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    Combined ultrasound and needle aspiration cytology in the assessment and management of hypofunctioning thyroid nodule. Walfish P G,Hazani E,Strawbridge H T,Miskin M,Rosen I B Annals of internal medicine We evaluated the efficacy of combining B-scan bistable and gray-scale ultrasound with needle aspiration cytology in assessing and managing solitary hypofunctioning solid and cystic nodules. Of the 150 cases surveyed, 90 had surgical follow-up histology for comparison to preoperative aspiration cytology results. Overall neoplasm rate in these 90 cases was 66%, increasing to 93% if colloid nodules were included. Adequate material for cytology preoperatively was obtained in 83 (92%). In cases with adequate preoperative needle aspiration cytology, there were 66 solid and 17 cystic or mixed lesions. Overall accuracy for differentiating benign from malignant nodules for solid lesions was 63 of 66 (95%), compared to 15 of 17 (88%) for predominantly cystic or mixed lesions. Of the 17 cases of proven carcinoma, correct preoperative cytology diagnosis for malignancy was obtained in 12 (71%). Malignancy was most often correctly diagnosed for solid papillary and metastatic cancer lesions. No false-positives were noted and atypical adenomas and Hürthle-cell adenomas have been correctly diagnosed. The simplicity and safety of these diagnostic procedures justify their use for "selective" surgery and particularly for those cases that have been initially assigned to conservative, nonsurgical therapy. 10.7326/0003-4819-87-3-270_1
    Thyroid nodules after high-dose external radiotherapy. Fine-needle aspiration cytology in diagnosis and management. Pretorius H T,Katikineni M,Kinsella T J,Barsky S H,Brennan M F,Chu E W,Robbins J JAMA From 1974 to 1980, we studied six patients, five treated for Hodgkin's disease and one for a hemangioma, in whom thyroid nodules developed after high-dose (2,500 to 4,000 rad) thyroid radiation. Fine-needle aspiration cytology of the thyroid in five cases showed moderate to severe cellular atypia in four (three of whom had elevated serum thyrotropin levels) and mild atypia in one (who was overtly hypothyroid). In the four with marked atypia, surgical pathology disclosed Hashimoto's thyroiditis in one, diffuse hyperplasia and epithelial atypia in two, and a sclerosing papillary carcinoma in one. Among five patients who had total thyroidectomy, three had carcinoma (microscopic papillary, papillary-follicular, or sclerosing papillary) in addition to one or more follicular adenomas or colloid nodules. Thyroid nodules and neoplasia may be more common than previously appreciated in patients exposed to high-dose radiation.
    The role of thyroid-stimulating antibodies of Graves' disease in differentiated thyroid cancer. Filetti S,Belfiore A,Amir S M,Daniels G H,Ippolito O,Vigneri R,Ingbar S H The New England journal of medicine 10.1056/NEJM198803243181206
    Outcome after treatment of high-risk papillary and non-Hürthle-cell follicular thyroid carcinoma. Taylor T,Specker B,Robbins J,Sperling M,Ho M,Ain K,Bigos S T,Brierley J,Cooper D,Haugen B,Hay I,Hertzberg V,Klein I,Klein H,Ladenson P,Nishiyama R,Ross D,Sherman S,Maxon H R Annals of internal medicine BACKGROUND:Treatment of differentiated thyroid cancer has been studied for many years, but the benefits of extensive initial thyroid surgery and the addition of radioiodine therapy or external radiation therapy remain controversial. OBJECTIVE:To determine the relations among extent of surgery, radioiodine therapy, and external radiation therapy in the treatment of high-risk papillary and non-Hürthle-cell follicular thyroid carcinoma. DESIGN:Analysis of data from a multicenter study. SETTING:14 institutions in the United States and Canada participating in the National Thyroid Cancer Treatment Cooperative Study Registry. PATIENT:385 patients with high-risk thyroid cancer (303 with papillary carcinoma and 82 with follicular carcinoma). MEASUREMENTS:Death, disease progression, and disease-free survival. RESULTS:Total or near-total thyroidectomy was done in 85.3% of patients with papillary carcinoma and 71.3% of patients with follicular cancer. Overall surgical complication rate was 14.3%. Total or near-total thyroidectomy improved overall survival (risk ratio [RR], 0.37 [95% CI, 0.18 to 0.75]) but not cancer-specific mortality, progression, or disease-free survival in patients with papillary cancer. No effect of extent of surgery was seen in patients with follicular thyroid cancer. Postoperative iodine-131 was given to 85.4% of patients with papillary cancer and 79.3% of patients with follicular cancer. In patients with papillary cancer, radioiodine therapy was associated with improvement in cancer-specific mortality (RR, 0.30 [CI, 0.09 to 0.93 by multivariate analysis only]) and progression (RR, 0.30 [CI, 0.13 to 0.72]). When tall-cell variants were excluded, the effect on outcome was not significant. After radioiodine therapy, patients with follicular thyroid cancer had improvement in overall mortality (RR, 0.17 [CI, 0.06 to 0.47]), cancer-specific mortality (RR, 0.12 [CI, 0.04 to 0.42]), progression (RR, 0.21 [CI, 0.08 to 0.56]), and disease-free survival (RR, 0.29 [CI, 0.08 to 1.01]). External radiation therapy to the neck was given to 18.5% of patients and was not associated with improved survival, lack of progression, or disease-free survival. CONCLUSIONS:This study supports improvement in overall and cancer-specific mortality among patients with papillary and follicular thyroid cancer after postoperative iodine-131 therapy. Radioiodine therapy was also associated with improvement in progression in patients with papillary cancer and improvement in progression and disease-free survival in patients with follicular carcinoma. 10.7326/0003-4819-129-8-199810150-00007
    Thyroid FNA and benign thyroid disease. Poller D,Yiangou C,Cummings M,Boote D Lancet (London, England) 10.1016/S0140-6736(05)73824-1
    Independent clonal origins of distinct tumor foci in multifocal papillary thyroid carcinoma. Shattuck Trisha M,Westra William H,Ladenson Paul W,Arnold Andrew The New England journal of medicine BACKGROUND:Papillary thyroid carcinoma is frequently multifocal. We investigated whether noncontiguous tumor foci arise from intraglandular metastases from a single primary tumor or originate as unrelated clones derived from independent precursors. METHODS:Using a polymerase-chain-reaction assay involving the human androgen receptor gene (HUMARA), we analyzed the patterns of X-chromosome inactivation of multiple distinct foci of well-differentiated multifocal papillary thyroid cancer from 17 women. RESULTS:Multiple thyroid tumor foci from 10 of 17 patients yielded DNA of adequate quality and were heterozygous for the HUMARA polymorphism and hence suitable for analysis. A single X chromosome was inactivated in each focus, consistent with its monoclonality. When the specific monoclonal configurations of each patient's discrete tumor foci were compared, discordant patterns indicative of independent origins were observed among the tumors from five patients; results in the remaining five were consistent with either a shared or independent clonal origin. CONCLUSIONS:Individual tumor foci in patients with multifocal papillary thyroid cancer often arise as independent tumors. 10.1056/NEJMoa044190
    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
