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    Advances in surgical therapy for thyroid cancer. Mazeh Haggi,Chen Herbert Nature reviews. Endocrinology Thyroid cancer is the most common malignancy of the endocrine system and its incidence has dramatically increased over the past three decades. Well-differentiated thyroid cancers (DTCs) are the main focus of this article, as they represent >90% of thyroid malignancies. This Review provides an overview of the controversies surrounding the optimal choice of surgery and extent of resection for patients with low-risk DTC or with papillary thyroid microcarcinoma, and the role of prophylactic central lymph node dissection. This Review also outlines the current surgical management of DTC and presents updated results for these techniques, along with important advances and current dilemmas in surgical approaches to treatment of these cancers. For example, endoscopic and robotic thyroidectomy are the two most recent innovations to present technical and other challenges to the endocrine surgeon; in addition, the risks as well as the advantages of same-day thyroid surgery, which has gained some acceptance, are detailed. Arguments for and against each approach are presented, along with supporting evidence. The authors' personal opinions are also provided for each topic. 10.1038/nrendo.2011.140
    Second Primary Cancer in Patients with Differentiated Thyroid Cancer: Does Radioiodine Play a Role? Silva-Vieira Margarida,Carrilho Vaz Sofia,Esteves Susana,Ferreira Teresa C,Limbert Edward,Salgado Lucília,Leite Valeriano Thyroid : official journal of the American Thyroid Association BACKGROUND:Well-differentiated thyroid cancer (WDTC) is the most common endocrine neoplasia, and its incidence is rising. Studies have reported an increased risk of second primary cancer (SPC) in WDTC survivors, but its relationship with radioiodine treatment (RAIT) and other risk factors remains controversial. This study evaluated whether RAIT is an independent risk factor for SPC in WDTC patients. METHODS:This was a retrospective single-center study. A total of 2031 patients with WDTC diagnosed between 1998 and 2009, treated and followed at the authors' tertiary cancer center, were included. RESULTS:The median age of patients was 48 years (range 5-90 years); 83% were women and 77% underwent RAIT. The median follow-up was 8.8 years (range 5.0-17.0 years). A total of 130 SPC were diagnosed: 108/1570 (6.9%) received RAIT (RAIT+) and 22/461 (4.8%) did not (RAIT-). The most common SPC was breast cancer (31%), followed by genitourinary and gastrointestinal cancer (18% each). The 10-year cumulative incidence of SPC was 8.2% in RAIT+ and 4.5% in RAIT-. The absolute risk increase in the RAIT+ group versus the RAIT- group at 10 years of follow-up was 0.039 [confidence interval (CI) 0.011-0.067] per patient-year. The number needed to harm (NNH) was 25.6 [CI 15.0-87.2], indicating that on average during a 10-year follow-up period, there is one additional case of SPC for every 26 patients receiving RAIT. When controlling for age, sex, and familial and personal histories of cancer, there was an 84% increase in the risk of SPC in the RAIT+ group compared to the RAIT- group (p = 0.026; relative risk = 1.84 [CI 1.02-3.31]). There was an association between SPC incidence and total cumulative activity administered, which was statistically significant >200 mCi. The incidence of SPC was higher in both the WDCT and the RAIT+ cohorts compared to the general population (standardized incidence ratios = 1.32 and 1.40, respectively). CONCLUSION:These results indicate that in spite of the low incidence of SPC in WDTC patients, the risk is increased after RAIT, particularly for activities >200 mCi. Thus, considering the excellent survival of patients with WDTC, clinicians need to weigh the risks and benefits of RAIT, especially in patients with low-risk thyroid cancer. 10.1089/thy.2016.0655
    Quality-of-Life Priorities in Patients with Thyroid Cancer: A Multinational European Organisation for Research and Treatment of Cancer Phase I Study. Singer Susanne,Husson Olga,Tomaszewska Iwona M,Locati Laura D,Kiyota Naomi,Scheidemann-Wesp Ulrike,Hofmeister Dirk,Winterbotham Melanie,Brannan Christine,Araújo Cláudia,Gamper Eva M,Kulis Dagmara,Rimmele Harald,Andry Guy,Licitra Lisa Thyroid : official journal of the American Thyroid Association BACKGROUND:The objectives of this study were to determine quality of life (QoL) issues that are relevant to thyroid cancer patients cross-culturally, and to identify those with highest relevance to them in addition to the more general issues covered by the core European Organisation for Research and Treatment of Cancer QoL questionnaire (EORTC QLQ-C30). METHODS:A systematic literature search provided a list of potentially relevant QoL issues to supplement the core questionnaire EORTC QLQ-C30, which is widely used in research and in care and addresses QoL issues relevant to all groups of cancer patients. A panel of experts revised this list, and thyroid cancer patients rated the issues regarding their relevance for QoL by selecting the 25 issues that they would include in a thyroid cancer-specific QoL module. RESULTS:The literature search and expert discussion provided a list of 71 QoL issues that was rated by thyroid cancer patients (n = 110) from seven countries. All issues were of high priority to at least some of the patients. The most frequently selected issues were sudden attacks of tiredness, exhaustion, quality of sleep, employment, social support, fear of cancer progression, fear of second operation, difficulties swallowing, and globus sensation. CONCLUSIONS:Thyroid cancer patients cross-culturally rate fatigue-related issues as highly important for their QoL, calling for increased efforts to find successful treatments for this problem. Vocational rehabilitation is also highly relevant for them and should therefore be an important aim of multidisciplinary care. The third important area of concern is psychological issues, especially fear of progression and of additional treatments. 10.1089/thy.2015.0640
    An update in international trends in incidence rates of thyroid cancer, 1973-2007. James Benjamin C,Mitchell Janeil M,Jeon Heedo D,Vasilottos Nektarios,Grogan Raymon H,Aschebrook-Kilfoy Briseis Cancer causes & control : CCC PURPOSE:Over the past several decades, there has been a reported increase in the incidence of thyroid cancer in many countries. We previously reported an increase in thyroid cancer incidence across continents between 1973 and 2002. Here, we provide an update on the international trends in thyroid cancer between 2003 and 2007. METHODS:We examined thyroid cancer incidence data from the Cancer Incidence in Five Continents (CI5) database for the period between 1973 and 2007 from 24 populations in the Americas, Asia, Europe, Africa and Oceania, and report on the time trends as well as the distribution by histologic type and gender worldwide. RESULTS:The incidence of thyroid cancer increased during the period from 1998-2002 to 2003-2007 in the majority of populations examined, with the highest rates observed among women, most notably in Israel and the United States SEER registry, at over 14 per 100,000 people. This update suggests that incidence is rising in a similar fashion across all regions of the world. The histologic and gender distributions in the updated CI5 are consistent with the previous report. CONCLUSIONS:Our analysis of the published CI5 data illustrates that the incidence of thyroid cancer increased between 1998-2002 and 2003-2007 in most populations worldwide, and rising rates continue in all regions of the world. 10.1007/s10552-018-1023-2
    Thyroid carcinoma. Sherman Steven I Lancet (London, England) Thyroid carcinomas are fairly uncommon and include disease types that range from indolent localised papillary carcinomas to the fulminant and lethal anaplastic disease. Several attempts to formulate a consensus about treatment of thyroid carcinoma have resulted in published guidelines for diagnosis and initial disease management. Multimodality treatments are widely recommended, although there is little evidence from prospective trials to support this approach. Surgical resection to achieve local disease control remains the cornerstone of primary treatment for most thyroid cancers, and is often followed by adjuvant radioiodine treatment for papillary and follicular types of disease. Thyroid hormone replacement therapy is used not only to rectify postsurgical hypothyroidism, but also because there is evidence to suggest that high doses that suppress thyroid stimulating hormone prevent disease recurrence in patients with papillary or follicular carcinomas. Treatment for progressive metastatic disease is often of limited benefit, and there is a pressing need for novel approaches in treatment of patients at high risk of disease-related death. In families with inherited thyroid cancer syndromes, early diagnosis and intervention based on genetic testing might prevent poor disease outcomes. Care should be carefully coordinated by members of an experienced multidisciplinary team, and patients should be provided with education about diagnosis, prognosis, and treatment options to allow them to make informed contributions to decisions about their care. 10.1016/s0140-6736(03)12488-9
    Cancers with increasing incidence trends in the United States: 1999 through 2008. Simard Edgar P,Ward Elizabeth M,Siegel Rebecca,Jemal Ahmedin CA: a cancer journal for clinicians Despite declines in incidence rates for the most common cancers, the incidence of several cancers has increased in the past decade, including cancers of the pancreas, liver, thyroid, and kidney and melanoma of the skin, as well as esophageal adenocarcinoma and certain subsites of oropharyngeal cancer associated with human papillomavirus (HPV) infection. Population-based incidence data compiled by the North American Association of Central Cancer Registries were used to examine trends in incidence rates from 1999 through 2008 for the 7 cancers listed by sex, age group, race/ethnicity, and stage at diagnosis. Joinpoint regression was used to calculate average annual percent changes in incidence rates (1999-2008). Rates for HPV-related oropharyngeal cancer, esophageal adenocarcinoma, cancer of the pancreas, and melanoma of the skin increased only in whites, except for esophageal adenocarcinoma, which also increased in Hispanic men. Liver cancer rates increased in white, black, and Hispanic men and in black women only. In contrast, incidence rates for thyroid and kidney cancers increased in all racial/ethnic groups, except American Indian/Alaska Native men. Increases in incidence rates by age were steepest for liver and HPV-related oropharyngeal cancers among those aged 55 [corrected] to 64 years and for melanoma of the skin in those aged 65 years and older. Notably, for HPV-related oropharyngeal cancer in men and thyroid cancer in women, incidence rates were higher in those aged 55 to 64 years than in those aged 65 years and older. Rates increased for both local and advanced stage diseases for most cancer sites. The reasons for these increasing trends are not entirely known. Part of the increase (for esophageal adenocarcinoma and cancers of the pancreas, liver, and kidney) may be linked to the increasing prevalence of obesity as well as increases in early detection practices for some cancers. These rising trends will exacerbate the growing cancer burden associated with population expansion and aging. Additional research is needed to determine the underlying reasons for these increasing trends. 10.3322/caac.20141
    Exposing the thyroid to radiation: a review of its current extent, risks, and implications. Sinnott Bridget,Ron Elaine,Schneider Arthur B Endocrine reviews Radiation exposure of the thyroid at a young age is a recognized risk factor for the development of differentiated thyroid cancer lasting for four decades and probably for a lifetime after exposure. Medical radiation exposure, however, occurs frequently, including among the pediatric population, which is especially sensitive to the effects of radiation. In the past, the treatment of benign medical conditions with external radiation represented the most significant thyroid radiation exposures. Today, diagnostic medical radiation represents the largest source of man-made radiation exposure. Radiation exposure related to the use of computerized tomography is rising exponentially, particularly in the pediatric population. There is direct epidemiological evidence of a small but significant increased risk of cancer at radiation doses equivalent to computerized tomography doses used today. Paralleling the increasing use of medical radiation is an increase in the incidence of papillary thyroid cancer. At present, it is unclear how much of this increase is related to increased detection of subclinical disease from the increased utilization of ultrasonography and fine-needle aspiration, how much is due to a true increase in thyroid cancer, and how much, if any, can be ascribed to medical radiation exposure. Fortunately, the amount of radiation exposure from medical sources can be reduced. In this article we review the sources of thyroid radiation exposure, radiation risks to the thyroid gland, strategies for reducing radiation exposure to the thyroid, and ways that endocrinologists can participate in this effort. Finally, we provide some suggestions for future research directions. 10.1210/er.2010-0003
