Diagnostic Accuracy and Value of 68Ga-Pentixafor PET/MRI in Tumor Localization for Cushing’s Disease

Academic Background

Cushing’s disease is the primary cause of Cushing’s syndrome, characterized by excessive secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland, often due to pituitary adenomas. Patients with chronic hypercortisolemia face various systemic complications, including metabolic, cardiovascular, immunological, and infectious diseases, leading to significantly increased mortality. Currently, endoscopic transsphenoidal surgery is the preferred treatment for Cushing’s disease, but 20%-30% of patients still experience persistent hypercortisolemia (non-remission) postoperatively, primarily due to incomplete tumor resection. Precise preoperative tumor localization can improve surgical outcomes; however, tumor localization in Cushing’s disease is diagnostically challenging, as most (>70%) ACTH-secreting pituitary tumors are microadenomas (<1.0 cm), and 25%-45% of these tumors are undetectable on MRI. Additionally, abnormal MRI signals in the pituitary background do not necessarily indicate functional adenomas, potentially leading to misjudgment during neurosurgery.

Recent research has highlighted the critical role of C-X-C chemokine receptor type 4 (CXCR4) in the neuroimmune regulation of anterior pituitary physiological functions. Overexpression of CXCR4 and its ligand promotes autocrine/paracrine proliferation in pituitary tumor cells, likely contributing to adenoma pathogenesis. The high expression of CXCR4 in ACTH-secreting pituitary tumors suggests its potential as a valuable molecular imaging marker. 68Ga-Pentixafor, a cyclic pentapeptide with high affinity for CXCR4, has been proven to be a suitable PET tracer for neuroendocrine tumors, including adrenal adenomas. This study aimed to evaluate the diagnostic accuracy and value of 68Ga-Pentixafor PET/MRI in localizing ACTH-secreting pituitary tumors in Cushing’s disease.

Source of the Paper

This paper was authored by Yue Wu, Yanfei Wu, Boyuan Yao, et al., from multiple departments including Radiology, Neurosurgery, and Nuclear Medicine at Huashan Hospital, Fudan University. The paper was published in December 2024 in the journal Radiology, titled “Diagnostic Accuracy and Value of CXCR4-Targeted PET/MRI Using 68Ga-Pentixafor for Tumor Localization in Cushing Disease.”

Research Process and Results

Research Process

This prospective single-center study included patients with Cushing’s disease scheduled for pituitary tumor resection from March 2023 to February 2024. All participants underwent preoperative 68Ga-Pentixafor PET/MRI and contrast-enhanced MRI. Two radiologists and nuclear medicine physicians analyzed the images, with surgical and histological findings serving as the reference standard. Diagnostic performance was compared using the McNemar test, and the Wilcoxon signed-rank test was used to compare the maximum standardized uptake value (SUVmax) between tumors and normal pituitary tissue. The correlation between SUVmax and histopathological or hormonal characteristics was analyzed using the Spearman coefficient and logistic regression tests.

Key Results

The study included 43 participants (median age 37 years, 35 females), with 44 pituitary lesions identified through imaging, 41 of which were confirmed as ACTH-secreting tumors. The sensitivity and diagnostic accuracy of 68Ga-Pentixafor PET/MRI were 92.7% (³⁸⁄₄₁ lesions) and 88.6% (³⁹⁄₄₄ lesions), respectively, both higher than those of contrast-enhanced MRI (78.0% [³²⁄₄₁ lesions] and 77.3% [³⁴⁄₄₄ lesions], respectively). When combined, the two techniques improved sensitivity to 100% (⁴¹⁄₄₁ lesions) and accuracy to 95.5% (⁴²⁄₄₄ lesions). The SUVmax of ACTH-secreting pituitary tumors was significantly higher than that of normal pituitary tissue (3.9 vs. 1.3, p < 0.001), and SUVmax showed positive correlations with CXCR4 H-score (r = 0.5, p < 0.001) and ACTH levels (r = 0.4, p = 0.01).

Conclusion

68Ga-Pentixafor PET/MRI demonstrated high sensitivity in localizing ACTH-secreting pituitary tumors, and 68Ga-Pentixafor uptake was associated with CXCR4 expression and ACTH levels. This technique holds promise for improving surgical strategies and remission rates in patients with Cushing’s disease, particularly in MRI-negative cases.

Research Highlights

1. High Sensitivity: 68Ga-Pentixafor PET/MRI demonstrated 92.7% sensitivity in localizing ACTH-secreting pituitary tumors, which increased to 100% when combined with contrast-enhanced MRI.
2. Differentiation Between Tumor and Normal Tissue: The SUVmax of ACTH-secreting pituitary tumors was significantly higher than that of normal pituitary tissue, indicating the technique’s ability to effectively distinguish between tumor and normal tissue.
3. Correlation with CXCR4 Expression: SUVmax showed a positive correlation with CXCR4 expression, suggesting that 68Ga-Pentixafor PET/MRI can reflect the molecular characteristics of the tumor.
4. Clinical Application Value: This technique has the potential to improve surgical strategies for Cushing’s disease patients, particularly in MRI-negative cases, by providing more accurate tumor localization and increasing surgical success and patient remission rates.

Research Significance and Value

This study is the first systematic evaluation of the diagnostic value of 68Ga-Pentixafor PET/MRI in Cushing’s disease, demonstrating its high sensitivity and accuracy in localizing ACTH-secreting pituitary tumors. The technique not only helps physicians more accurately locate tumors but also reflects the molecular characteristics of the tumor through SUVmax, providing a basis for personalized treatment. Particularly in MRI-negative cases, the application of 68Ga-Pentixafor PET/MRI may reduce the need for exploratory surgery and improve surgical success rates and patients’ quality of life. Future research should validate the technique’s diagnostic performance and application value in larger, more heterogeneous Cushing’s disease cohorts and explore its potential in differentiating central and peripheral ACTH secretion.

Other Valuable Information

The study’s limitations include a relatively small sample size, leading to statistical uncertainty, and the lack of healthy participants and other types of pituitary tumors as controls. Future research should expand the sample size to further validate the technique’s diagnostic performance and application value.