    BRAF mutation testing of thyroid fine-needle aspiration biopsy specimens for preoperative risk stratification in papillary thyroid cancer. Xing Mingzhao,Clark Douglas,Guan Haixia,Ji Meiju,Dackiw Alan,Carson Kathryn A,Kim Matthew,Tufaro Anthony,Ladenson Paul,Zeiger Martha,Tufano Ralph Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:This study investigated the utility of BRAF mutation testing of thyroid fine-needle aspiration biopsy (FNAB) specimens for preoperative risk stratification in papillary thyroid cancer (PTC). PATIENTS AND METHODS:We assessed the T1799A BRAF mutation status in thyroid FNAB specimens obtained from 190 patients before thyroidectomy for PTC and its association with clinicopathologic characteristics of the tumor revealed postoperatively. RESULTS:We observed a significant association of BRAF mutation in preoperative FNAB specimens with poorer clinicopathologic outcomes of PTC. In comparison with the wild-type allele, BRAF mutation strongly predicted extrathyroidal extension (23% v 11%; P = .039), thyroid capsular invasion (29% v 16%; P = .045), and lymph node metastasis (38% v 18%; P = .002). During a median follow-up of 3 years (range, 0.6 to 10 years), PTC persistence/recurrence was seen in 36% of BRAF mutation-positive patients versus 12% of BRAF mutation-negative patients, with an odds ratio of 4.16 (95% CI, 1.70 to 10.17; P = .002). The positive and negative predictive values for preoperative FNAB-detected BRAF mutation to predict PTC persistence/recurrence were 36% and 88% for overall PTC and 34% and 92% for conventional PTC, respectively. CONCLUSION:Preoperative BRAF mutation testing of FNAB specimens provides a novel tool to preoperatively identify PTC patients at higher risk for extensive disease (extrathyroidal extension and lymph node metastases) and those who are more likely to manifest disease persistence/recurrence. BRAF mutation, as a powerful risk prognostic marker, may therefore be useful in appropriately tailoring the initial surgical extent for patients with PTC. 10.1200/JCO.2008.20.1426
    Incidence of thyroid cancer in Italy, 1991-2005: time trends and age-period-cohort effects. Dal Maso L,Lise M,Zambon P,Falcini F,Crocetti E,Serraino D,Cirilli C,Zanetti R,Vercelli M,Ferretti S,Stracci F,De Lisi V,Busco S,Tagliabue G,Budroni M,Tumino R,Giacomin A,Franceschi S, Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:In Italy, some of the highest incidence rates (IRs) of thyroid cancer (TC) worldwide have been reported. PATIENTS AND METHODS:TC cases <85 years of age reported to Italian cancer registries during 1991-2005 were included. Age-standardized IRs were computed for all TC and age-period-cohort effects were estimated for papillary TC. RESULTS:IRs of TC were twofold higher in 2001-2005 than in 1991-1995 (18 and 8 per 100,000 women, 6 and 3 per 100,000 men, respectively). Increases were similar in the two sexes and nearly exclusively due to papillary TC. Increases of papillary TC by birth cohort were found in both sexes and among all age groups between 20 and 79 years. Age-period-cohort models showed a strong period effect in both sexes (rate ratio for 2001-2009 versus 1991-1995 = 2.5 in women and 2.3 in men), although IRs peaked at an earlier age in women (45-49 years) than men (65-69 years). CONCLUSION:The strength of the period effect in both sexes and the earlier onset in women than men strongly implicated increased medical surveillance in the upward trends of papillary TC incidence in Italy. The consequences of the current intense search for TC on morbidity and possible overtreatment, especially among young women, should be carefully evaluated. 10.1093/annonc/mdq467
    Cancer: Small papillary thyroid cancers--is BRAF of prognostic value? Soares Paula,Sobrinho-Simões Manuel Nature reviews. Endocrinology The growing incidence in thyroid cancer results mainly from the detection of small or very small papillary thyroid carcinomas. The management of patients with such small tumors represents a major clinical challenge. Could evaluation of the BRAF status of such tumors aid risk stratification and patient management? 10.1038/nrendo.2010.213
    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
    Molecular genetics and diagnosis of thyroid cancer. Nikiforov Yuri E,Nikiforova Marina N Nature reviews. Endocrinology Thyroid cancer is a common type of endocrine malignancy, and its incidence has been steadily increasing in many regions of the world. Initiation and progression of thyroid cancer involves multiple genetic and epigenetic alterations, of which mutations leading to the activation of the MAPK and PI3K-AKT signaling pathways are crucial. Common mutations found in thyroid cancer are point mutation of the BRAF and RAS genes as well as RET/PTC and PAX8/PPARγ chromosomal rearrangements. The mutational mechanisms seem to be linked to specific etiologic factors. Chromosomal rearrangements have a strong association with exposure to ionizing radiation and possibly with DNA fragility, whereas point mutations probably arise as a result of chemical mutagenesis. A potential role of dietary iodine excess in the generation of BRAF point mutations has also been proposed. Somatic mutations and other molecular alterations have been recognized as helpful diagnostic and prognostic markers for thyroid cancer and are beginning to be introduced into clinical practice, to offer a valuable tool for the management of patients with thyroid nodules. 10.1038/nrendo.2011.142
    Unusual thyroid tumors in a young woman. Yamashita Kentaro,Arimura Yoshiaki,Shinomura Yasuhisa Gastroenterology 10.1053/j.gastro.2011.08.003
    Strategies of radioiodine ablation in patients with low-risk thyroid cancer. Schlumberger Martin,Catargi Bogdan,Borget Isabelle,Deandreis Désirée,Zerdoud Slimane,Bridji Boumédiène,Bardet Stéphane,Leenhardt Laurence,Bastie Delphine,Schvartz Claire,Vera Pierre,Morel Olivier,Benisvy Danielle,Bournaud Claire,Bonichon Françoise,Dejax Catherine,Toubert Marie-Elisabeth,Leboulleux Sophie,Ricard Marcel,Benhamou Ellen, The New England journal of medicine BACKGROUND:It is not clear whether the administration of radioiodine provides any benefit to patients with low-risk thyroid cancer after a complete surgical resection. The administration of the smallest possible amount of radioiodine would improve care. METHODS:In our randomized, phase 3 trial, we compared two thyrotropin-stimulation methods (thyroid hormone withdrawal and use of recombinant human thyrotropin) and two radioiodine ((131)I) doses (i.e., administered activities) (1.1 GBq and 3.7 GBq) in a 2-by-2 design. Inclusion criteria were an age of 18 years or older; total thyroidectomy for differentiated thyroid carcinoma; tumor-node-metastasis (TNM) stage, ascertained on pathological examination (p) of a surgical specimen, of pT1 (with tumor diameter ≤1 cm) and N1 or Nx, pT1 (with tumor diameter >1 to 2 cm) and any N stage, or pT2N0; absence of distant metastasis; and no iodine contamination. Thyroid ablation was assessed 8 months after radioiodine administration by neck ultrasonography and measurement of recombinant human thyrotropin-stimulated thyroglobulin. Comparisons were based on an equivalence framework. RESULTS:There were 752 patients enrolled between 2007 and 2010; 92% had papillary cancer. There were no unexpected serious adverse events. In the 684 patients with data that could be evaluated, ultrasonography of the neck was normal in 652 (95%), and the stimulated thyroglobulin level was 1.0 ng per milliliter or less in 621 of the 652 patients (95%) without detectable thyroglobulin antibodies. Thyroid ablation was complete in 631 of the 684 patients (92%). The ablation rate was equivalent between the (131)I doses and between the thyrotropin-stimulation methods. CONCLUSIONS:The use of recombinant human thyrotropin and low-dose (1.1 GBq) postoperative radioiodine ablation may be sufficient for the management of low-risk thyroid cancer. (Funded by the French National Cancer Institute [INCa] and the French Ministry of Health; ClinicalTrials.gov number, NCT00435851; INCa number, RECF0447.). 10.1056/NEJMoa1108586
    Increasing incidence of thyroid cancer: controversies explored. Ito Yasuhiro,Nikiforov Yuri E,Schlumberger Martin,Vigneri Riccardo Nature reviews. Endocrinology Thyroid cancer is the most common endocrine malignancy and its incidence has been increasing considerably in the past few decades. Many studies have been published providing evidence for this increase; however, why thyroid cancer incidence keeps rising is still debated and there are conflicting reports of factors leading to the increase in its incidence. In this article, Nature Reviews Endocrinology asks four experts their opinions on some of the controversies surrounding the changing trends in thyroid cancer incidence. 10.1038/nrendo.2012.257
    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