    Meta-analysis and meta-review of thyroid cancer gene expression profiling studies identifies important diagnostic biomarkers. Griffith Obi L,Melck Adrienne,Jones Steven J M,Wiseman Sam M Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:An estimated 4% to 7% of the population will develop a clinically significant thyroid nodule during their lifetime. In many cases, preoperative diagnoses by needle biopsy are inconclusive. Thus, there is a clear need for improved diagnostic tests to distinguish malignant from benign thyroid tumors. The recent development of high-throughput molecular analytic techniques should allow the rapid evaluation of new diagnostic markers. However, researchers are faced with an overwhelming number of potential markers from numerous thyroid cancer expression profiling studies. MATERIALS AND METHODS:To address this challenge, we have carried out a comprehensive meta-review of thyroid cancer biomarkers from 21 published studies. A gene ranking system that considers the number of comparisons in agreement, total number of samples, average fold-change and direction of change was devised. RESULTS:We have observed that genes are consistently reported by multiple studies at a highly significant rate (P < .05). Comparison with a meta-analysis of studies reprocessed from raw data showed strong concordance with our method. CONCLUSION:Our approach represents a useful method for identifying consistent gene expression markers when raw data are unavailable. A review of the top 12 candidates revealed well known thyroid cancer markers such as MET, TFF3, SERPINA1, TIMP1, FN1, and TPO as well as relatively novel or uncharacterized genes such as TGFA, QPCT, CRABP1, FCGBP, EPS8 and PROS1. These candidates should help to develop a panel of markers with sufficient sensitivity and specificity for the diagnosis of thyroid tumors in a clinical setting. 10.1200/JCO.2006.06.7330
    BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Xing Mingzhao Endocrine reviews In recent years, the T1799A B-type Raf kinase (BRAF) mutation in thyroid cancer has received enthusiastic investigation, and significant progress has been made toward understanding its tumorigenic role and clinical significance. Among various thyroid tumors, this mutation occurs uniquely in papillary thyroid cancer (PTC), the most common endocrine malignancy, and some apparently PTC-derived anaplastic thyroid cancers. Many studies have found this mutation to be associated with those clinicopathological characteristics of PTC that are conventionally known to predict tumor progression and recurrence, including, for example, old patient age, extrathyroidal invasion, lymph node metastasis, and advanced tumor stages. Direct association of BRAF mutation with the clinical progression, recurrence, and treatment failure of PTC has also been demonstrated. The BRAF mutation has even been correlated with PTC recurrence in patients with conventionally low-risk clinicopathological factors. Some molecular mechanisms determining BRAF mutation-promoted progression and the aggressiveness of PTC have recently been uncovered. These include the down-regulation of major tumor suppressor genes and thyroid iodide-metabolizing genes and the up-regulation of cancer-promoting molecules, such as vascular endothelial growth factor, matrix metalloproteinases, nuclear transcription factor kappaB, and c-Met. Thus, BRAF mutation represents a novel indicator of the progression and aggressiveness of PTC. Significant advances have also occurred in the preclinical testing of new therapeutic strategies targeting the MAPK pathway aberrantly activated by BRAF mutation and other related mutations. New mitogen extracellular kinase (MEK) inhibitors developed recently are particularly promising therapeutic agents for thyroid cancer. With these advances, it has become clearer that BRAF mutation will likely have significant impact on the clinical management of PTC. 10.1210/er.2007-0007
    Molecular pathogenesis and mechanisms of thyroid cancer. Xing Mingzhao Nature reviews. Cancer Thyroid cancer is a common endocrine malignancy. There has been exciting progress in understanding its molecular pathogenesis in recent years, as best exemplified by the elucidation of the fundamental role of several major signalling pathways and related molecular derangements. Central to these mechanisms are the genetic and epigenetic alterations in these pathways, such as mutation, gene copy-number gain and aberrant gene methylation. Many of these molecular alterations represent novel diagnostic and prognostic molecular markers and therapeutic targets for thyroid cancer, which provide unprecedented opportunities for further research and clinical development of novel treatment strategies for this cancer. 10.1038/nrc3431
    Controversies in primary treatment of low-risk papillary thyroid cancer. McLeod Donald S A,Sawka Anna M,Cooper David S Lancet (London, England) In many parts of the world, incidence of papillary thyroid cancer is increasing faster than any other malignancy. Most papillary thyroid cancers that are diagnosed are small and are generally regarded as being low risk, with little or no effect on mortality. Papillary thyroid cancer is a clinical challenge because it is difficult to prove benefit from the traditional therapeutic triad for this disorder (ie, total thyroidectomy with or without prophylactic central neck dissection, radioiodine remnant ablation, and suppression of serum thyroid-stimulating hormone with levothyroxine). However, risk of disease recurrence might be reduced by these therapies in a subset of patients with more aggressive disease. In the past decade, professional societies and other groups have established evidence-based clinical practice guidelines for management of papillary thyroid cancer, but these efforts have been made difficult by a paucity of randomised controlled trials. In this review, we summarise epidemiological data for disease incidence, discuss some controversies in disease management, and outline a therapeutic framework founded in the best available medical evidence and existing recommendations from clinical practice guidelines. 10.1016/S0140-6736(12)62205-3
    Biologic and Clinical Perspectives on Thyroid Cancer. Fagin James A,Wells Samuel A The New England journal of medicine 10.1056/NEJMra1501993
    New developments in the diagnosis and treatment of thyroid cancer. Schneider David F,Chen Herbert CA: a cancer journal for clinicians Thyroid cancer exists in several forms. Differentiated thyroid cancers include those with papillary and follicular histologies. These tumors exist along a spectrum of differentiation, and their incidence continues to climb. A number of advances in the diagnosis and treatment of differentiated thyroid cancers now exist. These include molecular diagnostics and more advanced strategies for risk stratification. Medullary cancer arises from the parafollicular cells and not the follicular cells. Therefore, diagnosis and treatment differs from those of differentiated thyroid tumors. Genetic testing and newer adjuvant therapies have changed the diagnosis and treatment of medullary thyroid cancer. This review will focus on the epidemiology, diagnosis, workup, and treatment of both differentiated and medullary thyroid cancers, focusing specifically on newer developments in the field. 10.3322/caac.21195
    Outcome after ablation in patients with low-risk thyroid cancer (ESTIMABL1): 5-year follow-up results of a randomised, phase 3, equivalence trial. Schlumberger Martin,Leboulleux Sophie,Catargi Bogdan,Deandreis Desiree,Zerdoud Slimane,Bardet Stephane,Rusu Daniela,Godbert Yann,Buffet Camille,Schvartz Claire,Vera Pierre,Morel Olivier,Benisvy Danielle,Bournaud Claire,Toubert Marie-Elisabeth,Kelly Antony,Benhamou Ellen,Borget Isabelle The lancet. Diabetes & endocrinology BACKGROUND:In ESTIMABL1, a randomised phase 3 trial of radioactive iodine (I) administration after complete surgical resection in patients with low-risk thyroid cancer, 92% of patients had complete thyroid ablation at 6-10 months, defined as a recombinant human thyroid-stimulating hormone (rhTSH)-stimulated serum thyroglobulin concentration of 1 ng/mL or less and normal findings on neck ultrasonography. Equivalence was shown between low-activity (1·1 GBq) and high-activity (3·7 GBq) radioactive iodine and also between the use of rhTSH injections and thyroid hormone withdrawal. Here, we report outcomes after 5 years of follow-up. METHODS:This multicentre, randomised, open-label, equivalence trial was done at 24 centres in France. Between March 28, 2007, and Feb 25, 2010, we randomly assigned (1:1:1:1) adults with low-risk differentiated thyroid carcinoma who had undergone total thyroidectomy to one of four strategies, each combining one of two methods of thyrotropin stimulation (rhTSH or thyroid hormone withdrawal) and one of two radioactive iodine activities (1·1 GBq or 3·7 GBq). Randomisation was by computer-generated sequence, with variable block size. Follow-up consisted of a yearly serum thyroglobulin measurement on levothyroxine treatment. Measurement of rhTSH-stimulated thyroglobulin and neck ultrasonography were done at the discretion of the treating physician. No evidence of disease was defined as serum thyroglobulin of 1 ng/mL or less on levothyroxine treatment and normal results on neck ultrasonography, when performed. This study was registered with ClinicalTrials.gov, number NCT00435851. FINDINGS:726 patients (97% of the 752 patients originally randomised) were followed up. At a median follow-up since randomisation of 5·4 years (range 0·5-9·2), 715 (98%) had no evidence of disease. The other 11 had either structural disease (n=4), raised serum thyroglobulin concentration (n=5), or indeterminate findings on neck ultrasonography (n=2). At ablation, six of these patients had received 1·1 GBq radioactive iodine (five after rhTSH and one after withdrawal) and five had received 3·7 GBq (two after rhTSH and three after withdrawal). TSH-stimulated (either after rhTSH injections or thyroid hormone withdrawal according to the treatment group) thyroglobulin concentration measured at the time of ablation was prognostic for structural disease status at ablation, ablation status at 6-10 months, and the final outcome. INTERPRETATION:Our findings suggest that disease recurrence was not related to the strategy used for ablation. These data validate the use of 1·1 GBq radioactive iodine after rhTSH for postoperative ablation in patients with low-risk thyroid cancer. FUNDING:French National Cancer Institute (INCa), French Ministry of Health, and Sanofi Genzyme. 10.1016/S2213-8587(18)30113-X
    Interconnection between circadian clocks and thyroid function. Ikegami Keisuke,Refetoff Samuel,Van Cauter Eve,Yoshimura Takashi Nature reviews. Endocrinology Circadian rhythmicity is an approximately 24-h cell-autonomous period driven by transcription-translation feedback loops of specific genes, which are referred to as 'circadian clock genes'. In mammals, the central circadian pacemaker, which is located in the hypothalamic suprachiasmatic nucleus, controls peripheral circadian clocks. The circadian system regulates virtually all physiological processes, which are further modulated by changes in the external environment, such as light exposure and the timing of food intake. Chronic circadian disruption caused by shift work, travel across time zones or irregular sleep-wake cycles has long-term consequences for our health and is an important lifestyle factor that contributes to the risk of obesity, type 2 diabetes mellitus and cancer. Although the hypothalamic-pituitary-thyroid axis is under the control of the circadian clock via the suprachiasmatic nucleus pacemaker, daily TSH secretion profiles are disrupted in some patients with hypothyroidism and hyperthyroidism. Disruption of circadian rhythms has been recognized as a perturbation of the endocrine system and of cell cycle progression. Expression profiles of circadian clock genes are abnormal in well-differentiated thyroid cancer but not in the benign nodules or a healthy thyroid. Therefore, the characterization of the thyroid clock machinery might improve the preoperative diagnosis of thyroid cancer. 10.1038/s41574-019-0237-z
