Diagnosis of nodular thyroid disease: An update | Medicina Clínica (English Edition)

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CMT: carcinoma medular de tiroides; CPT: carcinoma papilar de tiroides; MEN: neoplasia endocrina múltiple; PAAF: punción-aspiración con aguja fina. aSistema de clasificación de la British Thyroid Association (<a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a>)<a class="elsevierStyleCrossRef" href="#bib0200">9</a>. bMicrocalcificaciones, hipoecogenicidad, márgenes irregulares, ausencia de halo, composición sólida, vascularización intranodular y un diámetro anteroposterior>transversal<a class="elsevierStyleCrossRef" href="#bib0215">12</a>. cC1-C6, clasificación de Bethesda (<a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a>)<a class="elsevierStyleCrossRefs" href="#bib0185">6,15,16</a>. dPanel de mutaciones, clasificador de expresión de genes y expresión de miRNA." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Juan J. Díez, Pedro Iglesias" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Juan J." 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Distribution of the screening rates of hazardous drinking and harmful drinking and brief advice obtained from ODHIN project.<a class="elsevierStyleCrossRef" href="#bib0145">29</a>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Antoni Gual, José Zarco, Joan Colom Farran, Jürgen Rehm" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Antoni" "apellidos" => "Gual" ] 1 => array:2 [ "nombre" => "José" "apellidos" => "Zarco" ] 2 => array:2 [ "nombre" => "Joan" "apellidos" => "Colom Farran" ] 3 => array:2 [ "nombre" => "Jürgen" "apellidos" => "Rehm" ] 4 => array:1 [ "colaborador" => "on behalf of the Group for the Study of Hypertension and Alcohol Use Disorder" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775315004625" "doi" => "10.1016/j.medcli.2015.07.014" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775315004625?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020616301838?idApp=UINPBA00004N" "url" => "/23870206/0000014600000002/v1_201605240650/S2387020616301838/v1_201605240650/en/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "cabecera" => "Diagnosis and treatment" "titulo" => "Diagnosis of nodular thyroid disease: An update" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "86" "paginaFinal" => "91" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Juan J. Díez, Pedro Iglesias" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Juan J." "apellidos" => "Díez" "email" => array:1 [ 0 => "juanjose.diez@salud.madrid.org" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Pedro" "apellidos" => "Iglesias" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Endocrinología, Hospital Universitario Ramón y Cajal, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá de Henares, Alcalá de Henares, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Actualización en el diagnóstico de la enfermedad nodular tiroidea" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2324 "Ancho" => 3100 "Tamanyo" => 317994 ] ] "descripcion" => array:1 [ "en" => "Algorithm suggested for the differential diagnosis of thyroid nodular disease considering the possible location of the novel diagnostic techniques (elastography, immunocytochemical markers and molecular markers). MTC: medullary thyroid carcinoma; PTC: papillary thyroid carcinoma; MEN: multiple endocrine neoplasm; FNA: fine-needle aspiration. a Classification system of the British Thyroid Association (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<a class="elsevierStyleCrossRef" href="#bib0200">9</a> b Microcalcifications, hypoechogenicity, irregular margins, absence of halo, solid content, intranodular vascularization and anteroposterior diameter>transverse diameter.<a class="elsevierStyleCrossRef" href="#bib0215">12</a> c C1-C6, Bethesda system (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0185">6,15,16</a> d Mutation panel, gene expression classifier and miRNA expression." ] ] ] "textoCompleto" => "IntroductionA thyroid nodule is the result of an abnormal growth of thyroid cells (benign or malignant) within the gland. It is estimated that 4–8% of subjects have nodular thyroid disease when using palpation as a detection method. But this percentage rises up to 13–67% with ultrasound.<a class="elsevierStyleCrossRef" href="#bib0160">1</a> In necropsy studies over half of subjects aged over 60 years have thyroid nodules.<a class="elsevierStyleCrossRef" href="#bib0165">2</a> The annual incidence is about 0.1%/year,<a class="elsevierStyleCrossRef" href="#bib0170">3</a> which implies that in Spain about 46,500 new nodules are diagnosed every year.The use of imaging tests, such as ultrasound, computed tomography and positron emission tomography, has led to finding thyroid nodules during the study of thyroid-unrelated diseases. The term incidentaloma has been coined to refer to these nodes. Its significance is not negligible, since they represent up to 20% of thyroid nodules studied at the endicronologist's office.