    Progress in molecular-based management of differentiated thyroid cancer. Xing Mingzhao,Haugen Bryan R,Schlumberger Martin Lancet (London, England) Substantial developments have occurred in the past 5-10 years in clinical translational research of thyroid cancer. Diagnostic molecular markers, such as RET-PTC, RAS, and BRAF(V600E) mutations; galectin 3; and a new gene expression classifier, are outstanding examples that have improved diagnosis of thyroid nodules. BRAF mutation is a prognostic genetic marker that has improved risk stratification and hence tailored management of patients with thyroid cancer, including those with conventionally low risks. Novel molecular-targeted treatments hold great promise for radioiodine-refractory and surgically inoperable thyroid cancers as shown in clinical trials; such treatments are likely to become a component of the standard treatment regimen for patients with thyroid cancer in the near future. These novel molecular-based management strategies for thyroid nodules and thyroid cancer are the most exciting developments in this unprecedented era of molecular thyroid-cancer medicine. 10.1016/S0140-6736(13)60109-9
    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
    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
    Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. Xing Mingzhao,Alzahrani Ali S,Carson Kathryn A,Shong Young Kee,Kim Tae Yong,Viola David,Elisei Rossella,Bendlová Bela,Yip Linwah,Mian Caterina,Vianello Federica,Tuttle R Michael,Robenshtok Eyal,Fagin James A,Puxeddu Efisio,Fugazzola Laura,Czarniecka Agnieszka,Jarzab Barbara,O'Neill Christine J,Sywak Mark S,Lam Alfred K,Riesco-Eizaguirre Garcilaso,Santisteban Pilar,Nakayama Hirotaka,Clifton-Bligh Roderick,Tallini Giovanni,Holt Elizabeth H,Sýkorová Vlasta Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:To investigate the prognostic value of BRAF V600E mutation for the recurrence of papillary thyroid cancer (PTC). PATIENTS AND METHODS:This was a retrospective multicenter study of the relationship between BRAF V600E mutation and recurrence of PTC in 2,099 patients (1,615 women and 484 men), with a median age of 45 years (interquartile range [IQR], 34 to 58 years) and a median follow-up time of 36 months (IQR, 14 to 75 months). RESULTS:The overall BRAF V600E mutation prevalence was 48.5% (1,017 of 2,099). PTC recurrence occurred in 20.9% (213 of 1,017) of BRAF V600E mutation-positive and 11.6% (125 of 1,082) of BRAF V600E mutation-negative patients. Recurrence rates were 47.71 (95% CI, 41.72 to 54.57) versus 26.03 (95% CI, 21.85 to 31.02) per 1,000 person-years in BRAF mutation-positive versus -negative patients (P < .001), with a hazard ratio (HR) of 1.82 (95% CI, 1.46 to 2.28), which remained significant in a multivariable model adjusting for patient sex and age at diagnosis, medical center, and various conventional pathologic factors. Significant association between BRAF mutation and PTC recurrence was also found in patients with conventionally low-risk disease stage I or II and micro-PTC and within various subtypes of PTC. For example, in BRAF mutation-positive versus -negative follicular-variant PTC, recurrence occurred in 21.3% (19 of 89) and 7.0% (24 of 342) of patients, respectively, with recurrence rates of 53.84 (95% CI, 34.34 to 84.40) versus 19.47 (95% CI, 13.05 to 29.04) per 1,000 person-years (P < .001) and an HR of 3.20 (95% CI, 1.46 to 7.02) after adjustment for clinicopathologic factors. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories. CONCLUSION:This large multicenter study demonstrates an independent prognostic value of BRAF V600E mutation for PTC recurrence in various clinicopathologic categories. 10.1200/JCO.2014.56.8253
    Genetics: The Cancer Genome Atlas maps papillary thyroid cancer. Killock David Nature reviews. Clinical oncology 10.1038/nrclinonc.2014.193
    Integrated genomic characterization of papillary thyroid carcinoma. Cell Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease. 10.1016/j.cell.2014.09.050
    Presence and Number of Lymph Node Metastases Are Associated With Compromised Survival for Patients Younger Than Age 45 Years With Papillary Thyroid Cancer. Adam Mohamed Abdelgadir,Pura John,Goffredo Paolo,Dinan Michaela A,Reed Shelby D,Scheri Randall P,Hyslop Terry,Roman Sanziana A,Sosa Julie A Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:Cervical lymph node metastases are recognized as a prognostic indicator only in patients age 45 years or older with papillary thyroid cancer (PTC); patients younger than age 45 years are perceived to have low-risk disease. The current American Joint Committee on Cancer staging for PTC in patients younger than age 45 years does not include cervical lymph node metastases. Our objective was to test the hypothesis that the presence and number of cervical lymph node metastases have an adverse impact on overall survival (OS) in patients younger than age 45 years with PTC. PATIENTS AND METHODS:Adult patients younger than age 45 years undergoing surgery for stage I PTC (no distant metastases) were identified from the National Cancer Data Base (NCDB; 1998-2006) and from SEER 1988-2006 data. Multivariable models were used to examine the association of OS with the presence of lymph node metastases and number of metastatic nodes. RESULTS:In all, 47,902 patients in NCDB (11,740 with and 36,162 without nodal metastases) and 21,855 in the SEER database (5,188 with and 16,667 without nodal metastases) were included. After adjustment, OS was compromised for patients with nodal metastases compared with patients who did not have them (NCDB: hazard ratio (HR), 1.32; 95% CI, 1.04 to 1.67; P = .021; SEER: HR, 1.29; 95% CI, 1.08 to 1.56; P = .006). After adjustment, increasing number of metastatic lymph nodes was associated with decreasing OS up to six metastatic nodes (HR, 1.12; 95% CI, 1.01 to 1.25; P = .03), after which more positive nodes conferred no additional mortality risk (HR, 0.99; 95% CI, 0.99 to 1.05; P = .75). CONCLUSION:Our results suggest that cervical lymph node metastases are associated with compromised survival in young patients, warranting consideration of revised American Joint Committee on Cancer staging. A change point of six or fewer metastatic lymph nodes seems to carry prognostic significance, thus advocating for rigorous preoperative screening for nodal metastases. 10.1200/JCO.2014.59.8391
    BRAF Mutation and Thyroid Cancer Recurrence. Xing Mingzhao Journal of clinical oncology : official journal of the American Society of Clinical Oncology 10.1200/JCO.2015.61.4016
    Thyroid cancer subtype downgraded to non-cancer. Tanday Sanjay The Lancet. Oncology 10.1016/S1470-2045(16)30089-4
    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
    Mutated BRAF and personalised medicine in differentiated thyroid cancer. Bible Keith C,Ryder Mabel The Lancet. Oncology 10.1016/S1470-2045(16)30230-3
    How Many Lymph Nodes Are Enough? Assessing the Adequacy of Lymph Node Yield for Papillary Thyroid Cancer. Robinson Timothy J,Thomas Samantha,Dinan Michaela A,Roman Sanziana,Sosa Julie Ann,Hyslop Terry Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:Patients who undergo surgery for papillary thyroid cancer with only a limited lymph node examination are thought to be at risk for potentially harboring occult disease. However, this risk has not been objectively quantified and may have implications for subsequent management and surveillance. METHODS:Data from the National Cancer Database (1998 to 2012) were used to characterize the distribution of nodal positivity of adult patients diagnosed with localized ≥ 1-cm papillary thyroid cancer who underwent thyroidectomy with one or more lymph nodes (LNs) examined. A β-binomial distribution was used to estimate the probability of occult nodal disease as a function of total number of LNs examined and pathologic tumor stage. RESULTS:A total of 78,724 patients met study criteria; 38,653 patients had node-positive disease. The probability of falsely identifying a patient as node negative was estimated to be 53% for patients with a single node examined and decreased to less than 10% when more than six LNs were examined. To rule out occult nodal disease with 90% confidence, six, nine, and 18 nodes would need to be examined for patients with T1b, T2, and T3 disease, respectively. Sensitivity analyses limited to patients likely undergoing prophylactic central neck dissection resulted in three, four, and eight nodes needed to provide comparable adequacy of LN evaluation. CONCLUSION:To our knowledge, our study provides the first empirically based estimates of occult nodal disease risk in patients after surgery for papillary thyroid cancer as a function of primary tumor stage and number of LNs examined. Our estimates provide an objective guideline for evaluating adequacy of LN yield for surgeons and pathologists in the treatment of papillary thyroid cancer, and especially intermediate-risk disease, for which use of adjuvant radioactive iodine and surveillance intensity are not currently standardized. 10.1200/JCO.2016.67.6437
