Serum and Tumor PD-L1 Expression and Aggressive Clinicopathologic Features in Papillary Thyroid Carcinoma

Importance: Aggressive variants of papillary thyroid carcinoma (PTC) represent a small but clinically consequential subset and may become radioactive iodine refractory, limiting treatment options. Programmed cell death 1 ligand 1 (PD-L1) has been evaluated in tumor tissue as a potential biomarker in PTC, but evidence for serum PD-L1, particularly in aggressive PTC, is limited. Objective: To determine whether serum PD-L1 levels and tumor PD-L1 expression are associated with aggressive clinicopathologic features of PTC. Design, Setting, and Participants: This retrospective cohort study included patients with PTC undergoing serum PD-L1 measurement by enzyme-linked immunosorbent assay and tumor PD-L1 by immunohistochemistry (E1L3N) at the Louisiana State University Health Shreveport and Overton Brooks Veterans Affairs Medical Center. Healthy controls, patients with benign thyroid disease, and patients with PTC (including aggressive and nonaggressive disease) were included. Statistical comparisons were performed using linear and logistic regression. Data were collected from January 2009 to December 2024, and data were analyzed from February to August 2025. Exposures: PTC was classified as aggressive if it demonstrated 1 or more of the following, defined a priori per the 2025 American Thyroid Association Risk of Recurrence framework: (1) macroscopic extrathyroidal extension, (2) bulky or invasive lymphadenopathy, (3) aggressive histology (tall cell, columnar cell, solid, or diffuse sclerosing variant), or (4) distant metastases. Main Outcomes and Measures: Differences in serum PD-L1 levels and tumor PD-L1 expression between aggressive and nonaggressive PTC; associations between serum PD-L1 and specific aggressive features; and correlation between serum PD-L1 levels and tumor PD-L1 expression. Disease-free survival (DFS) was analyzed using Kaplan-Meier estimator and Cox proportional hazards regression to evaluate the prognostic value of tumor and serum PD-L1 on recurrence outcomes. Results: Of 156 included patients, 116 (74.4%) were female and 40 (25.6%) were male, with a mean (SD) age of 49.2 (15.6) years. A total of 45 patients were healthy controls, 49 had benign thyroid disease, and 62 had PTC, including 31 with aggressive disease and 31 with nonaggressive disease. Serum PD-L1 levels were markedly higher in patients with aggressive PTC compared with healthy controls (β = 23.40; 95% CI, 9.12-37.67), benign thyroid disease (β = 20.78; 95% CI, 6.80-34.77), and nonaggressive PTC (β = 24.92; 95% CI, 8.95-40.88). On adjusted linear analysis of aggressive features, macroscopic extrathyroidal extension (β = 42.07; 95% CI, 23.04-61.10) and aggressive histology (β = 181.15; 95% CI, 126.08-236.23) were associated with higher serum PD-L1 levels but not bulky/invasive lymphadenopathy and distant metastasis. Tumor PD-L1 positivity was associated with BRAF V600E variation in PTC (odds ratio, 5.06; 95% CI, 1.03-30.67), with a stronger association after adjustment for PTC aggressiveness (odds ratio, 6.06; 95% CI, 1.12-43.63). Serum PD-L1 levels were not correlated with tumor PD-L1 expression (r = 0.17; 95% CI, -0.14 to 0.46). Conclusions and Relevance: In this cohort study, higher serum PD-L1 levels were associated with aggressive clinicopathologic features of PTC but not tumor PD-L1 expression. Serum PD-L1 may be a useful prognostic biomarker for aggressive PTC, including in settings where tumor PD-L1 assessment may be limited by sampling error and intratumoral heterogeneity.