<a class="elsevierStyleCrossRef" href="#bib0175">4</a> The aim of this paper has been to highlight the developments with impact on clinical practice that have occurred in the last decade in the area of diagnosis of thyroid nodules.Risk factorsAlthough most thyroid nodules are benign, the greatest challenge that the clinician faces is to discern between benign or malignant. To this purpose, the clinical data are still important. The standard risk factors for thyroid cancer are: nodules in patients with a history of cervical radiation in childhood, family history of papillary thyroid carcinoma (PTC), medullary thyroid carcinoma (MTC), multiple endocrine neoplasm, Cowden, Carney and Werner syndrome, extreme ages of life (<14 years or >70 years), male, rapid growth, firm consistency, binding to neighboring structures, presence of cervical lymphadenopathy or persistent dysphonia.<a class="elsevierStyleCrossRefs" href="#bib0180">5,6</a> However, most patients with thyroid cancer have none of these risk factors. A recent meta-analysis of 41 studies, including 29,678 nodules, has shown that the risk of thyroid cancer is higher in patients with previous head and neck irradiation, family history of thyroid cancer and in males. However, subjects under 18 or over 65 do not show higher risk.<a class="elsevierStyleCrossRef" href="#bib0190">7</a>The thyroid-stimulating hormone (TSH) has been considered a risk factor for thyroid cancer following a study of 1183 euthyroid patients with palpable goiter. Benignity of the nodule was judged by histology or monitoring of at least 2 years with repeated punctures.<a class="elsevierStyleCrossRef" href="#bib0195">8</a> The authors found an increased risk of thyroid cancer as TSH levels increased, even within the normal range. Other studies have failed to reproduce these data<a class="elsevierStyleCrossRef" href="#bib0190">7</a>. Therefore, currently no scientific evidence of sufficient quality is available to include serum TSH in diagnostic algorithms or for risk assessment of thyroid cancer.Diagnostic assessmentAnalytical assessmentRegardless of its potential value as a predictor of cancer, TSH levels should be quantified in all patients. Most of them showed normal levels. If TSH levels are below the lower limit of normal range, the risk of malignancy is minimal and potential hyperthyroidism should be assessed. In cases of high TSH, hypothyroidism study should be completed. In the absence of hypothyroidism, thyroid antibody determination should be limited to patients with suspected chronic lymphocytic thyroiditis.The determination of thyroglobulin is not useful in the study of thyroid nodules.<a class="elsevierStyleCrossRefs" href="#bib0180">5,9</a> The usefulness of calcitonin has been discussed. The prevalence of MTC in these cases is 0.4–1.4% and high levels of calcitonin may be false positives. Therefore, the guidelines consider that the determination of calcitonin may be useful if MTC is suspected, but it should not be determined routinely.<a class="elsevierStyleCrossRef" href="#bib0200">9</a>Imaging testsThyroid scintigraphy with 99mTc or 123I is not a useful test to distinguish between benign and malignant thyroid nodules. Most benign and almost all malignant nodules concentrate both radiotracers less avidly than the adjacent healthy tissue. Scintigraphy is a useful test in patients with low TSH to differentiate an autonomous nodule of a hyperactivemultinodular goiter.<a class="elsevierStyleCrossRef" href="#bib0185">6</a>CT and MRI are not tests of choice for evaluating thyroid nodules, while useful for assessing the size, extension and compression of airway in the intrathoracic goiter. These tests will be needed only in a minority of patients. Discovered by positron emission tomography, thyroid incidentalomas are of clinical interest since fluorodeoxyglucose hyperuptake may indicate the possibility of malignancy, which occurs in 35–46% of cases.<a class="elsevierStyleCrossRef" href="#bib0205">10</a>Thyroid ultrasound is undoubtedly the imaging test of choice for the study of all thyroid nodules. It reports on the morphology, number, size and characteristics of each nodule. Its usefulness is questionable for diagnosis, differential diagnosis, guidelines for the fine-needle aspiration (FNA) and patient followup.<a class="elsevierStyleCrossRef" href="#bib0200">9</a> Given the high prevalence of thyroid nodules in the general population, this test is not recommended as a screening test in patients with normal cervical palpation and low risk of thyroid cancer. Its indications are limited to patients with palpable nodule or multinodular goiter, lymphadenopathy suggestive of malignancy or at high risk of thyroid cancer.