Thyroid cancer (TC) remains the most common cancer in endocrinology. Differentiated thyroid cancer (DTC), the most common type of TC, generally has a favorable outlook with conventional treatment, which typically includes surgery along with radioiodine (RAI) therapy and thyroid-stimulating hormone (TSH) suppression through thyroid hormone therapy. However, a small subset of patients (less than 5%) develop resistance to RAI. This resistance occurs due to the loss of Na/I symporter (NIS) activity, which is crucial for iodine absorption in thyroid cells. The decline in NIS activity appears to be due to gene modifications, reconfigurations with irregular stimulation of signaling pathways such as MAPK and PI3K/Akt pathways. These molecular changes lead to a diminished ability of DTC cells to concentrate iodine, which makes RAI therapy ineffective. As a consequence, patients with radioiodine-refractory DTC require alternative treatments. Therapy with tyrosine kinase inhibitors (TKIs) has emerged as the primary treatment option to inhibit proliferation and growth of RAIR-DTC, targeting the pathways responsible for tumor progression. In this article, we analyze molecular processes responsible for RAI resistance and explore both conventional and emerging therapeutic strategies for managing RAIR-DTC, aiming to improve patient outcomes.

Non-functioning adrenal incidentalomas (NFAIs) have been placed in relationship with a higher risk of glucose profile anomalies, while the full-blown typical picture of Cushing’s syndrome (CS) and associated secondary (glucocorticoid-induced) diabetes mellitus is not explicitly confirmed in this instance. Our objective was to highlight the most recent data concerning the glucose profile, particularly, type 2 diabetes mellitus (T2DM) in NFAIs with/without mild autonomous cortisol secretion (MACS). This was a comprehensive review of the literature; the search was conducted according to various combinations of key terms. We included English-published, original studies across a 5-year window of publication time (from January 2020 until 1 April 2024) on PubMed. We excluded case reports, reviews, studies on T1DM or secondary diabetes, and experimental data. We identified 37 studies of various designs (14 retrospective studies as well 13 cross-sectional, 4 cohorts, 3 prospective, and 2 case–control studies) that analysed 17,391 individuals, with a female-to-male ratio of 1.47 (aged between 14 and 96 years). T2DM prevalence in MACS (affecting 10 to 30% of NFAIs) ranged from 12% to 44%. The highest T2DM prevalence in NFAI was 45.2% in one study. MACS versus (non-MACS) NFAIs (n = 16) showed an increased risk of T2DM and even of prediabetes or higher fasting plasma glucose or HbA1c (no unanimous results). T2DM prevalence was analysed in NFAI (N = 1243, female-to-male ratio of 1.11, mean age of 60.42) versus (non-tumour) controls (N = 1548, female-to-male ratio of 0.91, average age of 60.22) amid four studies, and two of them were confirmatory with respect to a higher rate in NFAIs. Four studies included a sub-group of CS compared to NFAI/MACS, and two of them did not confirm an increased rate of glucose profile anomalies in CS versus NFAIs/ACS. The longest period of follow-up with concern to the glycaemic profile was 10.5 years, and one cohort showed a significant increase in the T2DM rate at 17.9% compared to the baseline value of 0.03%. Additionally, inconsistent data from six studies enrolling 1039 individuals that underwent adrenalectomy (N = 674) and conservative management (N = 365) pinpointed the impact of the surgery in NFAIs. The regulation of the glucose metabolism after adrenalectomy versus baseline versus conservative management (n = 3) was improved. To our knowledge, this comprehensive review included one of the largest recent analyses in the field of glucose profile amid the confirmation of MACS/NFAI. In light of the rising incidence of NFAI/AIs due to easier access to imagery scans and endocrine evaluation across the spectrum of modern medicine, it is critical to assess if these patients have an increased frequency of cardio-metabolic disorders that worsen their overall comorbidity and mortality profile, including via the confirmation of T2DM.

We aimed to provide an updated narrative review with respect to the RET pathogenic variants and their implications at the clinical and molecular level in the diagnosis of medullary thyroid cancer (MTC)/multiple endocrine neoplasia (MEN) type 2, particularly with respect to the presence of cutaneous lichen amyloidosis (CLA). We searched English-language, in extenso original articles with no timeline nor study design restriction that were published on PubMed. A traditional interplay stands for CLA and MTC in MEN2 (not MEN3) confirmation. While the connection has been reported for more than three decades, there is still a large gap in understanding and addressing it. The majority of patients with MEN2A-CLA have RET pathogenic variants at codon 634; hence, it suggests an involvement of this specific cysteine residue in both disorders (most data agree that one-third of C634-positive subjects have CLA, but the ranges are between 9% and 50%). Females seem more prone to MEN2-CLA than males. Non-C634 germline RET pathogenic variants included (at a low level of statistical evidence) the following: RET V804M mutation in exon 14 for MTC-CLA (CLA at upper back); RET S891A mutation in exon 15 binding OSMR variant G513D (familial MTC and CLA comprising the lower legs to thighs, upper back, shoulders, arms, and forearms); and C611Y (CLA at interscapular region), respectively. Typically, CLA is detected at an early age (from childhood until young adulthood) before the actual MTC identification unless RET screening protocols are already applied. The time frame between CLA diagnosis and the identification of RET pathogenic variants was between 5 and 60 years according to one study. The same RET mutation in one family is not necessarily associated with the same CLA presentation. In MTC/MEN2 subjects, the most affected CLA area was the scapular region of the upper back. Alternatively, another hypothesis highlighted the fact that CLA is secondary to long-term prurit/notalgia paresthetica (NP) in MTC/MEN2. OSMR p. G513D may play a role in modifying the evolutionary processes of CLA in subjects co-harboring RET mutations (further studies are necessary to sustain this aspect). Awareness in CLA-positive patients is essential, including the decision of RET testing in selected cases.