ContextMorbidity of papillary thyroid carcinoma (PTC) is primarily related to locoregional and distant metastases. Extrathyroidal extension (ETE) is associated with adverse outcomes; however, the biological heterogeneity across its degrees – particularly minimal (mETE) versus gross ETE (gETE) – remains incompletely characterized. While BRAFV600E and TERT promoter (TERTp) mutations have been linked to aggressive disease, their contributions to ETE severity are not fully established. ObjectiveThis study aimed to compare clinical outcomes across different degrees of ETE and evaluate the association between molecular alterations and local aggressiveness in PTC. MethodsA total of 352 PTCs (242 mETE; 81 gETE-T3; 29 gETE-T4) were evaluated for lymph node and distant metastases, disease recurrence/persistence, and response to therapy. BRAFV600E and TERTp (C228T/C250T) mutations were analyzed in 68 mETE and 28 gETE tumors and correlated with clinical outcomes. ResultsIncreasing ETE severity was associated with progressively higher risks of lymph node and distant metastases, recurrence/persistence, and incomplete response to therapy (all P < 0.001), independent of other risk factors. BRAFV600E prevalence did not differ between tumors with mETE (82.4%) and gETE (71.4%). In contrast, TERTp mutations were more frequent in gETE (46.4%) than mETE (16.2%; P = 0.002) and were independently associated with gETE, distant metastases, and incomplete response to therapy. ConclusionGross ETE is associated with progressively worse clinical outcomes, particularly in gETE-T4 tumors. While BRAFV600E does not distinguish microscopic from macroscopic invasion, TERTp mutations are associated with invasive local behavior, distant metastases, and incomplete response to therapy. These findings suggest that TERTp status may refine risk stratification in PTC with extrathyroidal extension.
ObjectiveThe high prevalence of thyroid nodules and the frequent occurrence of nondiagnostic (ND) results on fine-needle aspiration (FNA) necessitate malignancy risk stratification to balance cancer detection while avoiding unnecessary repeat biopsies. This study evaluated malignancy rates and management strategies for nodules with ND cytology, stratified by the American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) score. MethodsThis retrospective study analyzed 342 consecutive patients with initial ND ultrasound-guided (USG) thyroid FNA at a high-volume, two-practitioner clinic between January 2019 and June 2024. Data collected from chart reviews included Bethesda cytopathology classifications, management approaches, and final histopathological diagnoses when available. ResultsAmong 3,717 thyroid FNAs performed during the study period, 342 (9.2%) were ND on initial sampling. The TI-RADS (TR) distribution for ND nodules was as follows: TR1 9.6%, TR2 9.9%, TR3 28.1%, TR4 45.3%, and TR5 7.0%. Initial management comprised repeat FNA in 170 (49.7%) patients, ultrasound (US) surveillance in 101 (29.5%), and surgery in 17 (5.0%); 54 (15.8%) patients were lost to follow-up. Of the repeat FNAs, 47 (27.6%) remained ND. Of the 33 surgical cases, malignancy was identified in six (1.8%) index nodules with initial ND cytology. Five malignancies occurred in TR4 nodules and one in a TR5 nodule. Importantly, no malignancies were identified among the 17 resected TR1–3 nodules. ConclusionFor experienced practitioners in a high-volume clinic, ND thyroid FNA cytology carries a low overall observed risk of malignancy (1.8%). TI-RADS scores should be taken into consideration to guide management decisions for ND cytology nodules between repeat FNA, US surveillance, or surgery.