<a class="elsevierStyleCrossRef" href="#bib0185">6</a>The ultrasound report is vital for malignancy risk stratification (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0190">7,9,11</a> A recent meta-analysis<a class="elsevierStyleCrossRef" href="#bib0190">7</a> found that the nodule features most associated to cancer were: anteroposterior diameter larger than the transverse diameter, absence of halo, microcalcifications, irregular edges, hypoechogenicity, solid nodule and intranodular vascularization. The positive predictive values reported for each of these individual characteristics have ranged from 9 to 70%. Therefore, today ultrasound is considered to obtain only acceptable predictive levels for malignancy when multiple features are present simultaneously in a thyroid nodule.<a class="elsevierStyleCrossRefs" href="#bib0215">12,13</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>In recent years attention has also been focused on the negative predictive value of ultrasound, in order to avoid unnecessary aspiration in benign nodules. Therefore, in 2009 the Thyroid Imaging Reporting and Data System (TIRADS)<a class="elsevierStyleCrossRef" href="#bib0225">14</a> defined the following categories according to their likelihood of malignancy (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>): TIRADS 2 (0%), TIRADS 3 (<5%), TIRADS 4 (5–80%), TIRADS 5 (>80%) and TIRADS 6 (100%). The negative predictive value in the baseline study that included 1007 nodules was 88%. The guidelines of the British Thyroid Association<a class="elsevierStyleCrossRef" href="#bib0200">9</a> also include a nodule classification system (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>), so that benign nodules (U2) would not require needle aspiration, while those confusing, indeterminate or suspicious for malignancy (U3–U5) should be aspirated.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Cytologic evaluationCurrent recommendations include FNA in nodules with any of the following characteristics<a class="elsevierStyleCrossRef" href="#bib0185">6</a>: (1) diameter >1cm, solid and hypoechoic, (2) of any size with ultrasound findings suggestive of extracapsular growth or lymph node metastases, (3) of any size in patients with a history of cervical radiation, PTC, MTC or type 2 multiple endocrine neoplasm in first-degree relative, previous thyroid cancer surgery, or increased calcitonin in the absence of interference, and (4) diameter <1cm with findings associated with malignancy.The nodules with increased uptake on scintigraphy should not be aspirated. The size is not specific for the detection of malignancy. Therefore, in multinodular goiters, the nodules should be selected by ultrasound criterion, not by size. The solid component should always be biopsied in mixed nodules. Thus, the cytologic diagnosis is more reliable and the rate of nondiagnostic samples is lower when the FNA is ultrasound-guided.<a class="elsevierStyleCrossRef" href="#bib0185">6</a>Extensions must be studied by cytopathologists experienced on thyroid disease. A minimum of 6 groups of well-preserved thyroid epithelial cells should be available, with at least 10 cells per group.<a class="elsevierStyleCrossRef" href="#bib0230">15</a> The diagnosis must use a standardized classification system such as Bethesda (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0185">6,15,16</a> FNA has an excellent diagnostic performance, with a 0–7% false positive rate and 1–11% false negatives. However, false negatives are reduced up to 1–2% when ultrasound-guided FNA is used.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>New imaging techniquesUltrasound elastography in real time is a new technique that uses ultrasound to assess tissue stiffness. There are two criteria for evaluating an elastography: a qualitative classification using a color scale (score of elasticity) and a quantitative classification by an index of elasticity or strain (strain index) which is obtained by comparing the value of the nodule against the surrounding tissue.<a class="elsevierStyleCrossRef" href="#bib0240">17</a> The shear wave technique is independent of the operator and uses a low-intensity focused ultrasound beam generating mechanical vibrations spreading depending on tissue elasticity.<a class="elsevierStyleCrossRef" href="#bib0245">18</a>Elastography has been used to select benign nodules that do not require FNA. In a prospective study, conducted in 126 malignant lesions and 372 benign lesions, Trimboli et al.<a class="elsevierStyleCrossRef" href="#bib0250">19</a> showed that adding elastography to conventional ultrasound increased test safety in the diagnosis of malignancy, up to a 97% sensitivity and a 97% negative predictive value. Therefore, the selection of the benign nodules that do not need fine needle aspiration is significantly improved with this technique. In other studies the positive predictive values of elastography have ranged 55–100% and 93–98% the negative.