    Deregulation of microRNA expression in thyroid neoplasias. Pallante Pierlorenzo,Battista Sabrina,Pierantoni Giovanna Maria,Fusco Alfredo Nature reviews. Endocrinology MicroRNAs (miRNAs) have emerged as a class of powerful gene expression regulators. Acting at the post-transcriptional level, miRNAs modulate the expression of at least one-third of the mRNAs that are encoded by the human genome. The expression of a single gene can be regulated by several miRNAs, and every miRNA has more than one target gene. Thus, the miRNA regulatory circuit, which affects essential cellular functions, is of enormous complexity. Moreover, a fundamental role for miRNAs has been determined in the onset and progression of human cancers. Here, we summarize the main alterations in miRNA expression that have been identified in thyroid neoplasias and examine the mechanisms through which miRNA deregulation might promote thyroid cell transformation. We also discuss how the emerging knowledge on miRNA deregulation could be harnessed for the diagnosis and treatment of thyroid neoplasias. 10.1038/nrendo.2013.223
    Pax-8-PPAR-γ fusion protein in thyroid carcinoma. Raman Priyadarshini,Koenig Ronald J Nature reviews. Endocrinology Thyroid carcinoma is the most common endocrine malignancy, and its incidence is continuing to increase. Most thyroid carcinomas contain one of several known driver mutations, such as the Val600Glu substitution in B-Raf, Ras mutations, RET gene fusions, or PAX8-PPARG gene fusions. The PAX8-PPARG gene fusion results in the production of a Pax-8-PPAR-γ fusion protein (PPFP), which is found in approximately one-third of follicular thyroid carcinomas, as well as some follicular-variant papillary thyroid carcinomas. In vitro and in vivo evidence indicates that PPFP is an oncoprotein. Although specific mechanisms of action remain to be defined, PPFP is considered to act as a dominant-negative inhibitor of wild-type PPAR-γ and/or as a unique transcriptional activator of subsets of PPAR-γ-responsive and Pax-8-responsive genes. Detection of the fusion transcript in thyroid nodule biopsy specimens can aid clinical decision-making when cytological findings are indeterminate. The PPAR-γ agonist pioglitazone is highly therapeutic in a transgenic mouse model of PPFP-positive thyroid carcinoma, suggesting that PPAR-γ agonists might be beneficial in patients with PPFP-positive thyroid carcinomas. 10.1038/nrendo.2014.115
    Endocrinology research-reflecting on the past decade and looking to the next. Herold Kevan C,Majzoub Joseph A,Melmed Shlomo,Pendergrass Merri,Schlumberger Martin Nature reviews. Endocrinology The inaugural issue of this journal, published in November 2005, included articles on thyroid cancer, type 2 diabetes mellitus, the metabolic syndrome, pituitary adenomas and obesity. 10 years later, we are still publishing articles on these topics (and many others). Although a great deal of progress has been made in our understanding of the pathogenesis, diagnosis and treatment of diseases of the endocrine system over the past 10 years, many challenges still remain. For this Viewpoint, we have asked five of our Advisory Board Members to comment on the progress and challenges from the past 10 years. They were also asked to offer their thoughts on where money should be spent going forward, and their predictions for what advances might be achieved in the next 10 years. 10.1038/nrendo.2015.164
    Diagnostic Utility of Molecular and Imaging Biomarkers in Cytological Indeterminate Thyroid Nodules. de Koster Elizabeth J,de Geus-Oei Lioe-Fee,Dekkers Olaf M,van Engen-van Grunsven Ilse,Hamming Jaap,Corssmit Eleonora P M,Morreau Hans,Schepers Abbey,Smit Jan,Oyen Wim J G,Vriens Dennis Endocrine reviews Indeterminate thyroid cytology (Bethesda III and IV) corresponds to follicular-patterned benign and malignant lesions, which are particularly difficult to differentiate on cytology alone. As ~25% of these nodules harbor malignancy, diagnostic hemithyroidectomy is still custom. However, advanced preoperative diagnostics are rapidly evolving.This review provides an overview of additional molecular and imaging diagnostics for indeterminate thyroid nodules in a preoperative clinical setting, including considerations regarding cost-effectiveness, availability, and feasibility of combining techniques. Addressed diagnostics include gene mutation analysis, microRNA, immunocytochemistry, ultrasonography, elastosonography, computed tomography, sestamibi scintigraphy, [18F]-2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), and diffusion-weighted magnetic resonance imaging.The best rule-out tests for malignancy were the Afirma® gene expression classifier and FDG-PET. The most accurate rule-in test was sole BRAF mutation analysis. No diagnostic had both near-perfect sensitivity and specificity, and estimated cost-effectiveness. Molecular techniques are rapidly advancing. However, given the currently available techniques, a multimodality stepwise approach likely offers the most accurate diagnosis, sequentially applying one sensitive rule-out test and one specific rule-in test. Geographical variations in cytology (e.g., Hürthle cell neoplasms) and tumor genetics strongly influence local test performance and clinical utility. Multidisciplinary collaboration and implementation studies can aid the local decision for one or more eligible diagnostics. 10.1210/er.2017-00133
    Geographic influences in the global rise of thyroid cancer. Kim Jina,Gosnell Jessica E,Roman Sanziana A Nature reviews. Endocrinology The incidence of thyroid cancer is on the rise, and this disease is projected to become the fourth leading type of cancer across the globe. From 1990 to 2013, the global age-standardized incidence rate of thyroid cancer increased by 20%. This global rise in incidence has been attributed to several factors, including increased detection of early tumours, the elevated prevalence of modifiable individual risk factors (for example, obesity) and increased exposure to environmental risk factors (for example, iodine levels). In this Review, we explore proven and novel hypotheses for how modifiable risk factors and environmental exposures might be driving the worldwide increase in the incidence of thyroid cancer. Although overscreening and the increased diagnosis of possibly clinically insignificant disease might have a role in certain parts of the world, other areas could be experiencing a true increase in incidence due to elevated exposure risks. In the current era of personalized medicine, national and international registry data should be applied to identify populations who are at increased risk for the development of thyroid cancer. 10.1038/s41574-019-0263-x
    Screening for differentiated thyroid cancer in selected populations. Lamartina Livia,Grani Giorgio,Durante Cosimo,Filetti Sebastiano,Cooper David S The lancet. Diabetes & endocrinology The main purpose of cancer screening programmes should not be to detect all cancers, but to discover potentially fatal or clinically relevant cancers. The US Preventive Services Task Force recommends against screening for thyroid cancer in the general, asymptomatic adult population, as such screening would result in harms that outweigh any potential benefits. This recommendation does not apply to patients with symptoms or to individuals at increased risk of thyroid cancer because of a history of exposure to ionising radiation (in childhood, as radioactive fallout, or in medical treatment as low-dose radiotherapy for benign conditions or high-dose radiation for malignancy), inherited genetic syndromes associated with thyroid cancer (eg, familial adenomatous polyposis), or one or more first-degree relatives with a history of thyroid cancer. We discuss the evidence for and against screening individuals who are at high risk, and consider the different screening tools available. 10.1016/S2213-8587(19)30324-9
    Thyroid transcription factors in development, differentiation and disease. Fernández Lara P,López-Márquez Arístides,Santisteban Pilar Nature reviews. Endocrinology Identification of the thyroid transcription factors (TTFs), NKX2-1, FOXE1, PAX8 and HHEX, has considerably advanced our understanding of thyroid development, congenital thyroid disorders and thyroid cancer. The TTFs are fundamental to proper formation of the thyroid gland and for maintaining the functional differentiated state of the adult thyroid; however, they are not individually required for precursor cell commitment to a thyroid fate. Although knowledge of the mechanisms involved in thyroid development has increased, the full complement of genes involved in thyroid gland specification and the signals that trigger expression of the genes that encode the TTFs remain unknown. The mechanisms involved in thyroid organogenesis and differentiation have provided clues to identifying the genes that are involved in human congenital thyroid disorders and thyroid cancer. Mutations in the genes that encode the TTFs, as well as polymorphisms and epigenetic modifications, have been associated with thyroid pathologies. Here, we summarize the roles of the TTFs in thyroid development and the mechanisms by which they regulate expression of the genes involved in thyroid differentiation. We also address the implications of mutations in TTFs in thyroid diseases and in diseases not related to the thyroid gland. 10.1038/nrendo.2014.186
    Papillary thyroid microcarcinoma: time to shift from surgery to active surveillance? Leboulleux Sophie,Tuttle R Michael,Pacini Furio,Schlumberger Martin The lancet. Diabetes & endocrinology The incidence of differentiated thyroid cancer is increasing greatly in high-income countries. Roughly 50% of this increase is attributable to the identification of intrathyroidal papillary thyroid microcarcinomas. Since mortality associated with these tumours remains low and stable, the increasing diagnosis has led to concerns about overdiagnosis and overtreatment. Management of papillary thyroid microcarcinomas should take into account the reported absence of mortality when diagnosed in the absence of lymph node metastases and distant metastases, as shown even in recent studies promoting active surveillance; a low recurrence rate of 1-5%; and the risk of permanent complications from surgery that cannot be decreased to less than 1-3%, even in high-volume tertiary care centres with experienced surgeons. On the basis of these data, active surveillance with curative intent, in which active treatment is delayed until the cancer shows signs of significant progression to avoid side-effects of treatment, should be considered in properly selected patients. 10.1016/S2213-8587(16)30180-2
    Iodine deficiency and thyroid disorders. Zimmermann Michael B,Boelaert Kristien The lancet. Diabetes & endocrinology Iodine deficiency early in life impairs cognition and growth, but iodine status is also a key determinant of thyroid disorders in adults. Severe iodine deficiency causes goitre and hypothyroidism because, despite an increase in thyroid activity to maximise iodine uptake and recycling in this setting, iodine concentrations are still too low to enable production of thyroid hormone. In mild-to-moderate iodine deficiency, increased thyroid activity can compensate for low iodine intake and maintain euthyroidism in most individuals, but at a price: chronic thyroid stimulation results in an increase in the prevalence of toxic nodular goitre and hyperthyroidism in populations. This high prevalence of nodular autonomy usually results in a further increase in the prevalence of hyperthyroidism if iodine intake is subsequently increased by salt iodisation. However, this increase is transient because iodine sufficiency normalises thyroid activity which, in the long term, reduces nodular autonomy. Increased iodine intake in an iodine-deficient population is associated with a small increase in the prevalence of subclinical hypothyroidism and thyroid autoimmunity; whether these increases are also transient is unclear. Variations in population iodine intake do not affect risk for Graves' disease or thyroid cancer, but correction of iodine deficiency might shift thyroid cancer subtypes toward less malignant forms. Thus, optimisation of population iodine intake is an important component of preventive health care to reduce the prevalence of thyroid disorders. 10.1016/S2213-8587(14)70225-6
    Leveraging the immune system to treat advanced thyroid cancers. French Jena D,Bible Keith,Spitzweg Christine,Haugen Bryan R,Ryder Mabel The lancet. Diabetes & endocrinology Inflammation has long been associated with the thyroid and with thyroid cancers, raising seminal questions about the role of the immune system in the pathogenesis of advanced thyroid cancers. With a growing understanding of dynamic tumour-immune cell interactions and the mechanisms by which tumour cells evade antitumour immunity, the field of cancer immunotherapy has been revolutionised. In this Review, we provide evidence to support the presence of an antitumour immune response in advanced thyroid cancers linked to cytotoxic T cells and NK cells. This antitumour response, however, is likely blunted by the presence of immunosuppressive pathways within the microenvironment, facilitated by tumour-associated macrophages or increased expression of negative regulators of cytotoxic T-cell function. Current and future efforts to incorporate immune-based therapies into existing tumour cell or endothelial-derived therapies-eg, with kinase inhibitors targeting tumour-associated macrophages or antibodies blocking negative regulators on T cells-could provide improved and durable responses for patients with disease that is otherwise refractory to treatment. 10.1016/S2213-8587(16)30277-7
