Nuove frontiere nel carcinoma midollare della tiroide: identificazione di nuovi biomarkers diagnostici

Background: medullary thyroid carcinoma (MTC) is rare thyroid cancer. The difficulty in management and the unfavorable outcome are mainly due to the absence of tools for early diagnosis. Recent studies have demonstrated the deregulation of microRNAs (miRNAs) in tumor samples from MTC patients. Extracellular plasma vesicles (pEVs) containing miRNA represent an emerging source of tumor biomarkers. There are no data from the circulating pEV-miRNAs in patients with MTC. Aim: to identify new circulating diagnostic biomarkers in MTC. Study design: multicenter, prospective, observational study enrolling adult patients with stage I-IV MTC (Group 1, n=23), compared to healthy subjects (Group 2, n=22). For Group 1 patients we collected: blood sample at the time of surgery and tumor tissue from the primary tumor. Step 1: pre-operative plasma from MTC patients (Group 1a) was compared to plasma from healthy subjects (Group 2). Step 2: pre-operative plasma from each MTC patients (Group 1a) was compared to tumor tissue of the same patient (Group 1b). Step 3: data from Step 1 and Step 2 were combined. Methods: the expression analysis of circulating (pEV) and tissue miRNAs was performed by RT-qPCR with TLDA technology analyzing 754 miRNAs. Results were considered statistically significant when P-values were <0.05 Results: 555 miRNAs are considered to be informative comparing Group 1a and Group 2, 44 of them differentially expressed between two groups. 603 miRNAs are considered to be informative, comparing Group 1a vs Group 1b, 209 of them differentially expressed and 394 equally expressed between two groups, respectively. Combining Step 1 and Step 2 results, 24 miRNAs were identified. Conclusions: a specific pattern of pEV-miRNAs was observed in MTC patients, which in part reflects tissue miRNAs arrangement. The 24 miRNAs identified represent potential diagnostic biomarkers in MTC, that could play an active role in the modulation of cellular pathways in targeted cells

Hereditary Neuroendocrine Tumor Syndromes

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Diagnosis and Differential Diagnosis of Medullary Thyroid Cancer

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Is thyroid nodule location associated with malignancy risk?

PURPOSE: Nodules located in the upper pole of the thyroid may carry a greater risk for malignancy than those in the lower pole. We conducted a study to analyze the risk of malignancy of nodules depending on location. METHODS: The records of patients undergoing thyroid-nodule fine-needle aspiration cytology (FNAC) at an academic thyroid cancer unit were prospectively collected. The nodules were considered benign in cases of a benign histology or cytology report, and malignant in cases of malignant histology. Pathological findings were analyzed based on the anatomical location of the nodules, which were also scored according to five ultrasonographic classification systems. RESULTS: Between November 1, 2015 and May 30, 2018, 832 nodules underwent FNAC, of which 557 had a definitive diagnosis. The prevalence of malignancy was not significantly different in the isthmus, right, or left lobe. Among the 227 nodules that had a precise longitudinal location noted (from 219 patients [155 females], aged 56.2±14.0 years), malignancy was more frequent in the middle lobe (13.2%; odds ratio [OR], 9.74; 95% confidence interval [CI], 1.95 to 48.59). This figure was confirmed in multivariate analyses that took into account nodule composition and the Thyroid Imaging, Reporting, and Data System (TIRADS) classification. Using the American College of Radiologists TIRADS, the upper pole location also demonstrated a slightly significant association with malignancy (OR, 6.92; 95% CI, 1.02 to 46.90; P=0.047). CONCLUSION: The risk of thyroid malignancy was found to be significantly higher for mid-lobar nodules. This observation was confirmed when suspicious ultrasonographic features were included in a multivariate model, suggesting that the longitudinal location in the lobe may be a risk factor independently of ultrasonographic appearance

Il ruolo dello screening per il carcinoma differenziato della tiroide in rapporto al sesso e in specifiche popolazioni

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Loss of function SETD2 mutations in poorly differentiated metastases from two Hürthle cell carcinomas of the thyroid

Hürthle cell carcinomas (HCC) are rare differentiated thyroid cancers that display low avidity for radioactive iodine and respond poorly to kinase inhibitors. Here, using next-generation sequencing, we analyzed the mutational status of primary tissue and poorly differentiated metastatic tissue from two HCC patients. In both cases, metastatic tissues harbored a mutation of SETD2, each resulting in loss of the SRI and WW domains of SETD2, a methyltransferase that trimethylates H3K36 (H3K36me3) and also interacts with p53 to promote its stability. Functional studies of the novel p.D1890fs6* mutation (case 1) revealed significantly reduced H3K36me3 levels in SETD2-mutated tissue and primary cell cultures and decreased levels of the active form of p53. Restoration of SETD2-wildtype expression in the SETD2-mutant cells significantly reduced the expression of four well-known stemness markers (OCT-4, SOX2, IPF1, Goosecoid). These findings suggest potential roles for SETD2 loss-of-function mutations in HCC progression, possibly involving p53 destabilization and promotion of stemness. Their prevalence and potential treatment implications in thyroid cancer, especially HCC, require further study

Pituitary function and morphology in Fabry disease.