<a class="elsevierStyleCrossRef" href="#bib0220">13</a> A meta-analysis of 31 studies involving over 5000 nodules analyzed showed that the sensitivity and specificity of elastography to differentiate benign from malignant nodules reached values of 79 and 77%, respectively, when using qualitative assessment by scores of elasticity, and 85 and 80%, respectively, when using quantitative assessment by strain index.<a class="elsevierStyleCrossRef" href="#bib0255">20</a>Elastography can also be a useful procedure in nodules with indeterminate or nondiagnostic cytology for the selection of those which should not undergo surgery. Rago et al.<a class="elsevierStyleCrossRef" href="#bib0240">17</a> studied 176 patients with one or more nodules with indeterminate or nondiagnostic cytology whose final histology was available after thyroidectomy. Elastography sensitivity in this series was 96.8% and 87.5% in the indeterminate and nondiagnostic cytology nodules respectively while specificity reached 91.8% and 86.7% respectively, for said nodules. Elastography has limited use in predominantly cystic nodules and nodules with coarse calcifications. In the nodules located on isthmus or lower poles, applying proper pressure in order to obtain reliable measures might not be possible.<a class="elsevierStyleCrossRef" href="#bib0255">20</a>New molecular markersImmunocytochemical markersIn the differential diagnosis of nodular thyroid disease different immunocytochemical markers have been used, such as galectin-3, cytokeratin-19, fibronectin, human bone marrow endothelial cells, cyclin D1, peroxisome proliferator-activated receptor gamma (PPARγ) and iodine carrier protein, among others. The positive samples for cytokeratin-19 showed a 81% sensitivity and a 73% specificity for the diagnosis of malignancy. In the case of galectin-3, sensitivity and specificity were 82 and 81%, respectively, and 77 and 83%, respectively, for human bone marrow endothelial cells. The combination of the 3 markers was associated with malignancy with a 85% sensitivity and a 97% specificity.<a class="elsevierStyleCrossRef" href="#bib0260">21</a>Genetic markersThe major clinical problem in the interpretation of the cytology is the attitude to indeterminate cytology specimens such as atypia or follicular lesions of uncertain significance. In recent years this problem has been addressed by two types of molecular studies.The gene expression classifier is a ruling-out system in which an algorithm analyzes the expression pattern of 142 genes through the analysis of messenger ribonucleic acids (mRNAs) obtained from FNA samples.<a class="elsevierStyleCrossRefs" href="#bib0265">22,23</a> The test aims to obtain high sensitivity and minimize the number of false negatives. The negative predictive value in early studies was very high.<a class="elsevierStyleCrossRef" href="#bib0265">22</a> However, this value decreases as the prevalence of cancer increases. Therefore, the gene expression classifier is more reliable when the lower risk of cancer in the patient population. More recent studies<a class="elsevierStyleCrossRef" href="#bib0270">23</a> have found negative predictive values slightly lower than the baseline (80–83%).The gene mutation panel studies gene point mutations such as BRAF, NRAS, HRAS, KRAS and RAS, as well as RET/PTC and PAX8/PPARγ<a class="elsevierStyleCrossRef" href="#bib0275">24</a> rearrangements. In a retrospective analysis of 513 samples of thyroid aspiration of 479 patients undergoing surgery, mutations were found in 22 of the 35 nodules that were ultimately diagnosed with thyroid cancer. The specificity of this test was 99, 97 and 96% for cytology with Bethesda categories 3, 4 and 5, respectively. The positive predictive values ranged 72–94%. According to these authors the likelihood of cancer was 100% when BRAF mutations and PAX8/PPARγ rearrangements and 84% when mutations in RAS.<a class="elsevierStyleCrossRef" href="#bib0280">25</a> Based on these results diagnostic lobectomy is recommended for nodules with follicular neoplasm cytology or suspected follicular neoplasm or suspected mutation-positive malignancy, while monitoring is recommended for atypia and follicular lesions of uncertain significance with negative mutation panel. However, it should be noted that the sensitivity of this test is low and has a 6–14% false negative rate.Micro-RNAMicro-RNA (miRNA) are small non-coding RNA molecules, generally 21–23 nucleotides, involved in the regulation of gene expression through suppression of target mRNA, leading to blocking the synthesis of proteins through mRNA destabilization and translational repression.<a class="elsevierStyleCrossRefs" href="#bib0285">26–28</a>Several studies have evaluated the role of miRNAs as diagnostic markers in thyroid cancer. Agretti et al.