    Mortality Risk Stratification by Combining BRAF V600E and TERT Promoter Mutations in Papillary Thyroid Cancer: Genetic Duet of BRAF and TERT Promoter Mutations in Thyroid Cancer Mortality. Liu Rengyun,Bishop Justin,Zhu Guangwu,Zhang Tao,Ladenson Paul W,Xing Mingzhao JAMA oncology IMPORTANCE:BRAF V600E and TERT promoter mutations can coexist in papillary thyroid cancer (PTC). This genetic duet was indicated to be involved in the aggressiveness of PTC, but its prognostic value in PTC-related mortality remains to be specifically established. OBJECTIVE:To establish the prognostic power of this genetic duet in PTC-specific mortality. DESIGN, SETTING, AND PARTICIPANTS:This genetic-clinical correlation study examined BRAF V600E and TERT promoter mutations (chr5:1,295,228C>T and chr5:1,295,250C>T) and PTC-specific mortality in 1051 patients (764 women and 287 men) with a median (interquartile range [IQR]) age of 46 (36-57) years, with a median (IQR) follow-up time of 89 (48-142) months (7.4 years). MAIN OUTCOMES AND MEASURES:BRAF V600E and TERT promoter mutation patterns and associated patient deaths caused by PTC. RESULTS:Papillary thyroid cancer-specific mortality occurred in 4 of 629 patients (0.6%) with neither mutation; 7 of 292 (2.4%) with BRAF V600E alone; 4 of 64 (6.3%) with TERT promoter mutation alone; and 15 of 66 (22.7%) with the genetic duet; and deaths per 1000-person years in patients harboring neither mutation, BRAF V600E alone, TERT mutation alone, or both mutations were 0.80 (95% CI, 0.30-2.13), 3.08 (95% CI, 1.47-6.46), 6.62 (95% CI, 2.48-17.64), and 29.86 (95% CI, 18.00-49.52), respectively. Compared with patients harboring neither mutation, HRs (95% CIs) for PTC-specific mortality were 3.08 (0.87-10.84) for BRAF V600E alone; 8.18 (2.04-32.75) with TERT mutation alone; and 37.77 (12.50-114.09) with both mutations. Papillary thyroid cancer-specific mortality for cases with both mutations remained significant (HR, 9.34; 95% CI, 2.53-34.48) after adjustment for clinicopathological factors, and the genetic duet showed a strong incremental and synergistic impact over either mutation alone. Kaplan-Meier analyses revealed a flat PTC-specific patient survival curve with neither mutation, a modest decline in the curve with either mutation alone, and a sharp decline in the curve with coexisting mutations. Even more robust mortality associations of the genetic duet were seen when only conventional-variant PTC (CPTC) was analyzed (HR, 54.46; 95% CI, 12.26-241.82), which remained strongly significant (HR, 18.56; 95% CI, 2.97-116.18) after adjustment for clinicopathological factors. CONCLUSIONS AND RELEVANCE:These results demonstrate a simple 4-genotype classification of PTC, particularly CPTC, with a disease-specific mortality risk order of the genetic duet>>>>BRAF V600E alone = TERT promoter mutation alone > wild-type for both genes, representing a powerful molecular prognostic system that can help pinpoint patients with the highest mortality risk. 10.1001/jamaoncol.2016.3288
    Exploring the Relationship Between Patient Age and Cancer-Specific Survival in Papillary Thyroid Cancer: Rethinking Current Staging Systems. Adam Mohamed Abdelgadir,Thomas Samantha,Hyslop Terry,Scheri Randall P,Roman Sanziana A,Sosa Julie A Journal of clinical oncology : official journal of the American Society of Clinical Oncology Purpose Patient age is considered to play a unique prognostic role in papillary thyroid cancer (PTC), with a distinct staging dichotomization at 45 years of age. This is based on older, limited data demonstrating a marked rise in mortality around the ages of 40 to 50 years. We hypothesized that age is associated with compromised survival from cancer, with no cutoff denoting survival difference. Patients and Methods Patients with PTC who had surgery were identified from the SEER database (1998 to 2012). Multivariable proportional hazards modeling utilizing several flexible smoothing approaches were used to examine the association between age and cancer-specific survival (CSS) and to determine whether there is an age cut point that is associated with CSS decrement. Results A total of 31,802 patients with PTC were included. Median age was 45 years (range, 2 to 105 years). Ten-year CSS according to age was as follows: 2 to 19 years, 99.8%; 20 to 29 years, 99.9%; 30 to 39 years, 99.8%; 40 to 49 years, 99.5%; 50 to 59 years, 98.1%; 60 to 69 years, 94.8%; 70 to 79 years, 91.5%; 80 to 89 years, 79.2%; and ≥ 90 years, 73.9%. After adjustment for patient demographic and clinicopathologic characteristics, increasing age was associated with increasing mortality from the disease in a dose-dependent fashion, without an apparent cut point. Each of the smoothing approaches demonstrated a similar linearity of risk over all ages and provided close measures of goodness of fit to the data. Conclusion Patient age is significantly associated with death from PTC in a linear fashion, without an apparent age cut point demarcating survival difference. These results challenge the appropriateness of a patient age cut point in current staging systems for PTC and argue for considering a revision in how we anticipate prognosis for patients with PTC. 10.1200/JCO.2016.68.9372
    Thyroid cancer: Overdiagnosis of papillary carcinoma - who benefits? Brito Juan P,Hay Ian D Nature reviews. Endocrinology 10.1038/nrendo.2016.224
    Frequency of Thyroid Carcinoma in Brazilian TP53 p.R337H Carriers With Li Fraumeni Syndrome. Formiga Maria Nirvana da Cruz,de Andrade Kelvin César,Kowalski Luiz Paulo,Achatz Maria Isabel JAMA oncology IMPORTANCE:Li Fraumeni syndrome (LFS) is associated with a wide variety of tumors; nevertheless, thyroid carcinoma has not been evaluated in this syndrome. Due to the Brazilian founder mutation p.R337H, some tumors that have not been described in the classic LFS have been observed in a higher-than-expected prevalence in Brazil. OBJECTIVE:To determine the frequency of thyroid carcinoma in Brazilian carriers of a founder TP53 p.R337H mutation. DESIGN, SETTING, AND PARTICIPANTS:We reviewed medical records of patients with LFS with germline TP53 p.R337H mutation. For a better understanding of the correlation between thyroid carcinoma and LFS, tumor profile data of Brazilian carriers were analyzed. We included data from 193 patients with LFS with the TP53 p.R337H mutation from the database of the Department of Oncogenetics from the A.C. Camargo Cancer Center. MAIN OUTCOMES AND MEASURES:Thyroid tumors found in this population were reviewed with regard to age at diagnosis, sex, histologic subtype, and other tumors presented by these patients. RESULTS:Overall, 101 of 193 TP53 p.R337H mutation carriers with LFS from 58 families were cancer affected and, among them, thyroid carcinoma presented a prevalence of 10.9% (3 men and 8 women). The mean age at diagnosis was 44 years (median [SD], 43 [14.77] years). All the cases were histologically classified as papillary carcinomas, with 2 of them exhibiting follicular variant. The most common other cancers in the patients with thyroid carcinoma were breast cancer (5 patients) and soft-tissue sarcoma (2 patients). CONCLUSIONS AND RELEVANCE:Thyroid carcinoma may be associated with the Brazilian founder TP53 p.R337H mutation. Knowledge about this genotype/phenotype correlation is relevant to adjusting the LFS screening recommendations to these specific carriers. 10.1001/jamaoncol.2016.6389
