CXCR4 serves as a new pathological biomarker for cortisol-producing adenomas

Abstract Cortisol-producing adenomas (CPA) lack specific pathological markers. This study aims to investigate the expression levels and diagnostic value of CXC chemokine receptor 4 (CXCR4), 11β-hydroxylase (CYP11B1), and aldosterone synthase (CYP11B2) for CPA. We retrospectively included 25 non-functional adrenocortical adenomas (NACA) and 102 functional adrenocortical adenomas (FACA), which comprising 45 CPAs and 57 aldosterone-producing adenomas (APA). Immunohistochemical staining of CXCR4, CYP11B1 and CYP11B2 was performed and quantified by the H-score system. Receiver operating characteristic (ROC) curve analysis was applied to evaluate the diagnostic performance. CXCR4 H-score was significantly higher in FACA compared to NACA (78 vs. 7, P < 0.001). CYP11B1 H-score was significantly higher in CPA than APA (109 vs. 28; P < 0.001), but was not significantly different between CPA and NACA (109 vs. 81, P = 0.202). Notably, CYP11B2 H-score in APA was significantly higher compared to both CPA and NACA. Area under the ROC curve (AUC) of CXCR4 for distinguishing NACA from FACA was 0.982, with an optimal cutoff value of CXCR4 > 18. In FACA group, CYP11B2 demonstrated higher AUC in differentiating CPA from APA compared to CYP11B1 (1.000 vs. 0.782), with an optimal cutoff of CYP11B2 > 76. A dual-marker strategy (CXCR4 > 18 + CYP11B2 ≤ 76) for distinguishing CPA from other adrenocortical adenomas achieved an AUC of 0.983, with a sensitivity of 97.78% and a specificity of 93.90%. Thus, CXCR4 could effectively discriminates FACA from NACA. A dual-marker strategy combined CXCR4 and CYP11B2 represents a promising novel approach for CPA pathological diagnosis.