Endocrine abnormalities are known to affect patients with Fabry disease (FD). Pituitary gland theoretically represents an ideal target for FD because of high vascularization and low proliferation rate. We explored pituitary morphology and function in a cohort of FD patients through a prospectic, monocentric study at an Academic Tertiary Center. The study population included 28 FD patients and 42 sex and age-matched normal subjects. The protocol included a contrast enhancement pituitary MRI, the assessment of pituitary hormones, anti-pituitary, and anti-hypothalamus antibodies. At pituitary MRI, an empty sella was found in 11 (39%) FD patients, and in 2 (5%) controls (p < 0.001). Pituitary volume was significantly smaller in FD than in controls (p < 0.001). Determinants of pituitary volume were age and alpha-galactosidase enzyme activity. Both parameters resulted independently correlated at multivariate analysis. Pituitary function was substantially preserved in FD patients. Empty sella is a common finding in patients with FD. The major prevalence in the elderly supports the hypothesis of a progressive pituitary shrinkage overtime. Pituitary function seems not to be impaired in FD. An endocrine workup with pituitary hormone assessment should be periodically performed in FD patients, who are already at risk of cardiovascular complications

Clinical and prognostic implications of the genetic diagnosis of hereditary NET syndromes in asymptomatic patients

Neuroendocrine tumors (NETs) can be sporadic or they can arise in complex hereditary syndromes. Patients with hereditary NETs can be identified before the development of tumors by performing genetic screenings. The aim of the study was to evaluate the clinical and prognostic impact of a preclinical genetic screening in subjects with hereditary NET syndromes. 46 subjects referred for hereditary NET syndrome [22 MEN1, 12 MEN2, 12 Familial Paragangliomatosis (FPGL)] were enrolled and divided in 2 groups (group A, 20 subjects with clinical appearance of NET before the genetic diagnosis; group B, 26 subjects with genetic diagnosis of hereditary NET syndromes before the clinical appearance of NETs). The main outcome measures were severity of disease, prognosis, and survival. The rate of surgery for MEN1-, MEN2-, FPGL4-related tumors was 90% in group A and 35% in group B (p<0.01). Both symptoms related to tumors and symptoms related to therapies were significantly less frequent in group B than in group A (p<0.05). Tumor stage was locally advanced or metastatic in 50% of group A and in no one of group B (p<0.01). The mortality rate was 25% in group A and 0% in group B (p<0.05). An early genetic screening for hereditary NET syndromes results in an improvement in clinical presentation and morbidity. A potential impact of the genetic screening on the mortality rate of these subjects is suggested and needs to be investigated in further and more appropriate studies

Taller-than-wide shape: a new definition improves the specificity of TIRADS systems

Introduction: A taller-than-wide (TTW) shape is a suspicious feature of thyroid nodules commonly defined as an anteroposterior/transverse diameter (AP/T) ratio &gt;1. An intraobserver variability of up to 18% in AP diameter evaluations has been described, which may lead to overreporting of this feature. To potentially improve the reliability of the TTW definition, we propose an arbitrary ratio of ≥1.2. Objective: The aim of this study was to estimate the impact of this definition on diagnostic performance. Methods: We prospectively analyzed 553 thyroid nodules referred for cytology evaluation at an academic center. Before fine-needle aspiration, two examiners jointly defined all sonographic features considered in risk stratification systems developed by the American Thyroid Association (ATA), the American Association of Clinical Endocrinologists (AACE), the American College of Radiology (ACR TIRADS), the European Thyroid Association (EU-TIRADS), and the Korean Society of Thyroid Radiology (K-TIRADS). TTW was defined according to the current definition (AP/T diameter ratio &gt;1) and an arbitrary alternative definition (AP/T ratio &gt;1.2). Results: The alternative definition classified fewer nodules as TTW (28, 5.1% vs. 94, 17%). The current and proposed definitions have a sensitivity of 26.2 and 11.9% (p = 0.03) and a specificity of 83.8 and 95.5% (p &lt; 0.001). Thus, as a single feature, the arbitrary definition has a lower sensitivity and a higher specificity. When applied to sonographic risk stratification systems, however, the proposed definition would increase the number of avoided biopsies (up to 58.2% for ACR TIRADS) and the specificity of all systems, without negative impact on sensitivity or diagnostic odds ratio. Conclusions: Re-defining TTW nodules as those with an AP/T ratio ≥1.2 improves this marker's specificity for malignancy. Using this definition in risk stratification systems will increase their specificity, reducing the number of suggested biopsies without significantly diminishing their overall diagnostic performance

Contemporary thyroid nodule evaluation and management

Context Approximately 60% of adults harbor one or more thyroid nodules. The possibility of cancer is the overriding concern, but only about 5% prove to be malignant. The widespread use of diagnostic imaging and improved access to healthcare favor the discovery of small, subclinical nodules and small papillary cancers. Overdiagnosis and overtreatment is associated with potentially excessive costs and non-negligible morbidity for patients. Evidence Acquisition We conducted a PubMed search for the recent English-language articles dealing with thyroid nodule management. Evidence Synthesis The initial assessment includes an evaluation of clinical risk factors and sonographic examination of the neck. Sonographic risk-stratification systems (e.g., Thyroid Imaging Reporting and Data Systems [TIRADS]) can be used to estimate the risk of malignancy and the need for biopsy based on nodule features and size. When cytology findings are indeterminate, molecular analysis of the aspirate may obviate the need for diagnostic surgery. Many nodules will not require biopsy. These nodules and those that are cytologically benign can be managed with long-term follow-up alone. If malignancy is suspected, options include surgery (increasingly less extensive), active surveillance or, in selected cases, minimally-invasive techniques. Conclusion Thyroid nodule evaluation is no longer a one-size-fits-all proposition. For most nodules, the likelihood of malignancy can be confidently estimated without resorting to cytology or molecular testing, and low-frequency surveillance is sufficient for most patients. When there are multiple options for diagnosis and/or treatment, they should be discussed with patients as frankly as possible to identify an approach that best meets their needs