The value of targeting CXCR4 with 68Ga-Pentixafor PET/MRI for Cushing's disease: a retrospective cohort study.

PURPOSE: 68Ga-pentixafor PET/MRI, which targets the C-X-C chemokine receptor type 4 (CXCR4), has been shown to significantly enhance lesion localization accuracy in Cushing’s disease (CD). However, a subgroup of CD tumors exhibits both reduced 68Ga-pentixafor uptake and low CXCR4 expression. In this study, we propose a CXCR4-based stratification of CD patients to evaluate the utility of this stratification for improving lesion localization accuracy, delineating clinical characteristics, predicting survival outcomes, and characterizing mutational features. METHODS: This retrospective study analyzed 138 patients with surgically and pathologically confirmed CD. Patient subsets underwent 68Ga-Pentixafor PET/MRI (n = 78), CXCR4 immunohistochemistry (n = 116), and targeted gene sequencing (n = 129). Follow-up data were available for 115 patients. RESULTS: The localization sensitivity and diagnostic accuracy of 68Ga-pentixafor PET/MRI reached 98.7% and 96.3% respectively, when combined with conventional contrast-enhanced MRI. The entire retrospective cohort (n = 138) was stratified into CXCR4-high (n = 95) and CXCR4-low (n = 43) groups using receiver operating characteristic (ROC) analysis. Compared with the CXCR4-high group, the CXCR4-low group exhibited a higher proportion of relapsed tumors (P = 0.005), a lower proportion of hypokalemia (P = 0.005), larger tumor diameter (P = 0.026) and volume (P = 0.013), lower ACTH staining intensity (P < 0.001), and worse progression-free survival (PFS) after 2.5 years (P = 0.041). The prevalence of tumors harboring ubiquitin-specific peptidase 8 (USP8) hotspot mutations was significantly lower in the CXCR4-low group (P = 0.04) among macroadenomas but not among microadenomas. CONCLUSION: CXCR4-targeted 68Ga-pentixafor PET/MRI helps achieve consistently high accuracy in localizing ACTH-secreting pituitary neuroendocrine tumors. CXCR4 expression demonstrates potential utility for stratifying CD patients, particularly for subtyping macroadenoma.