Cases

Abstract

Background: Sex-determining region Y-box 2 (SOX2) is a transcription factor essential for the maintenance of cellular pluripotency and epithelial stem cell renewal. Aberrant SOX2 expression has been reported in several squamous epithelial malignancies, suggesting a role in early neoplastic transformation. In the cervix, progressive cervical intraepithelial neoplasia (CIN) is characterized by increasing dysregulation of epithelial differentiation and proliferation, processes in which SOX2 may be critically involved. Emerging evidence indicates that elevated SOX2 expression correlates with higher CIN grades and may contribute to the progression from low-grade to high-grade lesions. Objectives: To evaluate SOX2 expression across CIN grades and its association with disease progression. Methods: In a balanced, archival cohort (n = 135; 27 per group: normal, CIN1, CIN2, CIN3, SCC), whole-slide images were analyzed using a pre-specified QuPath pipeline with fixed thresholds and area normalization. We performed immunohistochemical staining of available archival specimens to assess SOX2 protein expression. For staining, a rabbit monoclonal antibody (clone EP103) was used. Results: By group, the cervical tissues showed the following median expression levels of SOX2: normal tissue 45 [45–55], CIN1 120 [100–130], CIN2 100 [90–150], CIN3 150 [80–180], and SCC 150 [100–200] (trend: ρ = 0.568, p = 6.9 × 10⁻¹³). Conclusions: SOX2 expression was higher in high-grade lesions (CIN III/SCC), consistent with stem cell plasticity and the maintenance of stem cell–like properties by the cells, which, in turn, contribute to lesion progression.