Claudin-4 Expression as a Prognostic Biomarker in Colorectal Adenocarcinoma: Correlation with Lymphovascular Invasion, Lymph Node Metastasis, and Pathological Stage

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer mortality worldwide, with increasing incidence in Asia, including Indonesia. Claudin-4, a tight junction protein, plays a paradoxical role in epithelial barrier function and tumor progression. This study aimed to investigate the relationship between Claudin-4 expression and major prognostic parameters in colorectal adenocarcinoma. A total of 104 formalin-fixed paraffin-embedded tissue blocks of colorectal adenocarcinoma were analyzed immunohistochemically. Claudin-4 expression was categorized as strong (79.8%) or weak (20.2%) based on the Total Immunostaining Score (TIS). Statistical analysis revealed no significant association between Claudin-4 expression and age, sex, tumor location, or size. However, Claudin-4 expression was significantly negatively correlated with lymphovascular invasion (p = 0.020; OR = 0.314, 95% CI 0.114 - 0.861), lymph node metastasis (p = 0.011; OR = 0.283, 95% CI 0.103 - 0.778), and pathological stage (p = 0.028). No significant correlation was observed with distant metastasis. These findings suggest that Claudin-4 may serve as a prognostic biomarker reflecting tumor invasiveness, supporting its potential role in guiding risk stratification in CRC patients. HIGHLIGHTS Most colorectal adenocarcinoma cases (79.8%) showed strong Claudin-4 expression by immunohistochemistry. Low Claudin-4 expression was significantly linked to lymphovascular invasion and lymph node metastasis. Strong Claudin-4 expression was more common in early pathological stages, while advanced stages showed reduced expression. This study provides the first evidence from Indonesia on the prognostic role of Claudin-4 in colorectal adenocarcinoma. Findings support Claudin-4 as a promising biomarker to improve risk stratification in colorectal cancer patients. GRAPHICAL ABSTRACT

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