Salivary IL-8, CYFRA 21-1, and CD44 for early detection of oral squamous cell carcinoma: a systematic review and meta-analysis

Abstract

Objective: Early diagnosis of oral squamous cell carcinoma (OSCC) is a global concern, particularly in low-resource environments where invasive diagnostics limit population-wide screening. The purpose of this review is to evaluate the potential of salivary biomarkers: Interleukin-8 (IL-8), Cytokeratin 19 fragment (CYFRA 21-1), and Cluster of Differentiation 44 (CD44) in OSCC diagnosis.

Methods: A methodical search was conducted across PubMed, Embase, Scopus, and Web of Science databases till December 2024. Following PRISMA guidlines, studies quantifying salivary IL-8, CYFRA 21-1, and CD44 levels in OSCC patients and healthy controls were included. Using a bivariate random-effects model, we retrieved and combined sensitivity, specificity, and area under the summary receiver operating characteristic (SROC) curve. The QUADAS-2 tool was used to evaluate risk of bias. A standardized mean difference (SMD) meta-analysis was also performed to assess quantitative elevation in biomarker levels between cases and controls.

Results: Out of 311 articles reviewed, 20 eligible studies were included. IL-8, CYFRA 21-1, and CD44, individually, each biomarker demonstrated good diagnostic accuracy (with pooled AUCs of 0.88, 0.90, and 0.91, respectively), with CD44 showing overall highest diagnostic consistency. The combined biomarker panel exhibited significantly enhanced diagnostic precision (pooled AUC: 0.92; sensitivity: 88 %; specificity: 90 %). This combined metric was derived using a bivariate meta-analysis model applied to studies that evaluated at least two or more of the three biomarkers together. These findings were supported by corresponding forest plots and SROC curves, demonstrating low publication bias and moderate heterogeneity. Consistency across sample size, geographic origin, and assay technique were verified by subgroup analyses.

Conclusion: Salivary IL-8, CYFRA 21-1, and CD44 taken together provide a scientifically strong, non-invasive method for OSCC diagnosis on a uniform diagnostic panel. With good translational potential in both clinical and community-based screening systems. These results provide a strong scientific foundation for the development of a saliva-based point-of-care test (POCT) kit.

Keywords: CD44; CYFRA 21-1; Diagnostic; IL-8; OSCC; POCT; Salivary biomarkers.