    A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Romei Cristina,Ciampi Raffaele,Elisei Rossella Nature reviews. Endocrinology The rearranged during transfection (RET) proto-oncogene was identified in 1985 and, very soon thereafter, a rearrangement named RET/PTC was discovered in papillary thyroid carcinoma (PTC). After this discovery, other RET rearrangements were found in PTCs, particularly in those induced by radiation. For many years, it was thought that these genetic alterations only occurred in PTC, but, in the past couple of years, some RET/PTC rearrangements have been found in other human tumours. 5 years after the discovery of RET/PTC rearrangements in PTC, activating point mutations in the RET proto-oncogene were discovered in both hereditary and sporadic forms of medullary thyroid carcinoma (MTC). In contrast to the alterations found in PTC, the activation of RET in MTC is mainly due to activating point mutations. Interestingly, in the past year, RET rearrangements that were different to those described in PTC were observed in sporadic MTC. The identification of RET mutations is relevant to the early diagnosis of hereditary MTC and the prognosis of sporadic MTC. The diagnostic and prognostic role of the RET/PTC rearrangements in PTC is less relevant but still important in patient management, particularly for deciding if a targeted therapy should be initiated. In this Review, we discuss the pathogenic, diagnostic and prognostic roles of the RET proto-oncogene in both PTC and MTC. 10.1038/nrendo.2016.11
    Active surveillance for prostate and thyroid cancers: evolution in clinical paradigms and lessons learned. Lowenstein Lisa M,Basourakos Spyridon P,Williams Michelle D,Troncoso Patricia,Gregg Justin R,Thompson Timothy C,Kim Jeri Nature reviews. Clinical oncology The adverse effects of overdiagnosis and overtreatment observed in men with clinically insignificant prostate cancers after the introduction of prostate-specific antigen-based screening are now being observed in those with thyroid cancer, owing to the introduction of new imaging technologies. Thus, the evolving paradigm of active surveillance in prostate and thyroid cancers might be valuable in informing the development of future active surveillance protocols. The lessons learned from active surveillance and their implications include the need to minimize the use of broad, population-based screening programmes that do not incorporate patient education and the need for individualized or shared decision-making, which can decrease the extent of overtreatment. Furthermore, from the experience in patients with prostate cancer, we have learned that consensus is required regarding the optimal selection of patients for active surveillance, using more-specific evidence-based methods for stratifying patients by risk. In this Review, we describe the epidemiology, pathology and screening guidelines for the management of patients with prostate and thyroid cancers; the evidence of overdiagnosis and overtreatment; and provide overviews of existing international active surveillance protocols. 10.1038/s41571-018-0116-x
    Anaplastic thyroid carcinoma: from clinicopathology to genetics and advanced therapies. Molinaro Eleonora,Romei Cristina,Biagini Agnese,Sabini Elena,Agate Laura,Mazzeo Salvatore,Materazzi Gabriele,Sellari-Franceschini Stefano,Ribechini Alessandro,Torregrossa Liborio,Basolo Fulvio,Vitti Paolo,Elisei Rossella Nature reviews. Endocrinology Anaplastic thyroid carcinoma (ATC) is a rare malignancy, accounting for 1-2% of all thyroid cancers. Although rare, ATC accounts for the majority of deaths from thyroid carcinoma. ATC often originates in a pre-existing thyroid cancer lesion, as suggested by the simultaneous presence of areas of differentiated or poorly differentiated thyroid carcinoma. ATC is characterized by the accumulation of several oncogenic alterations, and studies have shown that an increased number of oncogenic alterations equates to an increased level of dedifferentiation and aggressiveness. The clinical management of ATC requires a multidisciplinary approach; according to recent American Thyroid Association guidelines, surgery, radiotherapy and/or chemotherapy should be considered. In addition to conventional therapies, novel molecular targeted therapies are the most promising emerging treatment modalities. These drugs are often multiple receptor tyrosine kinase inhibitors, several of which have been tested in clinical trials with encouraging results so far. Accordingly, clinical trials are ongoing to evaluate the safety, efficacy and effectiveness of these new agents. This Review describes the updated clinical and pathological features of ATC and provides insight into the molecular biology of this disease. The most recent literature regarding conventional, newly available and future therapies for ATC is also discussed. 10.1038/nrendo.2017.76
    Evolving molecularly targeted therapies for advanced-stage thyroid cancers. Bible Keith C,Ryder Mabel Nature reviews. Clinical oncology Increased understanding of disease-specific molecular targets of therapy has led to the regulatory approval of two drugs (vandetanib and cabozantinib) for the treatment of medullary thyroid cancer (MTC), and two agents (sorafenib and lenvatinib) for the treatment of radioactive- iodine refractory differentiated thyroid cancer (DTC) in both the USA and in the EU. The effects of these and other therapies on overall survival and quality of life among patients with thyroid cancer, however, remain to be more-clearly defined. When applied early in the disease course, intensive multimodality therapy seems to improve the survival outcomes of patients with anaplastic thyroid cancer (ATC), but salvage therapies for ATC are of uncertain benefit. Additional innovative, rationally designed therapeutic strategies are under active development both for patients with DTC and for patients with ATC, with multiple phase II and phase III randomized clinical trials currently ongoing. Continued effort is being made to identify further signalling pathways with potential therapeutic relevance in thyroid cancers, as well as to elaborate on the complex interactions between signalling pathways, with the intention of translating these discoveries into effective and personalized therapies. Herein, we summarize the progress made in molecular medicine for advanced-stage thyroid cancers of different histotypes, analyse how these developments have altered - and might further refine - patient care, and identify open questions for future research. 10.1038/nrclinonc.2016.19
    Differentiated thyroid cancer-personalized therapies to prevent overtreatment. Luster Markus,Weber Theresia,Verburg Frederik A Nature reviews. Endocrinology The concept of individualized therapy is rapidly gaining recognition in the management of patients with differentiated thyroid cancer (DTC). This Review provides an overview of the most important elements of this paradigm shift in DTC management and discusses the implications for clinical practice. In the majority of patients with DTC who have an inherently good prognosis, the extent of surgery, the dosage of (131)I therapy and the use of levothyroxine therapy are all aspects suitable for individualization, on the basis of both the stage of disease and the response to treatment. In individuals with advanced disease, newer imaging techniques, advances in (131)I therapy and the use of targeted molecular therapies (such as multitargeted kinase inhibitors) have provided new options for the personalized care of patients, for whom until recently no effective therapies were available. Individualized therapies could reduce adverse effects, including the sometimes debilitating hypothyroidism that used to be required before initiation of (131)I treatment, and major salivary gland damage, a common and unpleasant side effect of (131)I therapy. Highly individualized interdisciplinary treatment of patients with DTC might lead to improved outcomes with reduced severity and frequency of complications and adverse effects. However, in spite of ongoing research, personalized therapies remain in their infancy. 10.1038/nrendo.2014.100
    Thyroid cancer in 2013: Advances in our understanding of differentiated thyroid cancer. Reiners Christoph Nature reviews. Endocrinology Studies published in 2013 have addressed the question of whether the rising incidence of differentiated thyroid cancer is actually the result of overdiagnosis. Advances have also been made in the treatment of differentiated thyroid cancer, including improvements in radioiodine therapy. 10.1038/nrendo.2013.247
    Genomic Hallmarks of Thyroid Neoplasia. Giordano Thomas J Annual review of pathology The genomic landscape of thyroid cancers that are derived from follicular cells has been substantially elucidated through the coordinated application of high-throughput genomic technologies. Here, I review the common genetic alterations across the spectrum of thyroid neoplasia and present the resulting model of thyroid cancer initiation and progression. This model illustrates the striking correlation between tumor differentiation and overall somatic mutational burden, which also likely explains the highly variable clinical behavior and outcome of patients with thyroid cancers. These advances are yielding critical insights into thyroid cancer pathogenesis, which are being leveraged for the development of new diagnostic tools, prognostic and predictive biomarkers, and novel therapeutic approaches. 10.1146/annurev-pathol-121808-102139
    Low risk papillary thyroid cancer. Brito Juan P,Hay Ian D,Morris John C BMJ (Clinical research ed.) Thyroid cancer is one of the fastest growing diagnoses; more cases of thyroid cancer are found every year than all leukemias and cancers of the liver, pancreas, and stomach. Most of these incident cases are papillary in origin and are both small and localized. Patients with these small localized papillary thyroid cancers have a 99% survival rate at 20 years. In view of the excellent prognosis of these tumors, they have been denoted as low risk. The incidence of these low risk thyroid cancers is growing, probably because of the use of imaging technologies capable of exposing a large reservoir of subclinical disease. Despite their excellent prognosis, these subclinical low risk cancers are often treated aggressively. Although surgery is traditionally viewed as the cornerstone treatment for these tumors, there is less agreement about the extent of surgery (lobectomy v near total thyroidectomy) and whether prophylactic central neck dissection for removal of lymph nodes is needed. Many of these tumors are treated with radioactive iodine ablation and thyrotropin suppressive therapy, which-although effective for more aggressive forms of thyroid cancer-have not been shown to be of benefit in the management of these lesions. This review offers an evidence based approach to managing low risk papillary thyroid cancer. It also looks at the future of promising alternative surgical techniques, non-surgical minimally localized invasive therapies (ethanol ablation and laser ablation), and active surveillance, all of which form part of a more individualized treatment approach for low risk papillary thyroid tumors. 10.1136/bmj.g3045
    Thyroid cancer in 2015: Molecular landscape of thyroid cancer continues to be deciphered. Nikiforov Yuri E Nature reviews. Endocrinology 10.1038/nrendo.2015.217
    Advanced radioiodine-refractory differentiated thyroid cancer: the sodium iodide symporter and other emerging therapeutic targets. Spitzweg Christine,Bible Keith C,Hofbauer Lorenz C,Morris John C The lancet. Diabetes & endocrinology Approximately 30% of patients with advanced, metastatic differentiated thyroid cancer have radioiodine-refractory disease, based on decreased expression of the sodium iodide symporter SLC5A5 (NIS), diminished membrane targeting of NIS, or both. Patients with radioiodine-refractory disease, therefore, are not amenable to (131)I therapy, which is the initial systemic treatment of choice for non-refractory metastatic thyroid cancer. Patients with radioiodine-refractory cancer have historically had poor outcomes, partly because these cancers often respond poorly to cytotoxic chemotherapy. In the past decade, however, considerable progress has been made in delineating the molecular pathogenesis of radioiodine-refractory thyroid cancer. As a result of the identification of key genetic and epigenetic alterations and dysregulated signalling pathways, multiple biologically targeted drugs, in particular tyrosine-kinase inhibitors, have been evaluated in clinical trials with promising results and have begun to meaningfully impact clinical practice. In this Review, we summarise the current knowledge of the molecular pathogenesis of advanced differentiated thyroid cancer and discuss findings from clinical trials of targeted drugs in patients with radioiodine-refractory disease. Additionally, we focus on the molecular basis of loss of NIS expression, function, or both in refractory disease, and discuss preclinical and clinical data on restoration of radioiodine uptake. 10.1016/S2213-8587(14)70051-8