    A genome-wide association study yields five novel thyroid cancer risk loci. Gudmundsson Julius,Thorleifsson Gudmar,Sigurdsson Jon K,Stefansdottir Lilja,Jonasson Jon G,Gudjonsson Sigurjon A,Gudbjartsson Daniel F,Masson Gisli,Johannsdottir Hrefna,Halldorsson Gisli H,Stacey Simon N,Helgason Hannes,Sulem Patrick,Senter Leigha,He Huiling,Liyanarachchi Sandya,Ringel Matthew D,Aguillo Esperanza,Panadero Angeles,Prats Enrique,Garcia-Castaño Almudena,De Juan Ana,Rivera Fernando,Xu Li,Kiemeney Lambertus A,Eyjolfsson Gudmundur I,Sigurdardottir Olof,Olafsson Isleifur,Kristvinsson Hoskuldur,Netea-Maier Romana T,Jonsson Thorvaldur,Mayordomo Jose I,Plantinga Theo S,Hjartarson Hannes,Hrafnkelsson Jon,Sturgis Erich M,Thorsteinsdottir Unnur,Rafnar Thorunn,de la Chapelle Albert,Stefansson Kari Nature communications The great majority of thyroid cancers are of the non-medullary type. Here we report findings from a genome-wide association study of non-medullary thyroid cancer, including in total 3,001 patients and 287,550 controls from five study groups of European descent. Our results yield five novel loci (all with P<3 × 10): 1q42.2 (rs12129938 in PCNXL2), 3q26.2 (rs6793295 a missense mutation in LRCC34 near TERC), 5q22.1 (rs73227498 between NREP and EPB41L4A), 10q24.33 (rs7902587 near OBFC1), and two independently associated variants at 15q22.33 (rs2289261 and rs56062135; both in SMAD3). We also confirm recently published association results from a Chinese study of a variant on 5p15.33 (rs2736100 near the TERT gene) and present a stronger association result for a moderately correlated variant (rs10069690; OR=1.20, P=3.2 × 10) based on our study of individuals of European ancestry. In combination, these results raise several opportunities for future studies of the pathogenesis of thyroid cancer. 10.1038/ncomms14517
    Molecular profiling of thyroid nodule fine-needle aspiration cytology. Eszlinger Markus,Lau Lorraine,Ghaznavi Sana,Symonds Christopher,Chandarana Shamir P,Khalil Moosa,Paschke Ralf Nature reviews. Endocrinology The differential diagnosis and malignancy risk stratification of thyroid nodules requires multidisciplinary expertise and knowledge of both local ultrasonography practices and the local malignancy rates for a given fine-needle aspiration (FNA) result. Even in such a multidisciplinary setting, FNA cytology has the inherent limitation that indeterminate cytology results cannot distinguish between follicular adenomas, follicular thyroid carcinomas or follicular variant papillary thyroid carcinomas. Accumulating evidence suggests that this limitation can be overcome by using molecular diagnostic approaches. In this Review, we present the advantages and disadvantages of the different molecular diagnostic methodologies, which can be divided into two approaches: those that 'rule out' malignancy (to reduce the overtreatment of benign nodules) and those that 'rule in' malignancy (to optimize surgical planning). We identify microRNA classifiers as potential additional markers for use in a two-step diagnostic approach, consider the potential implications of the reclassification of noninvasive encapsulated follicular variant papillary thyroid carcinomas to noninvasive follicular thyroid neoplasms with papillary-like nuclear features and discuss the cost-effectiveness of molecular testing. Molecular FNA diagnostics is an important complementary addition to FNA cytology that could substantially reduce unnecessary surgery and better define the need for appropriate surgery in patients who have thyroid nodules with indeterminate FNA cytology. 10.1038/nrendo.2017.24
    Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974-2013. Lim Hyeyeun,Devesa Susan S,Sosa Julie A,Check David,Kitahara Cari M JAMA Importance:Thyroid cancer incidence has increased substantially in the United States over the last 4 decades, driven largely by increases in papillary thyroid cancer. It is unclear whether the increasing incidence of papillary thyroid cancer has been related to thyroid cancer mortality trends. Objective:To compare trends in thyroid cancer incidence and mortality by tumor characteristics at diagnosis. Design, Setting, and Participants:Trends in thyroid cancer incidence and incidence-based mortality rates were evaluated using data from the Surveillance, Epidemiology, and End Results-9 (SEER-9) cancer registry program, and annual percent change in rates was calculated using log-linear regression. Exposure:Tumor characteristics. Main Outcomes and Measures:Annual percent changes in age-adjusted thyroid cancer incidence and incidence-based mortality rates by histologic type and SEER stage for cases diagnosed during 1974-2013. Results:Among 77 276 patients (mean [SD] age at diagnosis, 48 [16] years; 58 213 [75%] women) diagnosed with thyroid cancer from 1974-2013, papillary thyroid cancer was the most common histologic type (64 625 cases), and 2371 deaths from thyroid cancer occurred during 1994-2013. Thyroid cancer incidence increased, on average, 3.6% per year (95% CI, 3.2%-3.9%) during 1974-2013 (from 4.56 per 100 000 person-years in 1974-1977 to 14.42 per 100 000 person-years in 2010-2013), primarily related to increases in papillary thyroid cancer (annual percent change, 4.4% [95% CI, 4.0%-4.7%]). Papillary thyroid cancer incidence increased for all SEER stages at diagnosis (4.6% per year for localized, 4.3% per year for regional, 2.4% per year for distant, 1.8% per year for unknown). During 1994-2013, incidence-based mortality increased 1.1% per year (95% CI, 0.6%-1.6%) (from 0.40 per 100 000 person-years in 1994-1997 to 0.46 per 100 000 person-years in 2010-2013) overall and 2.9% per year (95% CI, 1.1%-4.7%) for SEER distant stage papillary thyroid cancer. Conclusions and Relevance:Among patients in the United States diagnosed with thyroid cancer from 1974-2013, the overall incidence of thyroid cancer increased 3% annually, with increases in the incidence rate and thyroid cancer mortality rate for advanced-stage papillary thyroid cancer. These findings are consistent with a true increase in the occurrence of thyroid cancer in the United States. 10.1001/jama.2017.2719
    Senescent tumor cells lead the collective invasion in thyroid cancer. Kim Young Hwa,Choi Yong Won,Lee Jeonghun,Soh Euy Young,Kim Jang-Hee,Park Tae Jun Nature communications Cellular senescence has been perceived as a barrier against carcinogenesis. However, the senescence-associated secretory phenotype (SASP) of senescent cells can promote tumorigenesis. Here, we show senescent tumour cells are frequently present in the front region of collective invasion of papillary thyroid carcinoma (PTC), as well as lymphatic channels and metastatic foci of lymph nodes. In in vitro invasion analysis, senescent tumour cells exhibit high invasion ability as compared with non-senescent tumour cells through SASP expression. Collective invasion in PTC is led by senescent tumour cells characterized by generation of a C-X-C-motif ligand (CXCL)12 chemokine gradient in the front region. Furthermore, senescent cells increase the survival of cancer cells via CXCL12/CXCR4 signalling. An orthotopic xenograft in vivo model also shows higher lymphatic vessels involvement in the group co-transplanted with senescent cells and cancer cells. These findings suggest that senescent cells are actively involved in the collective invasion and metastasis of PTC. 10.1038/ncomms15208
    Farewell to a Cancer That Never Was. Lyon Jeff JAMA 10.1001/jama.2017.3969
    The genetic landscape of benign thyroid nodules revealed by whole exome and transcriptome sequencing. Ye Lei,Zhou Xiaoyi,Huang Fengjiao,Wang Weixi,Qi Yicheng,Xu Heng,Yang Shu,Shen Liyun,Fei Xiaochun,Xie Jing,Cao Min,Zhou Yulin,Zhu Wei,Wang Shu,Ning Guang,Wang Weiqing Nature communications The genomic alterations for benign thyroid nodule, especially adenomatoid nodule, one of the most common types of hyperplasia lesion, are ill-studied. Here, we show whole-exome sequencing and/or transcriptome sequencing data on adenomatoid nodules with or without coincidental papillary thyroid carcinoma (PTC). Somatic mutation of BRAF (22/32) is only detected in PTC, while mutations in SPOP (4/38), ZNF148 (6/38) and EZH1 (3/38) are found enriched in adenomatoid nodule. In an expanded cohort of adenomatoid nodule (n=259) mutually exclusive SPOP, EZH1 and ZNF148 mutations are identified in 24.3% of them. Adenomatoid nodules show very few overlapped mutations and distinct gene expression patterns with their coincidental PTC. Phylogenetic tree analysis uncovers that PTCs evolved independently from their matched benign nodules. Our findings reveal that benign nodules possess a unique molecular signature that differs from PTC and provide genomic evidence for the conventional belief that PTC and benign nodules have independent origin. 10.1038/ncomms15533
