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Background: The 2015 American Thyroid Association (ATA) guidelines recommend the following size cut-offs based on sonographic appearances for subjecting nodules to fine-needle aspiration (FNA) biopsy: low-risk 15mm, intermediate-risk and high-risk 10mm. Objective: We conducted a ‘real world’ study evaluating the diagnostic performance of the ATA cut-offs against increased thresholds, in the interest of safely limiting FNAs. Methods: We performed a retrospective analysis of prospectively collected data on 604 nodules which were sonographically risk stratified as per the ATA guidelines and subsequently subjected to ultrasound-guided FNA. Nodules were cytologically stratified into ‘benign’ (Bethesda class 2) and ‘non-benign’ (Bethesda classes 3-6). We obtained the negative predictive value (NPV), accuracy, FNAs that could be spared, missed ‘non-benign’ cytologies and missed carcinomas on histology, according to the ATA cut-offs compared to higher cut-offs. Results: In low-risk nodules, the high performance of NPV (≈91%) is unaffected by increasing the cut-off to 25mm, and accuracy improves by 39.4%; 46.8% of FNAs could be spared at the expense of few missed B3-B6 cytologies (7.9%) and no missed carcinomas. In intermediate-risk nodules, a 15mm cut-off increases the NPV by 11.3% and accuracy by 40.7%. The spared FNAs approach 50%, while B3-B6 cytologies are minimal, with no missed carcinomas. In high-risk nodules, low NPV (<35%) and accuracy (<46%) were obtained regardless of cut-off. Moreover, the spared FNAs achieved at higher cut-offs involved numerous missed ‘non-benign’ cytologies and carcinomas. Conclusion: It would be clinically safe to increase the ATA cut-offs for FNA in low-risk nodules to 25mm and in intermediate-risk nodules to 15mm.

Differences of sex development and maturation (SDM) represent a heterogeneous puzzle of rare conditions with a large genetic component whose management and treatment could be improved by an accurate classification of underlying molecular condition and Next Generation Sequencing (NGS) should represent the most appropriate approach. Therefore, we conducted a survey dedicated to the use and potential outcomes of NGS for SDM disorders diagnosis among the 53 health care providers (HCP) of the European Reference Network for rare endocrine conditions (ENDO-ERN). Response rate was 49% with a total of 26 HCPs from 13 countries. All HCPs, except one, performed NGS investigations for SDM disorders on 6720 patients, 3764 (56%) with Differences of Sex Development (DSD), including 811 unexplained Primary Ovarian Insufficiency (POI), and 2956 (44%) with Congenital Hypogonadotropic Hypogonadism (CHH). The approaches varied from targeted analysis of custom gene panels (range: 11-490 genes) in 81.5% of cases or Whole Exome Sequencing with extraction of a virtual panel in remaining cases. These analyses were performed for diagnostic purposes in 21 HCPs, supported by the National Health Systems in 16 cases. The likelihood of finding a variant ranged between 7 and 60%, mainly depending upon the number of analysed genes or criteria used for reporting, most HCPs also reporting variants of uncertain significance. These data illustrate the status of genetic diagnosis of DSD and CHH across Europe. In most countries these analyses are performed for diagnostic purposes, yielding highly variable results, thus suggesting the need for harmonization and general improvements of NGS approaches.

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