    Differentiated and anaplastic thyroid carcinoma: Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. Perrier Nancy D,Brierley James D,Tuttle R Michael CA: a cancer journal for clinicians Answer questions and earn CME/CNE This is a review of the major changes in the American Joint Committee on Cancer staging manual, eighth edition, for differentiated and anaplastic thyroid carcinoma. All patients younger than 55 years have stage I disease unless they have distant metastases, in which case, their disease is stage II. In patients aged 55 years or older, the presence of distant metastases confers stage IVB, while cases without distant metastases are further categorized based on the presence/absence of gross extrathyroidal extension, tumor size, and lymph node status. Patients aged 55 years or older whose tumor measures 4 cm or smaller (T1-T2) and is confined to the thyroid (N0, NX) have stage I disease, and those whose tumor measures greater than 4 cm and is confined to the thyroid (T3a) have stage II disease regardless of lymph node status. Patients aged 55 years or older whose tumor is confined to the thyroid and measures 4 cm or smaller (T1-T2) with any lymph node metastases present (N1a or N1b) have stage II disease. In patients who demonstrate gross extrathyroidal extension, the disease is considered stage II if only the strap muscles are grossly invaded (T3b); stage III if there is gross invasion of the subcutaneous tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve (T4a); or stage IVA if there is gross invasion of the prevertebral fascia or tumor encasing the carotid artery or internal jugular vein (T4b). The same T definitions will be used for both differentiated and anaplastic thyroid cancer, but the basic premise of the anatomic stage groups will remain the same. CA Cancer J Clin 2018;68:55-63. © 2017 American Cancer Society. 10.3322/caac.21439
    NADPH oxidases: new actors in thyroid cancer? Ameziane-El-Hassani Rabii,Schlumberger Martin,Dupuy Corinne Nature reviews. Endocrinology Hydrogen peroxide (H2O2) is a crucial substrate for thyroid peroxidase, a key enzyme involved in thyroid hormone synthesis. However, as a potent oxidant, H2O2 might also be responsible for the high level of oxidative DNA damage observed in thyroid tissues, such as DNA base lesions and strand breakages, which promote chromosomal instability and contribute to the development of tumours. Although the role of H2O2 in thyroid hormone synthesis is well established, its precise mechanisms of action in pathological processes are still under investigation. The NADPH oxidase/dual oxidase family are the only oxidoreductases whose primary function is to produce reactive oxygen species. As such, the function and expression of these enzymes are tightly regulated. Thyrocytes express dual oxidase 2, which produces most of the H2O2 for thyroid hormone synthesis. Thyrocytes also express dual oxidase 1 and NADPH oxidase 4, but the roles of these enzymes are still unknown. Here, we review the structure, expression, localization and function of these enzymes. We focus on their potential role in thyroid cancer, which is characterized by increased expression of these enzymes. 10.1038/nrendo.2016.64
    Screening for Thyroid Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. Lin Jennifer S,Bowles Erin J Aiello,Williams Selvi B,Morrison Caitlin C JAMA Importance:The incidence of detected thyroid cancer cases has been increasing in the United States since 1975. The majority of thyroid cancers are differentiated cancers with excellent prognosis and long-term survival. Objective:To systematically review the benefits and harms associated with thyroid cancer screening and treatment of early thyroid cancer in asymptomatic adults to inform the US Preventive Services Task Force. Data Sources:Searches of MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials for relevant studies published from January 1966 through January 2016, with active surveillance through December 2016. Study Selection:English-language studies conducted in asymptomatic adult populations. Data Extraction and Synthesis:Two reviewers independently appraised the articles and extracted relevant study data from fair- or good-quality studies. Random-effects meta-analyses were conducted to pool surgical harms. Main Outcomes and Measures:Thyroid cancer morbidity and mortality, test accuracy to detect thyroid nodules or thyroid cancer, and harms resulting from screening (including overdiagnosis) or treatment of thyroid cancer. Results:Of 10 424 abstracts, 707 full-text articles were reviewed, and 67 studies were included for this review. No fair- to good-quality studies directly examined the benefit of thyroid cancer screening. In 2 studies (n = 354), neck palpation was not sensitive to detect thyroid nodules. In 2 methodologically limited studies (n = 243), a combination of selected high-risk sonographic features was specific for thyroid malignancy. Three studies (n = 5894) directly addressed the harms of thyroid cancer screening, none of which suggested any serious harms from screening or ultrasound-guided fine-needle aspiration. No screening studies directly examined the risk of overdiagnosis. Two observational studies (n = 39 211) included cohorts of persons treated for well-differentiated thyroid cancer and persons with no surgery or surveillance; however, these studies did not adjust for confounders and therefore were not designed to determine if earlier or immediate treatment vs delayed or no surgical treatment improves patient outcomes. Based on 36 studies (n = 43 295), the 95% CI for the rate of surgical harm was 2.12 to 5.93 cases of permanent hypoparathyroidism per 100 thyroidectomies and 0.99 to 2.13 cases of recurrent laryngeal nerve palsy per 100 operations. Based on 16 studies (n = 291 796), treatment of differentiated thyroid cancer with radioactive iodine is associated with a small increase in risk of second primary malignancies and with increased risk of permanent adverse effects on the salivary gland, such as dry mouth. Conclusions and Relevance:Although ultrasonography of the neck using high-risk sonographic characteristics plus follow-up cytology from fine-needle aspiration can identify thyroid cancers, it is unclear if population-based or targeted screening can decrease mortality rates or improve important patient health outcomes. Screening that results in the identification of indolent thyroid cancers, and treatment of these overdiagnosed cancers, may increase the risk of patient harms. 10.1001/jama.2017.0562
    Thyroid cancer. Cabanillas Maria E,McFadden David G,Durante Cosimo Lancet (London, England) Thyroid cancer is the fifth most common cancer in women in the USA, and an estimated over 62 000 new cases occurred in men and women in 2015. The incidence continues to rise worldwide. Differentiated thyroid cancer is the most frequent subtype of thyroid cancer and in most patients the standard treatment (surgery followed by either radioactive iodine or observation) is effective. Patients with other, more rare subtypes of thyroid cancer-medullary and anaplastic-are ideally treated by physicians with experience managing these malignancies. Targeted treatments that are approved for differentiated and medullary thyroid cancers have prolonged progression-free survival, but these drugs are not curative and therefore are reserved for patients with progressive or symptomatic disease. 10.1016/S0140-6736(16)30172-6
    The changing incidence of thyroid cancer. Kitahara Cari M,Sosa Julie A Nature reviews. Endocrinology During the past few decades, the incidence of thyroid cancer has increased substantially in many countries, including the USA. The rise in incidence seems to be attributable both to the growing use of diagnostic imaging and fine-needle aspiration biopsy, which has led to enhanced detection and diagnosis of subclinical thyroid cancers, and environmental factors. The latest American Thyroid Association (ATA) practice guidelines for the management of adult patients with thyroid nodules and differentiated thyroid cancer differ substantially from the previous ATA guidelines published in 2009. Specifically, the problems of overdiagnosis and overtreatment of a disease that is typically indolent, where treatment-related morbidity might not be justified by a survival benefit, now seem to be acknowledged. As few modifiable risk factors for thyroid cancer have been established, the specific environmental factors that have contributed to the rising incidence of thyroid cancer remain speculative. However, the findings of several large, well-designed epidemiological studies have provided new information about exposures (such as obesity) that might influence the development of thyroid cancer. In this Review, we describe the changing incidence of thyroid cancer, suggest potential explanations for these trends, emphasize the implications for patients and highlight ongoing and potential strategies to combat this growing clinical and public health issue. 10.1038/nrendo.2016.110
    Evolving Understanding of the Epidemiology of Thyroid Cancer. Seib Carolyn Dacey,Sosa Julie Ann Endocrinology and metabolism clinics of North America The incidence of thyroid cancer worldwide has increased significantly over the past 3 decades, due predominantly to an increase in papillary thyroid cancer. Although most of these cancers are small and localized, population-based studies have documented a significant increase in thyroid cancers of all sizes and stages, in addition to incidence-based mortality for papillary thyroid cancer. This suggests that the increasing incidence of thyroid cancer is due in large part to increasing surveillance and overdiagnosis, but that there also appears to be a true increase in new cases of thyroid cancer. 10.1016/j.ecl.2018.10.002
    Gene Fusions in Thyroid Cancer. Yakushina Valentina D,Lerner Larisa V,Lavrov Alexander V Thyroid : official journal of the American Thyroid Association BACKGROUND:Gene fusions are known in many cancers as driver or passenger mutations. They play an important role in both the etiology and pathogenesis of cancer and are considered as potential diagnostic and prognostic markers and possible therapeutic targets. The spectrum and prevalence of gene fusions in thyroid cancer ranges from single cases up to 80%, depending on the specific type of cancer. During last three years, massive parallel sequencing technologies have revealed new fusions and allowed detailed characteristics of fusions in different types of thyroid cancer. SUMMARY:This article reviews all known fusions and their prevalence in papillary, poorly differentiated and anaplastic, follicular, and medullary carcinomas. The mechanisms of fusion formation are described. In addition, the mechanisms of oncogenic transformation, such as altered gene expression, forced oligomerization, and subcellular localization, are given. CONCLUSION:The prognostic value and perspectives of the utilization of gene fusions as therapeutic targets are discussed. 10.1089/thy.2017.0318
    Follicular thyroid cancer and Hürthle cell carcinoma: challenges in diagnosis, treatment, and clinical management. Grani Giorgio,Lamartina Livia,Durante Cosimo,Filetti Sebastiano,Cooper David S The lancet. Diabetes & endocrinology Follicular thyroid cancer is the second most common differentiated thyroid cancer histological type and has been overshadowed by its more common counterpart-papillary thyroid cancer-despite its unique biological behaviour and less favourable outcomes. In this Review, we comprehensively review the literature on follicular thyroid cancer to provide an evidence-based guide to the management of these tumours, to highlight the lack of evidence behind guideline recommendations, and to identify changes and challenges over the past decades in diagnosis, prognosis, and treatment. We highlight that correct identification of cancer in indeterminate cytological samples is challenging and ultrasonographic features can be misleading. Despite certain unique aspects of follicular thyroid cancer presentation and prognosis, no specific recommendations exist for follicular thyroid cancer and Hürthle cell carcinoma in evidence-based guidelines. Efforts should be made to stimulate additional research in this field. 10.1016/S2213-8587(17)30325-X
