Abstract / Summary
Abstract Background Prostate-specific membrane antigen (PSMA) is expressed in tumor-associated neovasculature and has been linked to aggressive disease and incomplete response to radioiodine (RAI) therapy in thyroid cancer, but validation in larger cohorts is limited. We investigated the association between endothelial PSMA expression and aggressive clinicopathological features in papillary thyroid carcinoma (PTC), and its association with initial RAI therapy response. Methods This retrospective single-center cohort study included 241 patients with classical PTC who underwent total thyroidectomy and initial RAI therapy. PSMA expression was assessed by immunohistochemistry in tumor endothelial cells using a composite score and categorized as none, low, medium, or high. Treatment response was classified according to the 2015 American Thyroid Association guidelines; excellent and indeterminate responses were grouped as favorable response, and biochemical and structural incomplete responses as incomplete response. Univariate and multivariate logistic regression analyses were performed. Results PSMA was expressed predominantly in tumor-associated endothelial cells and was absent in PTC cells, normal thyroid tissue, and Hashimoto’s thyroiditis; PSMA expression was detectable in 80.1% of patients. Higher PSMA expression was significantly associated with larger tumor size, multifocality, capsular invasion, extrathyroidal extension, aggressive histological variants, higher Ki-67 index, and higher recurrence risk stratification (all P < 0.05). In multivariate analysis, higher PSMA expression, high-risk recurrence stratification (vs intermediate-risk), and higher Ki-67 index were independently associated with short-term incomplete response to initial RAI at 6–12 months (all P < 0.05). The incomplete response rate increased from 12.1% in the low-PSMA group to 50.0% in the high-PSMA group. In the high-risk subgroup, nodal metastasis, higher Ki-67 index, and higher PSMA expression remained significantly associated with incomplete response. Conclusions In this retrospective PTC cohort, endothelial PSMA expression was associated with aggressive clinicopathological features and independently with short-term incomplete response to initial RAI at 6–12 months. These findings support PSMA as a candidate stromal/vascular biomarker for further investigation. Given its predominantly vascular expression and short follow-up, prospective long-term studies are needed to define its potential clinical utility in refining risk stratification.