    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
    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
    Is BRAF V600E Mutation the Explanation for Age-Associated Mortality Risk in Patients With Papillary Thyroid Cancer? Haymart Megan R Journal of clinical oncology : official journal of the American Society of Clinical Oncology 10.1200/JCO.2017.76.2583
    Patient Age-Associated Mortality Risk Is Differentiated by BRAF V600E Status in Papillary Thyroid Cancer. Shen Xiaopei,Zhu Guangwu,Liu Rengyun,Viola David,Elisei Rossella,Puxeddu Efisio,Fugazzola Laura,Colombo Carla,Jarzab Barbara,Czarniecka Agnieszka,Lam Alfred K,Mian Caterina,Vianello Federica,Yip Linwah,Riesco-Eizaguirre Garcilaso,Santisteban Pilar,O'Neill Christine J,Sywak Mark S,Clifton-Bligh Roderick,Bendlova Bela,Sýkorová Vlasta,Xing Mingzhao Journal of clinical oncology : official journal of the American Society of Clinical Oncology Purpose For the past 65 years, patient age at diagnosis has been widely used as a major mortality risk factor in the risk stratification of papillary thyroid cancer (PTC), but whether this is generally applicable, particularly in patients with different BRAF genetic backgrounds, is unclear. The current study was designed to test whether patient age at diagnosis is a major mortality risk factor. Patients and Methods We conducted a comparative study of the relationship between patient age at diagnosis and PTC-specific mortality with respect to BRAF status in 2,638 patients (623 men and 2,015 women) with a median age of 46 years (interquartile range, 35 to 58 years) at diagnosis and a median follow-up time of 58 months (interquartile range, 26 to 107 months). Eleven medical centers from six countries participated in this study. Results There was a linear association between patient age and mortality in patients with BRAF V600E mutation, but not in patients with wild-type BRAF, in whom the mortality rate remained low and flat with increasing age. Kaplan-Meier survival curves rapidly declined with increasing age in patients with BRAF V600E mutation but did not decline in patients with wild-type BRAF, even beyond age 75 years. The association between mortality and age in patients with BRAF V600E was independent of clinicopathologic risk factors. Similar results were observed when only patients with the conventional variant of PTC were analyzed. Conclusion The long-observed age-associated mortality risk in PTC is dependent on BRAF status; age is a strong, continuous, and independent mortality risk factor in patients with BRAF V600E mutation but not in patients with wild-type BRAF. These results question the conventional general use of patient age as a high-risk factor in PTC and call for differentiation between patients with BRAF V600E and wild-type BRAF when applying age to risk stratification and management of PTC. 10.1200/JCO.2017.74.5497
    Expanding the Options for Patient-Guided Decision Making in Papillary Thyroid Cancer. Yip Linwah,Carty Sally E JAMA 10.1001/jama.2017.18608
    Age-Associated Mortality Risk in Papillary Thyroid Cancer: Does BRAF Make a Real Difference? Melo Miguel,Gaspar da Rocha Adriana,Cancela E Penna Gustavo,Sobrinho-Simões Manuel,Soares Paula Journal of clinical oncology : official journal of the American Society of Clinical Oncology 10.1200/JCO.2018.77.8571
    Early evolutionary divergence between papillary and anaplastic thyroid cancers. Capdevila J,Mayor R,Mancuso F M,Iglesias C,Caratù G,Matos I,Zafón C,Hernando J,Petit A,Nuciforo P,Cameselle-Teijeiro J M,Álvarez C,Recio J A,Tabernero J,Matias-Guiu X,Vivancos A,Seoane J Annals of oncology : official journal of the European Society for Medical Oncology Background:Papillary thyroid cancer (PTC) is the most common thyroid carcinoma and exhibits an almost uniformly good prognosis, while anaplastic thyroid cancer (ATC) is less frequent and is one of the most aggressive cancers usually resistant to conventional treatment. Current hypothesis posits that ATC derives from PTC through the progressive acquisition of a discrete number of genomic alterations and implies that the mutational landscape of ATC resembles that of PTC. However, the clinical behaviour of ATC and PTC is radically different. We decided to address the disconnection between the clinical behaviour of ATC and PTC and the proposed model of the progressive development of ATC from PTC. Patients and methods:We carried out exome sequencing of DNA from 14 ATC specimens including three cases of concomitant ATC and PTC as well as their corresponding normal DNA from 14 patients. The sequencing results were validated using droplet digital PCR. We carried out immunohistochemistry and immunofluorescence studies of the concomitant ATC and PTC cases. In addition, we integrated our sequencing results with the existing TCGA data. Results:Most of the somatic mutations identified in the ATC component differed from the ones in PTC in the cases of concomitant ATC and PTC. The trunks of the phylogenetic trees representing the somatic mutations were short with long branches. In one case of concomitant PTC and ATC specimens, we observed an infiltration of PTC cells within the ATC component. Moreover, we integrated our results with data obtained from TCGA and observed that the most frequent mutations found in ATC presented high cancer cell fraction values and were significantly different from the PTC ones. Conclusion:ATC diverge from PTC early in tumour development and both tumour types evolve independently. Our work allows the understanding of the relationship between ATC and PTC facilitating the clinical management of these malignancies. 10.1093/annonc/mdy123
    Radioiodine Treatment of Well-Differentiated Thyroid Cancer: Balancing Risks and Benefits. Greenspan Bennett S Journal of clinical oncology : official journal of the American Society of Clinical Oncology 10.1200/JCO.2018.78.6384
    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
    Change in Diagnostic Criteria for Noninvasive Follicular Thyroid Neoplasm With Papillarylike Nuclear Features. Nikiforov Yuri E,Baloch Zubair W,Hodak Steven P,Giordano Thomas J,Lloyd Ricardo V,Seethala Raja R,Wenig Bruce M JAMA oncology 10.1001/jamaoncol.2018.1446
    Saving Thyroids - Overtreatment of Small Papillary Cancers. Welch H Gilbert,Doherty Gerard M The New England journal of medicine 10.1056/NEJMp1804426
    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
    Performance of a Multigene Genomic Classifier in Thyroid Nodules With Indeterminate Cytology: A Prospective Blinded Multicenter Study. Steward David L,Carty Sally E,Sippel Rebecca S,Yang Samantha Peiling,Sosa Julie A,Sipos Jennifer A,Figge James J,Mandel Susan,Haugen Bryan R,Burman Kenneth D,Baloch Zubair W,Lloyd Ricardo V,Seethala Raja R,Gooding William E,Chiosea Simion I,Gomes-Lima Cristiane,Ferris Robert L,Folek Jessica M,Khawaja Raheela A,Kundra Priya,Loh Kwok Seng,Marshall Carrie B,Mayson Sarah,McCoy Kelly L,Nga Min En,Ngiam Kee Yuan,Nikiforova Marina N,Poehls Jennifer L,Ringel Matthew D,Yang Huaitao,Yip Linwah,Nikiforov Yuri E JAMA oncology Importance:Approximately 20% of fine-needle aspirations (FNA) of thyroid nodules have indeterminate cytology, most frequently Bethesda category III or IV. Diagnostic surgeries can be avoided for these patients if the nodules are reliably diagnosed as benign without surgery. Objective:To determine the diagnostic accuracy of a multigene classifier (GC) test (ThyroSeq v3) for cytologically indeterminate thyroid nodules. Design, Setting, and Participants:Prospective, blinded cohort study conducted at 10 medical centers, with 782 patients with 1013 nodules enrolled. Eligibility criteria were met in 256 patients with 286 nodules; central pathology review was performed on 274 nodules. Interventions:A total of 286 FNA samples from thyroid nodules underwent molecular analysis using the multigene GC (ThyroSeq v3). Main Outcomes and Measures:The primary outcome was diagnostic accuracy of the test for thyroid nodules with Bethesda III and IV cytology. The secondary outcome was prediction of cancer by specific genetic alterations in Bethesda III to V nodules. Results:Of the 286 cytologically indeterminate