    Management of Low-Risk Papillary Thyroid Cancer. Iñiguez-Ariza Nicole M,Brito Juan P Endocrinology and metabolism (Seoul, Korea) The incidence of thyroid cancer has increased, mainly due to the incidental finding of low-risk papillary thyroid cancers (PTC). These malignancies grow slowly, and are unlikely to cause morbidity and mortality. New understanding about the prognosis of tumor features has led to reclassification of many tumors within the low-risk thyroid category, and to the development of a new one "very low-risk tumors." Alternative less aggressive approaches to therapy are now available including active surveillance and minimally invasive interventions. In this narrative review, we have summarized the available evidence for the management of low-risk PTC. 10.3803/EnM.2018.33.2.185
    Thyroid cancer management: from a suspicious nodule to targeted therapy. Perri Francesco,Giordano Antonio,Pisconti Salvatore,Ionna Franco,Chiofalo Maria G,Longo Francesco,Leopardo Davide,Della Vittoria Scarpati Giuseppina,Pezzullo Luciano Anti-cancer drugs Thyroid nodules are very common, and their frequency is four to five times higher in women than in men. Most of them are benign, with only a very little percentage revealing a malignant neoplasm. About 50% of thyroid nodules are detected by self-palpation of neck, whereas the other 50% are diagnosed by neck ultrasonography and following fine-needle aspiration. Management of thyroid nodules is very difficult, because benign nodules are prevalent, whereas thyroid carcinoma is uncommon, representing only 1% of all malignancies. A standard diagnostic approach is represented by 'first-level' exams, consisting in neck ultrasonography and serum thyroid-stimulating hormone measurement, followed, only for nodules that are suspicious of malignancy, by 'second-level' exams, consisting of fine-needle aspiration and mutational test, which does detect particular DNA mutations present only in malignant cells. In this review, we will analyze the genetics of thyroid cancer and its heterogeneity, and we will briefly describe the current available diagnostic and therapeutic approaches. 10.1097/CAD.0000000000000617
    Controversial Issues in Thyroid Cancer Management. Tuttle R Michael Journal of nuclear medicine : official publication, Society of Nuclear Medicine The lack of prospective randomized clinical trials for most management topics in differentiated thyroid cancer forces us to make management recommendations based on retrospective observational data, which are often incomplete, subject to selection bias, and conflicting. Therefore, it is not surprising that many aspects of thyroid cancer management remain controversial and not well defined. This review will examine the controversies surrounding 3 important topics in thyroid cancer management: the option of thyroid lobectomy as initial therapy, the use of preoperative neck imaging to optimize the completeness of the initial surgery, and the selective use of radioactive iodine for remnant ablation, adjuvant treatment, or treatment for known persistent or recurrent disease. As thyroid cancer management moves toward a much more risk-adapted approach to personalized recommendations, clinicians and patients must balance the risks and benefits of the potential options to arrive at a plan that is optimized regarding both patient preferences/values and the philosophy/experience of the local disease management team. 10.2967/jnumed.117.192559
    Controversies on the Use of Radioiodine in Thyroid Cancer: We Need More and Better Data. Pryma Daniel A Journal of nuclear medicine : official publication, Society of Nuclear Medicine 10.2967/jnumed.118.214197
    Follow-up of differentiated thyroid cancer - what should (and what should not) be done. Lamartina Livia,Grani Giorgio,Durante Cosimo,Borget Isabelle,Filetti Sebastiano,Schlumberger Martin Nature reviews. Endocrinology The treatment paradigm for thyroid cancer has shifted from a one-size-fits-all approach to more personalized protocols that range from active surveillance to total thyroidectomy followed by radioiodine remnant ablation. Accurate surveillance tools are available, but follow-up protocols vary widely between centres and clinicians, owing to the lack of clear, straightforward recommendations on the instruments and assessment schedule that health-care professionals should adopt. For most patients (that is, those who have had an excellent response to the initial treatment and have a low or intermediate risk of tumour recurrence), an infrequent assessment schedule is sufficient (such as a yearly determination of serum levels of TSH and thyroglobulin). Select patients will benefit from second-line imaging and more frequent assessments. This Review discusses the strengths and weaknesses of the surveillance tools and follow-up strategies that clinicians use as a function of the initial treatment and each patient's risk of recurrence. 10.1038/s41574-018-0068-3
    The impact of age on thyroid cancer staging. Kazaure Hadiza S,Roman Sanziana A,Sosa Julie A Current opinion in endocrinology, diabetes, and obesity PURPOSE OF REVIEW:Patient age at diagnosis is a well established prognostic factor for thyroid cancer survival; it is included in the American Joint Committee on Cancer (AJCC) thyroid cancer-staging system. This review provides an update on the epidemiology, risk stratification, and staging of differentiated thyroid cancer (DTC), in the context of patient age. RECENT FINDINGS:In the eighth edition AJCC staging system for DTC, the age cut-point was increased from 45 to 55 years. The appropriate age-cut point remains a subject of debate, as some studies have found a linear association of age and survival, and therefore, questioned the use of an age cut-point in the DTC staging system altogether. Emerging data on the additive role of molecular markers in the compromised survival of older patients with DTC raise the prospect of eventual inclusion of genetic markers in the management of patients and risk-stratification systems. SUMMARY:DTC staging is evolving. The pathogenesis of the compromised survival of older patients with DTC is complex, multifactorial, and not well understood. Recent advances in molecular testing are promising. More studies are needed prior to the formal inclusion of molecular markers in the staging system of DTC. 10.1097/MED.0000000000000430
    Routine thyroglobulin, neck ultrasound and physical examination in the routine follow up of patients with differentiated thyroid cancer-Where is the evidence? Gray Jessica L,Singh Gautam,Uttley Lesley,Balasubramanian Saba P Endocrine PURPOSE:Patients with differentiated thyroid cancer (DTC) typically have a favourable prognosis and recurrence as late as 45 years after diagnosis has been reported. International clinical guidelines for monitoring recommend routine thyroglobulin, ultrasound and physical examination for the detection of recurrence. The aim of this review was to systematically review whether routine monitoring using thyroglobulin (Tg), neck ultrasound and physical examination for recurrence in differentiated thyroid cancer patients is effective in improving patient survival and/or quality of life. METHODS:Primary studies were retrieved via a comprehensive search of three electronic bibliographic databases (PubMed, Web of Science Core Collection and Cochrane Library) without time restriction. Eligible studies must have reported on disease-free patients with DTC subject to long-term routine surveillance. The primary and secondary outcomes of interest were overall survival (or other survival parameters) and quality of life, respectively. RESULTS:Literature searches yielded 5529 citations, which were screened by two reviewers. 241 full texts were retrieved. No randomised controlled trials or two-arm cohort studies on the effectiveness of any of the three specified interventions were identified. However, three 'single-arm' studies reporting long-term follow-up outcomes in patients undergoing regular surveillance were identified and appraised. CONCLUSIONS:This review highlights a lack of empirical evidence to support current use of routine surveillance in DTC. Although early detection is possible, routine surveillance may lead to unnecessary intervention. 10.1007/s12020-018-1720-3
    Therapeutic advances in anaplastic thyroid cancer: a current perspective. Saini Shikha,Tulla Kiara,Maker Ajay V,Burman Kenneth D,Prabhakar Bellur S Molecular cancer Thyroid cancer incidence is increasing at an alarming rate, almost tripling every decade. In 2017, it was the fifth most common cancer in women. Although the majority of thyroid tumors are curable, about 2-3% of thyroid cancers are refractory to standard treatments. These undifferentiated, highly aggressive and mostly chemo-resistant tumors are phenotypically-termed anaplastic thyroid cancer (ATC). ATCs are resistant to standard therapies and are extremely difficult to manage. In this review, we provide the information related to current and recently emerged first-line systemic therapy (Dabrafenib and Trametinib) along with promising therapeutics which are in clinical trials and may be incorporated into clinical practice in the future. Different categories of promising therapeutics such as Aurora kinase inhibitors, multi-kinase inhibitors, epigenetic modulators, gene therapy using oncolytic viruses, apoptosis-inducing agents, and immunotherapy are reviewed. Combination treatment options that showed synergistic and antagonistic effects are also discussed. We highlight ongoing clinical trials in ATC and discuss how personalized medicine is crucial to design the second line of treatment. Besides using conventional combination therapy, embracing a personalized approach based on advanced genomics and proteomics assessment will be crucial to developing a tailored treatment plan to improve the chances of clinical success. 10.1186/s12943-018-0903-0
    Thyroid surgery for differentiated thyroid cancer - recent advances and future directions. Wang Tracy S,Sosa Julie Ann Nature reviews. Endocrinology Population-based studies have demonstrated that an increasing number of incidental thyroid nodules are being identified. The corresponding increase in thyroid-based diagnostic procedures, such as fine-needle aspiration biopsy, has in part led to an increase in the diagnoses of thyroid cancers and to more thyroid surgeries being performed. Small papillary thyroid cancers account for most of this increase in diagnoses. These cancers are considered to be low risk because of the excellent patient outcomes, with a 5-year disease-specific survival of >98%. As a result, controversy remains regarding the optimal management of newly diagnosed differentiated thyroid cancer, as the complications related to thyroidectomy (primarily recurrent laryngeal nerve injury and hypoparathyroidism) have considerable effects on patient quality of life. This Review highlights current debates, including undertaking active surveillance versus thyroid surgery for papillary thyroid microcarcinoma, the extent of thyroid surgery and lymphadenectomy for low-risk differentiated thyroid cancer, and the use of molecular testing to guide decision-making about whether surgery is required and the extent of the initial operation. This Review includes a discussion of current consensus guideline recommendations regarding these topics in patients with differentiated thyroid cancer. Additionally, innovative thyroidectomy techniques (including robotic and transoral approaches) are discussed, with an emphasis on patient preferences around decision-making and outcomes following thyroidectomy. 10.1038/s41574-018-0080-7
    Effect of Thyrotropin Suppression Therapy on Bone in Thyroid Cancer Patients. Papaleontiou Maria,Hawley Sarah T,Haymart Megan R The oncologist BACKGROUND:The thyroid cancer incidence is rising. Despite current guidelines, controversy exists regarding the degree and duration of thyrotropin suppression therapy. Also, its potential skeletal effects remain a concern to physicians caring for thyroid cancer patients. We conducted a review of published data to evaluate existing studies focusing on the skeletal effects of thyrotropin suppression therapy in thyroid cancer patients. MATERIALS AND METHODS:A systematic search of the PubMed, Ovid/Medline, and Cochrane Central Register of Controlled Trials databases was conducted. The retained studies were evaluated for methodological quality, and the study populations were categorized into premenopausal women, postmenopausal women, and men. RESULTS:Twenty-five pertinent studies were included. Seven studies were longitudinal and 18 were cross-sectional. Of the 25 included studies, 13 were assigned an excellent methodological quality score. Three of 5 longitudinal studies and 3 of 13 cross-sectional studies reported decreased bone mineral density (BMD) in premenopausal women; 2 of 4 longitudinal studies and 5 of 13 cross-sectional studies reported decreased BMD in postmenopausal women. The remaining studies showed no effect on BMD. The only longitudinal study of men showed bone mass loss; however, cross-sectional studies of men did not demonstrate a similar effect. CONCLUSION:Studies to date have yielded conflicting results on the skeletal effects of thyrotropin suppression therapy and a knowledge gap remains, especially for older adults and men. Existing data should be cautiously interpreted because of the variable quality and heterogeneity. Identifying groups at risk of adverse effects from thyrotropin suppression therapy will be instrumental to providing focused and tailored thyroid cancer treatment. IMPLICATIONS FOR PRACTICE:The standard treatment for thyroid cancer includes total thyroidectomy with or without radioactive iodine ablation, often followed by thyrotropin suppression therapy. Despite current guidelines, controversy exists regarding the degree and duration of thyrotropin suppression therapy, and discordant results have been reported on its adverse effects on bone. The present review provides physicians with existing data on the skeletal effects of thyrotropin suppression therapy, highlighting the need for further research to identify the groups at risk of adverse skeletal effects. This knowledge will aid in developing tailored thyroid cancer treatment. 10.1634/theoncologist.2015-0179
