Context:
Fine-needle aspiration biopsy (FNAB) is the most sensitive and specific tool for the differential diagnosis of thyroid malignancy. Some limitations of FNAB can be overcome by the molecular ...analysis of FNAB. This review analyzes the current state and problems of the molecular analysis of FNAB as well as possible goals for increasing the diagnostic rate, especially in the indeterminate/follicular lesion cytological group.
Evidence Acquisition:
Twenty publications were evaluated for the diagnostic material and assay systems used, the type, and the number of mutations screened. Sensitivity, specificity, and false-negative and false-positive rates were calculated for all publications.
Evidence Synthesis:
Testing for a panel of somatic mutations is most promising to reduce the number of indeterminate FNAB. A mean sensitivity of 63.7% was achieved for indeterminate lesions. However, there is a broad sensitivity range for the investigation of mutations in the indeterminate lesions. Therefore, additional molecular markers should be defined by mRNA and microRNA expression studies and evaluated in FNAB samples of thyroid carcinomas without known somatic mutations, and especially for the many benign nodules in the indeterminate/follicular lesion fine-needle aspiration cytology category. This approach should improve the differential diagnosis of indeterminate/follicular lesion FNAB samples.
Conclusion:
Testing for a panel of somatic mutations has led to an improvement of sensitivity/specificity for indeterminate/follicular proliferation FNAB samples. Further methodological improvements, standardizations, and further molecular markers should soon lead to a broader application of molecular FNAB cytology for the differential diagnosis of thyroid nodules and to a substantial reduction of diagnostic surgeries.
Fine-needle aspiration biopsy (FNAB) is currently the most sensitive and specific tool for the presurgical differential diagnosis of thyroid malignancy, but has also substantial limitations. While ...approximately 75% of FNAB reveal benign lesions and 5% already cytologically prove malignancy, up to 20% of FNAB show follicular proliferation for which follicular adenoma, follicular carcinoma, and follicular variant of papillary carcinoma can only be distinguished histologically, thus requiring thyroid surgery. However, new biomarkers that might improve the accuracy of FNAB come along with the discovery of more and more details of the molecular etiology of thyroid tumors. So far molecular testing for somatic mutations is most promising (e.g.,
BRAF), since the proposed biomarkers from mRNA- and miRNA-expression studies need further evaluation, especially in FNAB samples. Nevertheless, the application of molecular markers will significantly improve thyroid tumor diagnosis and thus it will help to prevent unnecessary surgeries and it will also help to guide mutation-specific targeted therapies.
Summary Background Patients with radioactive iodine (131 I)-refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis because of the absence of effective treatment ...options. In this study, we assessed the efficacy and safety of orally administered sorafenib in the treatment of patients with this type of cancer. Methods In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (DECISION), we investigated sorafenib (400 mg orally twice daily) in patients with radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed within the past 14 months. Adult patients (≥18 years of age) with this type of cancer were enrolled from 77 centres in 18 countries. To be eligible for inclusion, participants had to have at least one measurable lesion by CT or MRI according to Response Evaluation Criteria In Solid Tumors (RECIST); Eastern Cooperative Oncology Group performance status 0–2; adequate bone marrow, liver, and renal function; and serum thyroid-stimulating hormone concentration lower than 0·5 mIU/L. An interactive voice response system was used to randomly allocate participants in a 1:1 ratio to either sorafenib or matching placebo. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival, assessed every 8 weeks by central independent review. Analysis was by intention to treat. Patients in the placebo group could cross over to open-label sorafenib upon disease progression. Archival tumour tissue was examined for BRAF and RAS mutations, and serum thyroglobulin was measured at baseline and at each visit. This study is registered with ClinicalTrials.gov , number NCT00984282 , and with the EU Clinical Trials Register, number EudraCT 2009–012007–25. Findings Patients were randomly allocated on a 1:1 basis to sorafenib or placebo. The intention-to-treat population comprised 417 patients (207 in the sorafenib group and 210 in the placebo group) and the safety population was 416 patients (207 in the sorafenib group and 209 in the placebo group). Median progression-free survival was significantly longer in the sorafenib group (10·8 months) than in the placebo group (5·8 months; hazard ratio HR 0·59, 95% CI 0·45–0·76; p<0·0001). Progression-free survival improved in all prespecified clinical and genetic biomarker subgroups, irrespective of mutation status. Adverse events occurred in 204 of 207 (98·6%) patients receiving sorafenib during the double-blind period and in 183 of 209 (87·6%) patients receiving placebo. Most adverse events were grade 1 or 2. The most frequent treatment-emergent adverse events in the sorafenib group were hand–foot skin reaction (76·3%), diarrhoea (68·6%), alopecia (67·1%), and rash or desquamation (50·2%). Interpretation Sorafenib significantly improved progression-free survival compared with placebo in patients with progressive radioactive iodine-refractory differentiated thyroid cancer. Adverse events were consistent with the known safety profile of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory differentiated thyroid cancer. Funding Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary).