nodules, 206 (72%) were benign, 69 (24%) malignant, and 11 (4%) noninvasive follicular thyroid neoplasms with papillary-like nuclei (NIFTP). A total of 257 (90%) nodules (154 Bethesda III, 93 Bethesda IV, and 10 Bethesda V) had informative GC analysis, with 61% classified as negative and 39% as positive. In Bethesda III and IV nodules combined, the test demonstrated a 94% (95% CI, 86%-98%) sensitivity and 82% (95% CI, 75%-87%) specificity. With a cancer/NIFTP prevalence of 28%, the negative predictive value (NPV) was 97% (95% CI, 93%-99%) and the positive predictive value (PPV) was 66% (95% CI, 56%-75%). The observed 3% false-negative rate was similar to that of benign cytology, and the missed cancers were all low-risk tumors. Among nodules testing positive, specific groups of genetic alterations had cancer probabilities varying from 59% to 100%. Conclusions and Relevance:In this prospective, blinded, multicenter study, the multigene GC test demonstrated a high sensitivity/NPV and reasonably high specificity/PPV, which may obviate diagnostic surgery in up to 61% of patients with Bethesda III to IV indeterminate nodules, and up to 82% of all benign nodules with indeterminate cytology. Information on specific genetic alterations obtained from FNA may help inform individualized treatment of patients with a positive test result. 10.1001/jamaoncol.2018.4616
    Recurrence after low-dose radioiodine ablation and recombinant human thyroid-stimulating hormone for differentiated thyroid cancer (HiLo): long-term results of an open-label, non-inferiority randomised controlled trial. Dehbi Hakim-Moulay,Mallick Ujjal,Wadsley Jonathan,Newbold Kate,Harmer Clive,Hackshaw Allan The lancet. Diabetes & endocrinology BACKGROUND:Two large randomised trials of patients with well-differentiated thyroid cancer reported in 2012 (HiLo and ESTIMABL1) found similar post-ablation success rates at 6-9 months between a low administered radioactive iodine (I) dose (1·1 GBq) and the standard high dose (3·7 GBq). However, recurrence rates following radioactive iodine ablation have previously only been reported in observational studies, and recently in ESTIMABL1. We aimed to compare recurrence rates between radioactive iodine doses in HiLo. METHODS:HiLo was a non-inferiority, parallel, open-label, randomised controlled factorial trial done at 29 centres in the UK. Eligible patients were aged 16-80 years with histological confirmation of differentiated thyroid cancer requiring radioactive iodine ablation (performance status 0-2, tumour stage T1-T3 with the possibility of lymph-node involvement but no distant metastasis and no microscopic residual disease, and one-stage or two-stage total thyroidectomy). Patients were randomly assigned (1:1:1:1) to 1·1 GBq or 3·7 GBq ablation, each prepared with either recombinant human thyroid-stimulating hormone (rhTSH) or thyroid hormone withdrawal. Patients were followed up at annual clinic visits. Recurrences were diagnosed at each hospital with a combination of established methods according to national standards. We used Kaplan-Meier curves and hazard ratios (HRs) for time to first recurrence, which was a pre-planned secondary outcome. This trial is registered with ClinicalTrials.gov, number NCT00415233. RESULTS:Between Jan 16, 2007, and July 1, 2010, 438 patients were randomly assigned. At the end of the follow-up period in Dec 31, 2017, median follow-up was 6·5 years (IQR 4·5-7·6) in 434 patients (217 in the low-dose group and 217 in the high-dose group). Confirmed recurrences were seen in 21 patients: 11 who had 1·1 GBq ablation and ten who had 3·7 GBq ablation. Four of these (two in each group) were considered to be persistent disease. Cumulative recurrence rates were similar between low-dose and high-dose radioactive iodine groups (3 years, 1·5% vs 2·1%; 5 years, 2·1% vs 2·7%; and 7 years, 5·9% vs 7·3%; HR 1·10 [95% CI 0·47-2·59]; p=0·83). No material difference in risk was seen for T3 or N1 disease. Recurrence rates were also similar among patients who were prepared for ablation with rhTSH and those prepared with thyroid hormone withdrawal (3 years, 1·5% vs 2·1%; 5 years, 2·1% vs 2·7%; and 7 years, 8·3% vs 5·0%; HR 1·62 [95% CI 0·67-3·91]; p=0·28). Data on adverse events were not collected during follow-up. INTERPRETATION:The recurrence rate among patients who had 1·1 GBq radioactive iodine ablation was not higher than that for 3·7 GBq, consistent with data from large, recent observational studies. These findings provide further evidence in favour of using low-dose radioactive iodine for treatment of patients with low-risk differentiated thyroid cancer. Our data also indicate that recurrence risk was not affected by use of rhTSH. FUNDING:Cancer Research UK. 10.1016/S2213-8587(18)30306-1
    Diagnosis of thyroid cancer using deep convolutional neural network models applied to sonographic images: a retrospective, multicohort, diagnostic study. Li Xiangchun,Zhang Sheng,Zhang Qiang,Wei Xi,Pan Yi,Zhao Jing,Xin Xiaojie,Qin Chunxin,Wang Xiaoqing,Li Jianxin,Yang Fan,Zhao Yanhui,Yang Meng,Wang Qinghua,Zheng Zhiming,Zheng Xiangqian,Yang Xiangming,Whitlow Christopher T,Gurcan Metin Nafi,Zhang Lun,Wang Xudong,Pasche Boris C,Gao Ming,Zhang Wei,Chen Kexin The Lancet. Oncology BACKGROUND:The incidence of thyroid cancer is rising steadily because of overdiagnosis and overtreatment conferred by widespread use of sensitive imaging techniques for screening. This overall incidence growth is especially driven by increased diagnosis of indolent and well-differentiated papillary subtype and early-stage thyroid cancer, whereas the incidence of advanced-stage thyroid cancer has increased marginally. Thyroid ultrasound is frequently used to diagnose thyroid cancer. The aim of this study was to use deep convolutional neural network (DCNN) models to improve the diagnostic accuracy of thyroid cancer by analysing sonographic imaging data from clinical ultrasounds. METHODS:We did a retrospective, multicohort, diagnostic study using ultrasound images sets from three hospitals in China. We developed and trained the DCNN model on the training set, 131 731 ultrasound images from 17 627 patients with thyroid cancer and 180 668 images from 25 325 controls from the thyroid imaging database at Tianjin Cancer Hospital. Clinical diagnosis of the training set was made by 16 radiologists from Tianjin Cancer Hospital. Images from anatomical sites that were judged as not having cancer were excluded from the training set and only individuals with suspected thyroid cancer underwent pathological examination to confirm diagnosis. The model's diagnostic performance was validated in an internal validation set from Tianjin Cancer Hospital (8606 images from 1118 patients) and two external datasets in China (the Integrated Traditional Chinese and Western Medicine Hospital, Jilin, 741 images from 154 patients; and the Weihai Municipal Hospital, Shandong, 11 039 images from 1420 patients). All individuals with suspected thyroid cancer after clinical examination in the validation sets had pathological examination. We also compared the specificity and sensitivity of the DCNN model with the performance of six skilled thyroid ultrasound radiologists on the three validation sets. FINDINGS:Between Jan 1, 2012, and March 28, 2018, ultrasound images for the four study cohorts were obtained. The model achieved high performance in identifying thyroid cancer patients in the validation sets tested, with area under the curve values of 0·947 (95% CI 0·935-0·959) for the Tianjin internal validation set, 0·912 (95% CI 0·865-0·958) for the Jilin external validation set, and 0·908 (95% CI 0·891-0·925) for the Weihai external validation set. The DCNN model also showed improved performance in identifying thyroid cancer patients versus skilled radiologists. For the Tianjin internal validation set, sensitivity was 93·4% (95% CI 89·6-96·1) versus 96·9% (93·9-98·6; p=0·003) and specificity was 86·1% (81·1-90·2) versus 59·4% (53·0-65·6; p<0·0001). For the Jilin external validation set, sensitivity was 84·3% (95% CI 73·6-91·9) versus 92·9% (84·1-97·6; p=0·048) and specificity was 86·9% (95% CI 77·8-93·3) versus 57·1% (45·9-67·9; p<0·0001). For the Weihai external validation set, sensitivity was 84·7% (95% CI 77·0-90·7) versus 89·0% (81·9-94·0; p=0·25) and specificity was 87·8% (95% CI 81·6-92·5) versus 68·6% (60·7-75·8; p<0·0001). INTERPRETATION:The DCNN model showed similar sensitivity and improved specificity in identifying patients with thyroid cancer compared with a group of skilled radiologists. The improved technical performance of the DCNN model warrants further investigation as part of randomised clinical trials. FUNDING:The Program for Changjiang Scholars and Innovative Research Team in University in China, and National Natural Science Foundation of China. 10.1016/S1470-2045(18)30762-9