    Postsurgical Management of Differentiated Thyroid Cancer in China. Wei Wei-Jun,Zhang Guo-Qiang,Luo Quan-Yong Trends in endocrinology and metabolism: TEM Postsurgical management of differentiated thyroid cancer in China has gained a great success in the last twenty years, but there are still gaps to be filled. Here, we briefly review the current status and also extend an outlook for future development. 10.1016/j.tem.2017.10.008
    Thyroid cancer surgery guidelines in an era of de-escalation. Kovatch K J,Hoban C W,Shuman A G European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology Well-differentiated thyroid carcinoma has seen a tremendous rise in global incidence over the past three decades, largely owing to widespread screening and identification of small, incidentally detected tumors. With this increased incidence has emerged a movement questioning whether all cases of thyroid cancer merit a treatment approach focused on oncologic completeness. Such trends towards thoughtful, evidence-based treatment de-escalation paradigms reflect better risk stratification of thyroid cancers, and recognition that not all detected disease poses a threat to health or survival. Thus, national and professional guidelines are evolving to incorporate higher thresholds for surgery, acceptance of less than total thyroidectomy in specific circumstances, higher thresholds for adjuvant therapy, and introduction of the role of active surveillance for selected cases of low risk disease. Despite these common themes, there are significant differences among guidelines. This lack of consensus in guidelines persists due to variation in clinical practice patterns, differences in consideration and interpretation of existing evidence, cultural and geographical considerations, and resources available for both diagnosis and treatment. 10.1016/j.ejso.2017.03.005
    Post-treatment surveillance of thyroid cancer. Wang L Y,Ganly I European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology An increased incidence of differentiated thyroid cancer (DTC) has resulted in an increased population of thyroid cancer survivors requiring ongoing disease surveillance. Our institution's risk-adapted surveillance strategy is based on a contemporary understanding of disease biology, guided by analysis of prognostic factors and balanced application of available surveillance modalities. The goal of this strategy is to detect recurrent disease early, identify patients who would benefit from further treatment and reduce over investigation of low-risk patients. This article describes our center's risk-stratified approach to the postoperative surveillance of patients with differentiated thyroid cancer with reference to the recent 2015 American Thyroid Association management guidelines. 10.1016/j.ejso.2017.07.004
    Prognostic markers in well differentiated papillary and follicular thyroid cancer (WDTC). Gillanders S L,O'Neill J P European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology OBJECTIVES:WDTC (papillary and follicular thyroid cancer) make up around 90% of all thyroid tumours. Overall, the prognosis in patients with WDTC is excellent. However, there are small cohorts of patients who experience a more aggressive form of disease which is often associated with certain poor prognostic factors. Identifying these patients at an early stage is imperative for guiding treatment decisions. With recent developments in this area we plan to discuss the current evidence surrounding prognostic markers. METHODS:The literature regarding prognostic factors in WDTC was reviewed using an electronic database Medline - Pubmed. Using the MeSH search engine specific prognostic factors including age, size, grade, lymph node involvement, distant metastasis, extension/invasion, ethnic background, radioactive iodine avidity, and thyroglobulin level and their association with WDTC were evaluated. A broader search of prognostic markers in thyroid cancer was also carried out to avoid missing other pertinent markers. RESULTS:Multiple clinical and pathologic variables have been shown to be poor prognostic factors in WDTC with statistical significance. Extensive extrathyroidal extension and age may be the most important factors when predicting clinical outcomes in WDTC, although the age threshold may be increased from 45 to 55 years in due course. CONCLUSIONS:Management of WDTC has changed considerably over the last two years as reflected in evolving British and American Thyroid Guidelines. In all cases a combined multi-disciplinary approach, with consideration of the available guidelines and stratification systems should be utilised when planning an individualised treatment program to offer the best contemporary care to WDTC patients. 10.1016/j.ejso.2017.07.013
    Growing incidence of thyroid carcinoma in recent years: Factors underlying overdiagnosis. Sanabria Alvaro,Kowalski Luiz P,Shah Jatin P,Nixon Iain J,Angelos Peter,Williams Michelle D,Rinaldo Alessandra,Ferlito Alfio Head & neck There is an increasing incidence of well-differentiated thyroid cancer worldwide. Much of the increase is secondary to increased detection of small, low-risk tumors, with questionable clinical significance. This review addresses the factors that contribute to the increasing incidence and considers environmental, and patient-based and clinician-led influences. Articles addressing the causes of the increased incidence were critically reviewed. A complex interplay of environmental, medical, and social pressures has resulted in increased awareness of the thyroid disease risk, increased screening of thyroid cancers, and increased diagnosis of thyroid cancers. Although there is evidence to suggest that the true disease incidence may be changing slightly, most of the increase is related to factors that promote early diagnosis of low-risk lesions, which is resulting in a significant phenomenon of overdiagnosis. An improved understanding of these pressures at a global level will enable healthcare policymakers to react appropriately to this challenge in the future. 10.1002/hed.25029
    Management of recurrent/persistent nodal disease in patients with differentiated thyroid cancer: a critical review of the risks and benefits of surgical intervention versus active surveillance. Tufano Ralph P,Clayman Gary,Heller Keith S,Inabnet William B,Kebebew Electron,Shaha Ashok,Steward David L,Tuttle R Michael, Thyroid : official journal of the American Thyroid Association BACKGROUND:The primary goals of this interdisciplinary consensus statement are to define the eligibility criteria for management of recurrent and persistent cervical nodal disease in patients with differentiated thyroid cancer (DTC) and to review the risks and benefits of surgical intervention versus active surveillance. METHODS:A writing group was convened by the Surgical Affairs Committee of the American Thyroid Association and was tasked with identifying the important clinical elements to consider when managing recurrent/persistent nodal disease in patients with DTC based on the available evidence in the literature and the group's collective experience. SUMMARY:The decision on how best to manage individual patients with suspected recurrent/persistent nodal disease is challenging and requires the consideration of a significant number of variables outlined by the members of the interdisciplinary team. Here we report on the consensus opinions that were reached by the writing group regarding the technical and clinical issues encountered in this patient population. CONCLUSIONS:Identification of recurrent/persistent disease requires a team decision-making process that includes the patient and physicians as to what, if any, intervention should be performed to best control the disease while minimizing morbidity. Several management principles and variables involved in the decision making for surgery versus active surveillance were developed that should be taken into account when deciding how best to manage a patient with DTC and suspected recurrent or persistent cervical nodal disease. 10.1089/thy.2014.0098
    American Thyroid Association statement on preoperative imaging for thyroid cancer surgery. Yeh Michael W,Bauer Andrew J,Bernet Victor A,Ferris Robert L,Loevner Laurie A,Mandel Susan J,Orloff Lisa A,Randolph Gregory W,Steward David L, Thyroid : official journal of the American Thyroid Association BACKGROUND:The success of surgery for thyroid cancer hinges on thorough and accurate preoperative imaging, which enables complete clearance of the primary tumor and affected lymph node compartments. This working group was charged by the Surgical Affairs Committee of the American Thyroid Association to examine the available literature and to review the most appropriate imaging studies for the planning of initial and revision surgery for thyroid cancer. SUMMARY:Ultrasound remains the most important imaging modality in the evaluation of thyroid cancer, and should be used routinely to assess both the primary tumor and all associated cervical lymph node basins preoperatively. Positive lymph nodes may be distinguished from normal nodes based upon size, shape, echogenicity, hypervascularity, loss of hilar architecture, and the presence of calcifications. Ultrasound-guided fine-needle aspiration of suspicious lymph nodes may be useful in guiding the extent of surgery. Cross-sectional imaging (computed tomography with contrast or magnetic resonance imaging) may be considered in select circumstances to better characterize tumor invasion and bulky, inferiorly located, or posteriorly located lymph nodes, or when ultrasound expertise is not available. The above recommendations are applicable to both initial and revision surgery. Functional imaging with positron emission tomography (PET) or PET-CT may be helpful in cases of recurrent cancer with positive tumor markers and negative anatomic imaging. 10.1089/thy.2014.0096
    2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Haugen Bryan R,Alexander Erik K,Bible Keith C,Doherty Gerard M,Mandel Susan J,Nikiforov Yuri E,Pacini Furio,Randolph Gregory W,Sawka Anna M,Schlumberger Martin,Schuff Kathryn G,Sherman Steven I,Sosa Julie Ann,Steward David L,Tuttle R Michael,Wartofsky Leonard Thyroid : official journal of the American Thyroid Association BACKGROUND:Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association's (ATA's) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer. METHODS:The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations for therapeutic interventions. We developed a similarly formatted system to appraise the quality of such studies and resultant recommendations. The guideline panel had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members. RESULTS:The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, use of molecular markers, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to screening for thyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy, and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using imaging and serum thyroglobulin, thyroid hormone therapy, management of recurrent and metastatic disease, consideration for clinical trials and targeted therapy, as well as directions for future research. CONCLUSIONS:We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders. 10.1089/thy.2015.0020
