Genomic Characterization of Papillary Thyroid Carcinoma: Age Differences in Tumor Aggressiveness and Immune Infiltration

<b>Background:</b> Adolescents and young adults (AYA) with papillary thyroid carcinoma (PTC) often present with more extensive cervical lymph node metastasis (LNM) than older adults (AD). We aimed to identify age-associated molecular and immune features that might explain this phenotype and to explore potential translational implications for managing aggressive AYA PTC. <b>Methods:</b> We analyzed clinical and transcriptomic data from 501 PTC cases in The Cancer Genome Atlas (TCGA), stratified as AYA (<30 years, n = 64) and AD (≥30 years, n = 437). An institutional RNA-seq cohort (n = 13; 7 AYA, 6 AD) was used to screen for differentially expressed genes (DEGs). DEGs were defined by <i>p</i> ≤ 0.05 and |log2 fold change| ≥ 1. Intersection with invasion- and dissemination-related gene sets yielded a final age-related DEG list. Functional enrichment (GO/KEGG via DAVID), PPI network analysis (STRING, Cytoscape/cytoHubba), and immune deconvolution (CIBERSORT LM22) were performed. Protein-level validation was carried out by immunohistochemistry (IHC) in an independent cohort (n = 56; 28 AYA, 28 AD). Statistical comparisons used chi-square/Fisher's exact tests for categorical variables, <i>t</i>-tests or nonparametric tests for continuous variables, and EdgeR with FDR correction for transcriptomic analyses. <b>Results:</b> In TCGA, LNM was more frequent in AYA than in AD (62.1% vs. 47.8%, <i>p</i> = 0.031). From intersected analyses, we identified 239 core DEGs distinguishing highly invasive, age-related tumors. Key upregulated genes in AYA included <i>CXCR4</i>, <i>OPCML</i> and <i>S100A2</i>; downregulated genes included <i>ATP1A3</i>, <i>CHL1</i>, <i>HLA-DRA</i> and <i>IL-1β</i>. Enriched pathways involved extracellular matrix organization, cell adhesion, calcium signaling and canonical oncogenic cascades (PI3K-Akt, MAPK, Wnt, Ras). Immune deconvolution showed reduced naïve B cells, M1 and M2 macrophages and resting mast cells and an increased proportion of M0 macrophages in AYA tumors. IHC validated differential protein expression for seven markers. Collectively, the data indicate an immune-suppressed, immune-excluded microenvironment in AYA PTC. <b>Conclusions:</b> AYA PTC exhibits distinct molecular and immune features that may underlie its propensity for lymphatic dissemination. These findings support evaluation of translational strategies, such as CXCR4 inhibition, restoration of antigen presentation, and macrophage reprogramming, to convert "cold" tumors into immune-permissive lesions. Validation in larger, prospective, multicenter cohorts is required.