The present review deals with the functional roles of iodine and its metabolism. The main biological function of iodine concerns its role in the biosynthesis of thyroid hormones (THs) by the thyroid gland. In addition, however, further biological roles of iodine have emerged. Precisely, due to its significant action as scavenger of reactive oxygen species (ROS), iodine is thought to represent one of the oldest antioxidants in living organisms. Moreover, iodine oxidation to hypoiodite (IO⁻) has been shown to possess strong bactericidal as well as antiviral and antifungal activity. Finally, and importantly, iodine has been demonstrated to exert antineoplastic effects in human cancer cell lines. Thus, iodine, through the action of different tissue-specific peroxidases, may serve different evolutionarily conserved physiological functions that, beyond TH biosynthesis, encompass antioxidant activity and defense against pathogens and cancer progression.

Over the last few years, a great advance has been made in the comprehension of the molecular pathogenesis underlying thyroid cancer progression, particularly for the papillary thyroid cancer (PTC), which represents the most common thyroid malignancy. Putative cancer driver mutations have been identified in more than 98% of PTC, and a new PTC classification into molecular subtypes has been proposed in order to resolve clinical uncertainties still present in the clinical management of patients. Additionally, the prognostic stratification systems have been profoundly modified over the last decade, with a view to refine patients’ staging and being able to choose a clinical approach tailored on single patient’s needs. Here, we will briefly discuss the recent changes in the clinical management of thyroid nodules, and review the current staging systems of thyroid cancer patients by analyzing promising clinicopathological features (i.e., gender, thyroid auto-immunity, multifocality, PTC histological variants, and vascular invasion) as well as new molecular markers (i.e., BRAF/TERT promoter mutations, miRNAs, and components of the plasminogen activating system) potentially capable of ameliorating the prognosis of PTC patients.

Ultrasound often represents the first diagnostic step for thyroid nodule evaluation in clinical practice, but baseline US alone is not always effective enough to achieve thyroid nodule characterization. In the last decades new ultrasound techniques, such as CEUS, have been introduced to evaluate thyroid parenchyma as recommended by EFSUMB guidelines, for use in clinical research field, although its role is not yet clear. Several papers show the potential utility of CEUS in the differential diagnosis of benign and malignant thyroid nodules and in the analysis of lymph node involvement in neoplastic pathology. Therefore, we carried out an evaluation of the literature concerning the role of CEUS in three specific areas: the characterization of the thyroid nodule, the evaluation of minimally invasive treatment and loco-regional staging of the lymph node in proven thyroid cancer. According to evidence reported, CEUS can also play an operative role in nodular thyroid pathology as it is able to guide ablation procedures on thyroid nodule and metastatic lymph nodes, to assess the radicality of surgery, to evaluate disease relapse at the level of the margins of ablated regions and to monitor the clinical evolution of necrotic areas in immediate post-treatment setting.

The new immunotherapy targeting the programmed cell death 1 (PD-1) receptor and its cognate ligand PD-L1 has renewed hopes of eradicating the most difficult human cancers to treat. Among these, there are the poorly differentiated and anaplastic thyroid cancers, unresponsive to all the therapies currently in use. In the present review we will summarize information regarding the expression of PD-L1 in the different thyroid cancer histotypes, its correlation with clinicopathological features, and its potential prognostic value. Then, we will evaluate the available data indicating the PD-1/PD-L1 axis as a promising target for thyroid cancer therapy.

The American Joint Committee on Cancer has revised the Tumor-Node-Metastasis (TNM) staging system for papillary thyroid cancer (PTC) patients. We examined the impact of this new classification (TNM-8) on patient stratification and estimated the prognostic value of clinicopathological features for the disease-free interval (DFI) in a cohort of 1148 PTC patients. Kaplan–Meier analyses showed that all clinicopathological parameters analyzed, except age and multifocality, were associated significantly with DFI. Cox regression identified tall cell PTC variant and stage as independent risk factors for DFI. When the stage was replaced with age, tumor size, and lymph node (LN) metastases in the set of covariates, the lateral LN metastases stood out as the strongest independent predictor of DFI, followed by tall cell variant and age. A noteworthy result emerging from these analyzes is that regression models had lower Akaike and Bayesian information criterions if variables were categorized based on the TNM-7. In addition, we examined data from a different PTC patient cohort, acquired from The Cancer Genome Atlas database, to verify whether the DFI prediction could be enhanced by further clinicopathological and molecular parameters. However, none of these was found to be a significant predictor of DFI in the Cox model.

Epidemiological studies aimed at defining the association of thyroid diseases with extra-thyroidal malignancies (EM) have aroused considerable interest in the possibility of revealing common genetic and environmental factors underlying disease etiology and progression. Over the years, multiple lines of evidence indicated a significant relationship between thyroid carcinomas and other primary EM, especially breast cancer. For the latter, a prominent association was also found with benign thyroid diseases. In particular, a meta-analysis revealed an increased risk of breast cancer in patients with autoimmune thyroiditis, and our recent work demonstrated that the odds ratio (OR) for breast cancer was raised in both thyroid autoantibody-positive and -negative patients. However, the OR was significantly lower for thyroid autoantibody-positive patients compared to the negative ones. This is in agreement with findings showing that the development of thyroid autoimmunity in cancer patients receiving immunotherapy is associated with better outcome and supports clinical evidence that breast cancer patients with thyroid autoimmunity have longer disease-free interval and overall survival. These results seem to suggest that factors other than oncologic treatments may play a role in the initiation and progression of a second primary malignancy. The molecular links between thyroid autoimmunity and breast cancer remain, however, unidentified, and different hypotheses have been proposed. Here, we will review the epidemiological, clinical, and experimental data relating thyroid diseases and breast cancer, as well as the possible hormonal and molecular mechanisms underlying such associations.