    Management of thyroid cancer: United Kingdom National Multidisciplinary Guidelines. Mitchell A L,Gandhi A,Scott-Coombes D,Perros P The Journal of laryngology and otology This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. This paper provides recommendations on the management of thyroid cancer in adults and is based on the 2014 British Thyroid Association guidelines. Recommendations • Ultrasound scanning (USS) of the nodule or goitre is a crucial investigation in guiding the need for fine needle aspiration cytology (FNAC). (R) • FNAC should be considered for all nodules with suspicious ultrasound features (U3-U5). If a nodule is smaller than 10 mm in diameter, USS guided FNAC is not recommended unless clinically suspicious lymph nodes on USS are also present. (R) • Cytological analysis and categorisation should be reported according to the current British Thyroid Association Guidance. (R) • Ultrasound scanning assessment of cervical nodes should be done in FNAC-proven cancer. (R) • Magnetic resonance imaging (MRI) or computed tomography (CT) should be done in suspected cases of retrosternal extension, fixed tumours (local invasion with or without vocal cord paralysis) or when haemoptysis is reported. When CT with contrast is used pre-operatively, there should be a two-month delay between the use of iodinated contrast media and subsequent radioactive iodine (I131) therapy. (R) • Fluoro-deoxy-glucose positron emission tomography imaging is not recommended for routine evaluation. (G) • In patients with thyroid cancer, assessment of extrathyroidal extension and lymph node disease in the central and lateral neck compartments should be undertaken pre-operatively by USS and cross-sectional imaging (CT or MRI) if indicated. (R) • For patients with Thy 3f or Thy 4 FNAC a diagnostic hemithyroidectomy is recommended. (R) • Total thyroidectomy is recommended for patients with tumours greater than 4 cm in diameter or tumours of any size in association with any of the following characteristics: multifocal disease, bilateral disease, extrathyroidal spread (pT3 and pT4a), familial disease and those with clinically or radiologically involved nodes and/or distant metastases. (R) • Subtotal thyroidectomy should not be used in the management of thyroid cancer. (G) • Central compartment neck dissection is not routinely recommended for patients with papillary thyroid cancer without clinical or radiological evidence of lymph node involvement, provided they meet all of the following criteria: classical type papillary thyroid cancer, patient less than 45 years old, unifocal tumour, less than 4 cm, no extrathyroidal extension on ultrasound. (R) • Patients with metastases in the lateral compartment should undergo therapeutic lateral and central compartment neck dissection. (R) • Patients with follicular cancer with greater than 4 cm tumours should be treated with total thyroidectomy. (R) • I131 ablation should be carried out only in centres with appropriate facilities. (R) • Serum thyroglobulin (Tg) should be checked in all post-operative patients with differentiated thyroid cancer (DTC), but not sooner than six weeks after surgery. (R) • Patients who have undergone total or near total thyroidectomy should be started on levothyroxine 2 µg per kg or liothyronine 20 mcg tds after surgery. (R) • The majority of patients with a tumour more than 1 cm in diameter, who have undergone total or near-total thyroidectomy, should have I131 ablation. (R) • A post-ablation scan should be performed 3-10 days after I131 ablation. (R) • Post-therapy dynamic risk stratification at 9-12 months is used to guide further management. (G) • Potentially resectable recurrent or persistent disease should be managed with surgery whenever possible. (R) • Distant metastases and sites not amenable to surgery which are iodine avid should be treated with I131 therapy. (R) • Long-term follow-up for patients with differentiated thyroid cancer (DTC) is recommended. (G) • Follow-up should be based on clinical examination, serum Tg and thyroid-stimulating hormone assessments. (R) • Patients with suspected medullary thyroid cancer (MTC) should be investigated with calcitonin and carcino-embryonic antigen levels (CEA), 24 hour catecholamine and nor metanephrine urine estimation (or plasma free nor metanephrine estimation), serum calcium and parathyroid hormone. (R) • Relevant imaging studies are advisable to guide the extent of surgery. (R) • RET (Proto-oncogene tyrosine-protein kinase receptor) proto-oncogene analysis should be performed after surgery. (R) • All patients with known or suspected MTC should have serum calcitonin and biochemical screening for phaeochromocytoma pre-operatively. (R) • All patients with proven MTC greater than 5 mm should undergo total thyroidectomy and central compartment neck dissection. (R) • Patients with MTC with lateral nodal involvement should undergo selective neck dissection (IIa-Vb). (R) • Patients with MTC with central node metastases should undergo ipsilateral prophylactic lateral node dissection. (R) • Prophylactic thyroidectomy should be offered to RET-positive family members. (R) • All patients with proven MTC should have genetic screening. (R) • Radiotherapy may be useful in controlling local symptoms in patients with inoperable disease. (R) • Chemotherapy with tyrosine kinase inhibitors may help in controlling local symptoms. (R) • For individuals with anaplastic thyroid carcinoma, initial assessment should focus on identifying the small proportion of patients with localised disease and good performance status, which may benefit from surgical resection and other adjuvant therapies. (G) • The surgical intent should be gross tumour resection and not merely an attempt at debulking. (G). 10.1017/S0022215116000578
    American Thyroid Association Guidelines on the Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of Encapsulated Follicular Variant Papillary Thyroid Carcinoma Without Invasion to Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features. Haugen Bryan R,Sawka Anna M,Alexander Erik K,Bible Keith C,Caturegli Patrizio,Doherty Gerard M,Mandel Susan J,Morris John C,Nassar Aziza,Pacini Furio,Schlumberger Martin,Schuff Kathryn,Sherman Steven I,Somerset Hilary,Sosa Julie Ann,Steward David L,Wartofsky Leonard,Williams Michelle D Thyroid : official journal of the American Thyroid Association American Thyroid Association (ATA) leadership asked the ATA Thyroid Nodules and Differentiated Thyroid Cancer Guidelines Task Force to review, comment on, and make recommendations related to the suggested new classification of encapsulated follicular variant papillary thyroid carcinoma (eFVPTC) without capsular or vascular invasion to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The task force consists of members from the 2015 guidelines task force with the recusal of three members who were authors on the paper under review. Four pathologists and one endocrinologist were added for this specific review. The manuscript proposing the new classification and related literature were assessed. It is recommended that the histopathologic nomenclature for eFVPTC without invasion be reclassified as a NIFTP, given the excellent prognosis of this neoplastic variant. This is a weak recommendation based on moderate-quality evidence. It is also noted that prospective studies are needed to validate the observed patient outcomes (and test performance in predicting thyroid cancer outcomes), as well as implications on patients' psychosocial health and economics. 10.1089/thy.2016.0628
    Screening for Thyroid Cancer: US Preventive Services Task Force Recommendation Statement. ,Bibbins-Domingo Kirsten,Grossman David C,Curry Susan J,Barry Michael J,Davidson Karina W,Doubeni Chyke A,Epling John W,Kemper Alex R,Krist Alex H,Kurth Ann E,Landefeld C Seth,Mangione Carol M,Phipps Maureen G,Silverstein Michael,Simon Melissa A,Siu Albert L,Tseng Chien-Wen JAMA Importance:The incidence of thyroid cancer detection has increased by 4.5% per year over the last 10 years, faster than for any other cancer, but without a corresponding change in the mortality rate. In 2013, the incidence rate of thyroid cancer in the United States was 15.3 cases per 100 000 persons. Most cases of thyroid cancer have a good prognosis; the 5-year survival rate for thyroid cancer overall is 98.1%. Objective:To update the US Preventive Services Task Force (USPSTF) recommendation on screening for thyroid cancer. Evidence Review:The USPSTF reviewed the evidence on the benefits and harms of screening for thyroid cancer in asymptomatic adults, the diagnostic accuracy of screening (including neck palpation and ultrasound), and the benefits and harms of treatment of screen-detected thyroid cancer. Findings:The USPSTF found inadequate direct evidence on the benefits of screening but determined that the magnitude of the overall benefits of screening and treatment can be bounded as no greater than small, given the relative rarity of thyroid cancer, the apparent lack of difference in outcomes between patients who are treated vs monitored (for the most common tumor types), and observational evidence showing no change in mortality over time after introduction of a mass screening program. The USPSTF found inadequate direct evidence on the harms of screening but determined that the overall magnitude of the harms of screening and treatment can be bounded as at least moderate, given adequate evidence of harms of treatment and indirect evidence that overdiagnosis and overtreatment are likely to be substantial with population-based screening. The USPSTF therefore determined that the net benefit of screening for thyroid cancer is negative. Conclusions and Recommendation:The USPSTF recommends against screening for thyroid cancer in asymptomatic adults. (D recommendation). 10.1001/jama.2017.4011
    Systematic Review of Trends in the Incidence Rates of Thyroid Cancer. Wiltshire Joseph J,Drake Thomas M,Uttley Lesley,Balasubramanian Sabapathy P Thyroid : official journal of the American Thyroid Association BACKGROUND:A large proportion of global increase in thyroid cancer (TC) incidence has been attributed to increased detection of papillary thyroid cancer (PTC). Nonetheless, some reports support a real increase in incidence. This study aimed to perform a systematic review to evaluate the changing trends in TC incidence and summarize potential risk factors predisposing to this trend. METHODS:Literature published in the English language between 1980 and August 2014 was searched via PubMed (MEDLINE) and OvidSP (EMBASE). Original studies on changes in TC incidence in defined geographic areas that described clear methods of case selection and population estimates were included. Data on incidence rates and risk factors were collected. RESULTS:Of 4719 manuscripts, 60 studies were included, of which 31 were from Europe, 13 from North America, and the rest from Asia (n = 9), Oceania (n = 4), and South America (n = 3). Fifty-three articles reported a significant increase in incidence (highest was a 10-fold increase in South Korea), six reported stable rates, and one noted a decrease. PTC was the commonest type reported to have increased in incidence (in 10 studies with relevant data). Follicular TC increased in incidence (in four studies), albeit at a lower rate compared with PTC. Data on risk factors were sparse; factors discussed included ionizing radiation, iodine deficiency, and supplementation. CONCLUSION:This systematic review strongly supports a widespread and persistent increase in TC incidence. Evidence for over-detection of PTC as the predominant influence includes increased numbers of smaller size tumors and improved or unchanged survival. 10.1089/thy.2016.0100
    The association between thyroid cancer and insulin resistance, metabolic syndrome and its components: A systematic review and meta-analysis. Yin De-Tao,He Huanan,Yu Kun,Xie Jing,Lei Mengyuan,Ma Runsheng,Li Hongqiang,Wang Yongfei,Liu Zhen International journal of surgery (London, England) BACKGROUND:Thyroid cancer is rapidly increasing in incidence worldwide in the past several decades, same as the incidence of metabolic syndrome. We performed a system review and meta-analysis of the association between metabolic syndrome, its components and insulin resistance and thyroid cancer incidence. METHODS:We searched several computer-assisted databases PUBMED, EMBASE and ISI Web of Science to identify studies published before 31st January 2018. Every study must report either risk estimates of thyroid cancer incidence with 95% confidence interval (CI) or related data can speculate. Two investigators independently identified eligible studies and extracted data. Evaluating the summaries of relative risk estimates use both fixed and random effects methods. RESULTS:We found 42 articles met the inclusion criteria of this review. There is an increased risk for thyroid cancer for patients with insulin resistance (relative risk [RR] = 1.59, 95%confidence interval [CI] = 1.12-2.27, P = 0.01), dysglycemia (RR = 1.40, 95%CI = 1.15-1.70,P < 0.001), high BMI (RR = 1.35,95%CI = 1.23-1.48,P < 0.001) and hypertension(RR = 1.34,95%CI = 1.22-1.47, p < 0.001). However, patients with dyslipidemia, both total cholesterol (RR = 1.09, 95%CI = 0.98-1.21, P = 0.13) and triglyceride (RR = 1.01, 95%CI = 0.91-1.12, P = 0.82) was not associated with thyroid cancer. CONCLUSIONS:Our meta-analysis showed Insulin Resistance, dysglycemia, high BMI and hypertension significantly increased the thyroid cancer risk. These results may help identify people with high risk of thyroid cancer and change to healthy life style. 10.1016/j.ijsu.2018.07.013