Abstract The review of achievements in thyroid cancer (TC) transcriptomics aims to show how they have deepened our understanding of the processes underlying malignant transformation and the mechanisms of TC progression. The review starts with the earliest studies on the gene expression profile of papillary thyroid cancer (PTC), briefly describes diagnostic advances enabled by transcriptomic methods, and focuses on mechanisms in which interactions between tumor cells and the microenvironment are crucial for the progression from papillary to anaplastic cancer. A deeper understanding of these processes was possible with single-cell RNA-seq. Such studies identified subpopulations in the tumor microenvironment, including cancer-associated fibroblasts (CAFs) and immune cells, that exhibit marked differences in their molecular phenotypes. Taken together, these findings extended the scope of TC transcriptomics beyond the characterization of malignant thyroid cells alone and highlighted the dynamic interactions between tumor cells and the surrounding microenvironment. Single-cell RNA-seq of aggressive TC supports the concept that stromal remodeling is closely associated with TC dedifferentiation and gives new insights into the mechanisms underlying PTC progression. In conclusion, transcriptomic research has substantially changed our understanding of TC biology. It has provided not only diagnostic tools that enable accurate decisions regarding the need for thyroid surgery in cytologically indeterminate thyroid nodules but has also enhanced our understanding of the mechanisms underlying the PTC transition to anaplastic cancer. Although conclusions drawn from transcriptomic studies require independent validation, the insights gained from these studies provide a comprehensive view of the mechanisms of TC progression and are likely to find clinical applications.
ObjectiveThyroid nodules with indeterminate cytology often undergo diagnostic surgery despite a relatively low risk of malignancy, and molecular testing is limited by cost and availability. Because the Warburg effect is independent of cytological category, we evaluated intranodular lactate across all Bethesda categories, with emphasis on indeterminate cytology. MethodsThis is a prospective, cross-sectional study of 338 surgically treated thyroid nodules at a single tertiary referral center, with histopathology as the reference standard. Nodules were classified according to the Bethesda System and TI-RADS. Lactate was measured with a portable analyzer from the solid component of each nodule and from extranodular thyroid parenchyma, with capillary lactate as a systemic control. Performance was assessed using ROC analysis, sensitivity, specificity, likelihood ratios, and Bayesian post-test probabilities. ResultsLactate increased progressively from extranodular parenchyma (1.85 ± 0.49 mmol/L) to benign (2.30 ± 0.96) and malignant nodules (4.69 ± 1.92 mmol/L; P < 0.0001). The optimal cutoff was 3.0 mmol/L (AUC: 0.90 overall; 0.83 in Bethesda III–IV), with 91% sensitivity and 83% specificity. Negative predictive value was 92% for Bethesda I/III/IV/V and 95.6% for Bethesda III/IV. Lactate did not differ between classic and follicular papillary carcinoma subtypes (P = 0.34), and no extranodular sample affected by lymphocytic thyroiditis exceeded the cutoff. Estimated relative reduction in diagnostic surgery was 61.7% (Bethesda III–IV) and 48.5% (Bethesda III–V). ConclusionIntranodular lactate is a feasible, low-cost metabolic biomarker that performs consistently across cytological categories, with greatest clinical value in Bethesda I, III, and IV nodules, where it may substantially reduce unnecessary diagnostic surgery.
Thyroid hormones (THs) are increasingly recognized as important regulators of innate immune cell function. As innate immune cells are essential for combating infections, TH status may, therefore, be a determinant of susceptibility to developing infections. Investigations into the effects of THs on various innate immune cells, including monocytes, macrophages, dendritic cells, and neutrophils, have revealed that these cells express all TH components and that their immune functions are modulated by TH status. Experimental studies in animals have demonstrated that hypothyroidism is associated with increased mortality during infections, largely due to impaired pathogen clearance and elevated pathogen loads. While the impact of THs on infection outcomes is well investigated in animal models, their role in human susceptibility to infection remains underappreciated. This review examines the clinical evidence for altered infection risk in both hypo- and hyperthyroid states, including rare syndromes of reduced sensitivity to thyroid hormone, and combines clinical data with mechanistic studies at the cellular level. Collectively, these findings highlight the critical role of THs in host defense and underscore the need for further research into their clinical relevance in human infectious diseases.