    Contemporary Debates in Adult Papillary Thyroid Cancer Management. McLeod Donald S A,Zhang Ling,Durante Cosimo,Cooper David S Endocrine reviews An ever-increasing population of patients with papillary thyroid cancer is engaging with health care systems around the world. Numerous questions about optimal management have arisen that challenge conventional paradigms. This is particularly the case for patients with low-risk disease, who comprise most new patients. At the same time, new therapies for patients with advanced disease are also being introduced, which may have the potential to prolong life. This review discusses selected controversial issues in adult papillary thyroid cancer management at both ends of the disease spectrum. These topics include: (i) the role of active surveillance for small papillary cancers; (ii) the extent of surgery in low-risk disease (lobectomy vs total thyroidectomy); (iii) the role of postoperative remnant ablation with radioiodine; (iv) optimal follow-up strategies in patients, especially those who have only undergone lobectomy; and (v) new therapies for advanced disease. Although our current management is hampered by the lack of large randomized controlled trials, we are fortunate that data from ongoing trials will be available within the next few years. This information should provide additional evidence that will decrease morbidity in low-risk patients and improve outcomes in those with distant metastatic disease. 10.1210/er.2019-00085
    Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Filetti S,Durante C,Hartl D,Leboulleux S,Locati L D,Newbold K,Papotti M G,Berruti A, Annals of oncology : official journal of the European Society for Medical Oncology 10.1093/annonc/mdz400
    Immunotherapy for Anaplastic Thyroid Carcinoma. Lim Annette M,Solomon Benjamin J Journal of clinical oncology : official journal of the American Society of Clinical Oncology 10.1200/JCO.20.01437
    Lymph node metastasis prediction of papillary thyroid carcinoma based on transfer learning radiomics. Yu Jinhua,Deng Yinhui,Liu Tongtong,Zhou Jin,Jia Xiaohong,Xiao Tianlei,Zhou Shichong,Li Jiawei,Guo Yi,Wang Yuanyuan,Zhou Jianqiao,Chang Cai Nature communications Non-invasive assessment of the risk of lymph node metastasis (LNM) in patients with papillary thyroid carcinoma (PTC) is of great value for the treatment option selection. The purpose of this paper is to develop a transfer learning radiomics (TLR) model for preoperative prediction of LNM in PTC patients in a multicenter, cross-machine, multi-operator scenario. Here we report the TLR model produces a stable LNM prediction. In the experiments of cross-validation and independent testing of the main cohort according to diagnostic time, machine, and operator, the TLR achieves an average area under the curve (AUC) of 0.90. In the other two independent cohorts, TLR also achieves 0.93 AUC, and this performance is statistically better than the other three methods according to Delong test. Decision curve analysis also proves that the TLR model brings more benefit to PTC patients than other methods. 10.1038/s41467-020-18497-3
    Global patterns and trends in incidence and mortality of thyroid cancer in children and adolescents: a population-based study. Vaccarella Salvatore,Lortet-Tieulent Joannie,Colombet Murielle,Davies Louise,Stiller Charles A,Schüz Joachim,Togawa Kayo,Bray Freddie,Franceschi Silvia,Dal Maso Luigino,Steliarova-Foucher Eva, The lancet. Diabetes & endocrinology BACKGROUND:There has been a considerable increase in thyroid cancer incidence among adults in several countries in the past three decades, attributed primarily to overdiagnosis. We aimed to assess global patterns and trends in incidence and mortality of thyroid cancer in children and adolescents, in view of the increased incidence among adults. METHODS:We did a population-based study of the observed incidence (in 49 countries and territories) and mortality (in 27 countries) of thyroid cancer in children and adolescents aged 0-19 years using data from the International Incidence of Childhood Cancer Volume 3 study database, the WHO mortality database, and the cancer incidence in five continents database (CI5plus; for adult data [age 20-74 years]). We analysed temporal trends in incidence rates, including absolute changes in rates, and the strength of the correlation between incidence rates in children and adolescents and in adults. We calculated the average annual number of thyroid cancer deaths and the age-standardised mortality rates for children and adolescents. FINDINGS:Age-standardised incidence rates of thyroid cancer among children and adolescents aged 0-19 years ranged from 0·4 (in Uganda and Kenya) to 13·4 (in Belarus) cancers per 1 million person-years in 2008-12. The variability in the incidence rates was mostly accounted for by the papillary tumour subtype. Incidence rates were almost always higher in girls than in boys and increased with age in both sexes. Rapid increases in incidence between 1998-2002 and 2008-12 were observed in almost all countries. Country-specific incidence rates in children and adolescents were strongly correlated (r>0·8) with rates in adults, as were the temporal changes in the respective incidence rates (r>0·6). Thyroid cancer deaths in those aged younger than 20 years were less than 0·1 per 10 million person-years in each country. INTERPRETATION:The pattern of thyroid cancer incidence in children and adolescents mirrors the pattern seen in adults, suggesting a major role for overdiagnosis, which, in turn, can lead to overtreatment, lifelong medical care, and side effects that can negatively affect quality of life. We suggest that the existing recommendation against screening for thyroid cancer in the asymptomatic adult population who are free from specific risk factors should be extended to explicitly recommend against screening for thyroid cancer in similar populations of children and adolescents. FUNDING:International Agency for Research on Cancer and the Union for International Cancer Control; French Institut National du Cancer; Italian Association of Cancer Research; and Italian Ministry of Health. 10.1016/S2213-8587(20)30401-0
    The importance of the RET gene in thyroid cancer and therapeutic implications. Nature reviews. Endocrinology Since the discovery of the RET receptor tyrosine kinase in 1985, alterations of this protein have been found in diverse thyroid cancer subtypes. RET gene rearrangements are observed in papillary thyroid carcinoma, which result in RET fusion products. By contrast, single amino acid substitutions and small insertions and/or deletions are typical of hereditary and sporadic medullary thyroid carcinoma. RET rearrangements and mutations of extracellular cysteines facilitate dimerization and kinase activation, whereas mutations in the RET kinase coding domain drive dimerization-independent kinase activation. Thus, RET kinase inhibition is an attractive therapeutic target in patients with RET alterations. This approach was initially achieved using multikinase inhibitors, which affect multiple deregulated pathways that include RET kinase. In clinical practice, use of multikinase inhibitors in patients with advanced thyroid cancer resulted in therapeutic efficacy, which was associated with frequent and sometimes severe adverse effects. However, remarkable progress has been achieved with the identification of novel potent and selective RET kinase inhibitors for the treatment of advanced thyroid cancer. Although expanded clinical validation in future trials is needed, the sustained antitumoural activity and the improved safety profile of these novel compounds is opening a new exciting era in precision oncology for RET-driven cancers. 10.1038/s41574-021-00470-9