With the widespread use of sensitive imaging techniques, which include neck visualization, a conspicuous number of thyroid nodules emerge and demand attention. Most lesions are benign, asymptomatic, ...and do not warrant treatment. In the case of cancer diagnosis, most are small, intrathyroidal and indolent neoplasms that can safely be managed conservatively. There is a pronounced need for more cost-effective, risk-adapted approaches to the management of this highly prevalent condition, taking the wishes of the patient into consideration. Thus, the present guidelines aim at providing a clinical practice guide for the initial workup and the subsequent management of adult individuals harboring thyroid nodules. Importantly, these guidelines are not intended to cover the management of thyroid malignancy. The manuscript and the specific recommendations were developed by reconciling the best available research evidence with the knowledge and clinical experience of the panelists and updating aspects of a number of previous European Thyroid Association guidelines.
Abstract Hyperthyroidism is a clinical state that results from high thyroid hormone levels which has multiple etiologies, manifestations, and potential therapies. Excluding the autoimmune Graves ...disease, autonomic adenomas account for the most import cause of non-autoimmune hyperthyroidism. Activating germline mutations of the TSH receptor are rare etiologies for hyperthyroidism. They can be inherited in an autosomal dominant manner (familial or hereditary, FNAH), or may occur sporadically as a de novo condition, also called: persistent sporadic congenital non-autoimmune hyperthyroidism (PSNAH). These three conditions: autonomic adenoma, FNAH and PSNAH constitute the inheritable and sporadic non-autoimmune hyperthyroidism. Particularities in epidemiology, etiology, molecular and clinical aspects of these three entities will be discussed in this review in order to guide to an accurate diagnosis allowing among others genetic counseling and presymptomatic diagnosis for the affected families. The optimal treatment based on the right diagnosis will avoid consequences of a persistent or relapsing hyperthyroidism.
Thyroid nodules affect up to 65% of the population. Although fine needle aspirate (FNA) cytology is the gold standard for diagnosis, 15-30% of results are indeterminate. Molecular testing may aid in ...the diagnosis of nodules and potentially reduce unnecessary surgery. However, these tests are associated with significant costs. The objective of this study was to evaluate the cost-effectiveness of Afirma, a commercially available molecular test, in cytologically indeterminate thyroid nodules.
The base case was a solitary thyroid nodule with no additional high-risk features and an indeterminate FNA. Decision tree analysis was performed from the single payer perspective with a 1-year time horizon. Costing data were collected through micro-costing methodology. A probabilistic sensitivity analysis was performed. The primary outcome was the incremental cost effectiveness ratio (ICER) of cost per thyroid surgery avoided.
Over 1 year, mean cost estimates were $8176.28 with 0.58 effectiveness for the molecular testing strategy and $6016.83 with 0.07 effectiveness for current standard management. The ICER was $4234.22 per surgery avoided. At a willingness-to-pay (WTP) threshold of $5000 per surgery avoided, molecular testing is cost-effective with 63% certainty.
This cost-effectiveness analysis suggests utilizing Afirma for indeterminate solitary thyroid nodules is a cost-effective strategy for avoiding unnecessary thyroid surgery. With a $5000 WTP threshold, molecular testing has a 63% chance of being the more cost-effective strategy. The cost effectiveness varies based on the cost of the molecular test and the value of Afirma for patients with indeterminate thyroid nodules depends on the WTP threshold to avoid unnecessary thyroid surgery.
