On 31 July 2026, Professor Paolo Beck-Peccoz passed away — an outstanding Italian endocrinologist, one of the foremost experts in the field of hypothalamic-pituitary-thyroid disorders, a scientist, clinician and mentor to several generations of endocrinologists.
BACKGROUND . The Bethesda category IV comprises thyroid nodules of indeterminate malignant potential. As a result, most patients undergo diagnostic surgery that more often confirms a benign lesion. The search for additional preoperative criteria remains relevant. The aim of this study was to assess the diagnostic potential of plasma proteomic markers for the differential diagnosis of benign and malignant thyroid neoplasms within the Bethesda category IV. MATERIALS AND METHODS . This study included 174 patients with Bethesda IV cytology in whom a plasma proteomic profile was obtained and a histological diagnosis was established, comprising 104 benign and 70 malignant lesions. Protein concentrations were estimated by multiple reaction monitoring. RESULTS . The groups were comparable in sex, age, disease duration, thyroid-stimulating hormone level. Patients with malignant lesions had higher concentrations of keratin 19, galectin-3, CD14 differentiation antigen, thrombospondin-1, epidermal growth factor, and filamin-A. The largest areas under the ROC curve were obtained for CD14 differentiation antigen (0.729; 95% CI 0.650–0.808), keratin 19 (0.727; 0.646–0.808), and galectin-3 (0.710; 0.627–0.792). Strong positive correlations were found between keratin 19 and galectin-3 (r=0.82), CD14 differentiation antigen and galectin-3 (r=0.80), and keratin 19 and CD14 differentiation antigen (r=0.78; p < 0.001). CONCLUSION . Several plasma proteins differ between benign and malignant lesions within the Bethesda category IV. Keratin 19, galectin-3, and CD14 differentiation antigen showed the highest, although moderate, differential diagnostic performance. The obtained concentration estimates are semi-quantitative and require quantitative validation before use as clinical thresholds. Taken together, the data indicate that these proteins reflect epithelial proliferative activity rather than a malignancy-specific signal, which limits their standalone diagnostic application.
BACKGROUND: Thyroid nodules with a cytological diagnosis of oncocytic follicular neoplasm (FN) are associated with a moderate risk of malignancy of approximately 30%. Management usually involves choosing between diagnostic surgery, typically hemithyroidectomy, and active surveillance. Identification of additional predictors of malignancy could contribute to more accurate risk assessment and personalized management. AIM: To analyze the histological, clinical, and ultrasound characteristics of oncocytic follicular neoplasms and to assess their association with the risk of malignancy. MATERIALS AND METHODS: This observational study included a consecutive series of all surgically treated cases of oncocytic FN (diagnostic category IV according to the Bethesda System) at the Endocrinology Research Centre over a 2-year period (2021–2022). A retrospective review of medical records was performed to assess histological tumor types, patient age and sex, and ultrasound features of the nodules. According to the histological diagnosis, cases were divided into malignant, benign, and low-risk neoplasm groups to identify possible differences in clinical and ultrasound characteristics. RESULTS: The final cohort included 81 cases with oncocytic FN: 23 malignant lesions, 55 benign lesions, and 3 cases of noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Oncocytic carcinoma was the most common malignant type (n=10), however, a substantial proportion of malignant cases were represented by other histological diagnoses, including classic and oncocytic subtypes of papillary thyroid carcinoma, as well as follicular thyroid carcinoma. Regional lymph node involvement was detected in only one case of papillary thyroid carcinoma. The risk of malignancy in the final cohort was 28.4% (95% CI 19.7–39.0) and was not associated with sex, age, nodule size, or solitary versus multinodular thyroid disease. No ultrasound feature differed significantly or showed a trend toward a difference between the benign and malignant groups. The distribution of EU-TIRADS categories also did not differ between the groups. CONCLUSION: This study suggests the absence of reliable ultrasound and clinical predictors of malignancy risk in thyroid nodules with oncocytic FN cytological pattern. These findings indicate that other approaches to risk refinement are needed to guide the choice of optimal management for nodules with this cytological pattern.
BACKGROUND: Among differentiated thyroid carcinoma (DTC) cases, patients classified into the intermediate and high postoperative risk groups for recurrence account for over at least 35% of all cases. However, the optimal management strategy, the clinical utility of radioiodine therapy (RAIT), and the factors determining its efficacy remain insufficiently elucidated. Although the prognostic significance of mutations in BRAF, TERT, TP53, and RAS genes has been well described, their impact on the functional activity of the sodium–iodide symporter (NIS), the degree of cellular differentiation, and the relationship with RAIT responsiveness has not been clearly established. AIM: To assess the relationship between the mutational profile of the primary tumor and clinical outcomes after RAIT in patients with intermediate/high-risk DTC, and to identify candidate genes associated with poor therapeutic response. MATERIALS AND METHODS: Next-generation sequencing (NGS) was performed on DNA extracted from formalin-fixed paraffin-embedded (FFPE) samples of primary DTC tumors (N=28). Clinical and anamnestic data of patients meeting inclusion criteria were retrospectively analyzed. The MEDLINE, Google Scholar, and STRING databases were searched for candidate genes implicated in NIS regulation and poor RAIT response. Of the 68 potential genes, 51 distinct mutations were identified in the analyzed samples. Statistical analysis was conducted to evaluate the correlation between clinical characteristics and molecular profiles using Statistica v.12 software (TIBCO Software Inc., USA). RESULTS: The median follow-up duration was 22.5 [16; 62] months. The median number of somatic variants per patient detected by the targeted sequencing panel was 4.5 [3; 8] (range 1–22). The most frequent variants involved BRAF, PTEN, PIGU, and TG. In the subgroup with unfavorable outcomes, clustering of mutations was observed in BRAF, COL5A1, CTNNB1, DUOX2, AKT1, ALK, ERBB2, GLI1, HORMAD2, IYD, NOTCH3, SLC5A8, SMAD3, and TSHR. The difference in the total number of somatic variants between outcome groups did not reach statistical significance (p=0.755). The presence of distant metastases (M1) emerged as a strong predictor of poor outcome (p<0.001), while coexisting autoimmune thyroiditis had no significant impact (p=0.309). CONCLUSION: The absence of a significant difference in the number of somatic variants between patients with favorable and unfavorable responses (p=0.755), together with the clustering of pathogenic mutations in specific genes in the radioiodine-refractory group, suggests that the activation of specific oncogenic signaling pathways, rather than overall genomic instability, is a key determinant of tumor behavior in this solid tumor type. Resistance or incomplete response to radioiodine therapy may result from the concurrent activation of multiple oncogenic signaling pathways, including MAPK, PI3K/AKT/ mTOR, TSH–TSH receptor, TGF-β/SMAD3, Sonic Hedgehog, and β-catenin/Wnt signaling. Further evaluation of candidate genes implicated in aggressive disease behavior in differentiated thyroid cancer is warranted in larger patient cohorts, with particular emphasis on transcript-level expression analyses.