Small papillary thyroid carcinomas have contributed to the worldwide increased incidence of differentiated thyroid cancer observed over the past decades. However, the mortality rate has not changed ...over the same period of time, raising questions about the possibility that thyroid cancer patients, especially those with small tumors, are overdiagnosed and overtreated. Molecular prognostic marker able to discriminate aggressive thyroid cancers from those with an indolent course would be of great relevance to tailor the therapeutic approach and reduce overtreatment. Mutations in the TERT promoter were recently reported to correlate strongly with aggressiveness in advanced forms of thyroid cancer, holding promise for a possible clinical application. The occurrence and potential clinical relevance of TERT mutations in papillary thyroid microcarcinomas (mPTCs) is currently unknown. This study aimed to analyze the occurrence of two TERT promoter mutations (-124C>T and -146C>T) and their potential association with unfavorable clinical features in a large cohort of mPTCs.
A total of 431 mPTCs cases were collected from six Italian institutions, and TERT promoter mutational status was assessed by a next-generation sequencing approach.
TERT promoter mutations were found in 4.7% of the analyzed mPTCs, showing that even microcarcinomas carry mutations in this gene. Correlation analysis showed that TERT promoter mutations are not associated with aggressive features or clinical outcome in the cohort analyzed.
TERT mutations are present but uncommon in mPTCs. Apparently, in mPTCs, the occurrence of TERT mutations is not correlated with unfavorable clinical features.
Recently, it has been demonstrated that the fat-derived protein adiponectin is an important insulin-sensitizing adipocytokine which is downregulated in insulin resistance and obesity and ...replenishment of which in adiponectin-deficient states improves insulin sensitivity. To clarify the regulation of adiponectin gene expression, 3T3-L1 adipocytes were treated with various hormones known to induce insulin resistance in vivo and adiponectin mRNA was measured by quantitative real-time reverse transcription–polymerase chain reaction. Interestingly, treatment of 3T3-L1 cells with 100 nM insulin, 10 ng/ml tumor necrosis factor (TNF) α, or 100 nM dexamethasone for 16 h suppressed adiponectin gene expression by about 50 to 85% while angiotensin 2, growth hormone, and triiodothyronine did not have any effect. Furthermore, insulin reduced the level of adiponectin mRNA in a dose- and time-dependent fashion with inhibition detectable at concentrations as low as 10 nM insulin and as early as 4 h after effector addition. The inhibitory effect of insulin was partially reversed by pretreatment of 3T3-L1 cells with pharmacological inhibitors of p44/42 mitogen-activated protein (MAP) kinase, phosphatidylinositol (PI) 3-kinase, and p70S6 kinase. Moreover, the negative effects of insulin, TNFα, and dexamethasone on adiponectin gene expression could be completely reversed by withdrawal of the hormones for 24 h. Taken together, our results suggest that adiponectin gene expression is reversibly downregulated by insulin, TNFα, and dexamethasone. The data support the concept of adiponectin being an important selectively controlled modulator of insulin sensitivity.
Somatic mutations can be identified in two-thirds of papillary and follicular thyroid carcinomas and 'hot' thyroid nodules, whereas equivalent mutations relevant for benign 'cold' thyroid nodules are ...unknown. This Review summarizes current knowledge about early molecular conditions for nodular and tumor transformation in the thyroid gland. We reconstruct a line of events that could explain the predominant neoplastic character (i.e. originating from a single mutated cell) of thyroid nodular lesions. This process might be triggered by the oxidative nature of thyroid hormone synthesis or additional oxidative stress caused by iodine deficiency or smoking. If the antioxidant defense is not effective, this oxidative stress can cause DNA damage followed by an increase in the spontaneous mutation rate, which is a platform for tumor genesis. The hallmark of thyroid physiology--H2O2 production during hormone synthesis--is therefore very likely to be the ultimate cause of frequent mutagenesis in the thyroid gland. DNA damage and mutagenesis could provide the basis for the frequent nodular transformation of endemic goiters.
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