<a class="elsevierStyleCrossRef" href="#bib0285">26</a> showed that the expression panel of 3 miRNAs (miR-146b, miR-155 and miR-221) in 53 indeterminate FNA samples of thyroid allowed to distinguish between benign nodules and PTCs with a 60% sensitivity and 58% specificity. Kitano et al.<a class="elsevierStyleCrossRef" href="#bib0290">27</a> reported that miR-7 was the best predictor for distinguishing malignant and benign nodules in 95 thyroid FNA samples, with a 100% sensitivity, but low specificity (29%). A recent meta-analysis<a class="elsevierStyleCrossRef" href="#bib0295">28</a> of 7 assays with 361 cytological samples obtained from 341 patients, concluded that three miRNAs (miR-30a-3p, -30d, -7) were significantly downregulated in PTC. Multiple miRNA assays have a higher sensitivity (87% vs 71%) to differentiate malignant from benign thyroid nodules compared to single miRNA assays. However, the former show a lower specificity (75% vs 84%).New forms of clinical managementThe study of thyroid nodule has traditionally involved the participation of multiple medical specialties with a large number of visits and poor efficiency of health care. In recent years we have witnessed a shift from the traditional model to one that increases the efficiency by reducing the number of visits at high-resolution consultations (HRCs) or unique consultation.There are 2 types of thyroid nodule HRCs currently in our country. One involves thyroid ultrasound (and FNA if necessary) in the radiology department, with subsequent evaluation by the endocrinologist, while the second method involves ultrasound at the endocrinologist's office.<a class="elsevierStyleCrossRefs" href="#bib0175">4,29</a>.<a class="elsevierStyleCrossRef" href="#bib0305">30</a> Including in-office ultrasound at the endocrinologist's reduces the number of visits and lost work hours, thus obtaining a social benefit. The use of in-office ultrasound by endocrinologists reduces the time required for diagnosis and initiate treatment and decreases the number of visits of patients in different hospital departments. All this leads to cost savings and time delay in diagnosis of thyroid nodular disease.Recently, Castells et al.<a class="elsevierStyleCrossRef" href="#bib0300">29</a> have shown that the availability of in-offce ultrasound, with the possibility of thyroid nodule aspiration with in situ cytologic specimen evaluation, improves the diagnostic efficiency and quality of healthcare. These authors showed that the number of punctures needed for a diagnosis is reduced with the use of in-office ultrasound since the number of punctures with insufficient material is lower.<a class="elsevierStyleCrossRef" href="#bib0300">29</a> In short, as Argüelles et Tofé<a class="elsevierStyleCrossRef" href="#bib0310">31</a> point out, the option of ultrasound in the hands of the endocrinologist is simpler, cheaper and therefore more efficient.Future visionThe positioning of the new procedures, both imaging and molecular studies in the diagnostic algorithm of thyroid nodules has not been defined yet. <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> is a proposal for the possible location of these new methods in the classical scheme of decision making in patients with nodular thyroid disease. Elastography might be useful in benign nodules to avoid FNA in high-elasticity cases. But it also lays at the point of decision making about surgery or observation in patients with indeterminate or nondiagnostic FNA. The use of different immunocytochemical techniques can become an attractive tool to increase the diagnostic value of thyroid cytology. Similarly, molecular genetics techniques might constitute a useful tool for selecting patients for surgery more accurately and therefore improve the diagnostic yield of the samples obtained through thyroid FNA. The experience with these techniques is still limited. Thus, further studies are required to establish their actual clinical usefulness. Finally, it is expected that thyroid nodule HRC will be increasingly implemented in the immediate future in specialized care centers, which will contribute to the optimization of resources, streamlining diagnosis and improved clinical outcomes.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Conflict of interestsThe authors report no conflict of interest regarding the contents of this article." "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Risk factors" ] 2 => array:3 [ "identificador" => "sec0015" "titulo" => "Diagnostic assessment" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Analytical assessment" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Imaging tests" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Cytologic evaluation" ] ] ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "New imaging techniques" ] 4 => array:3 [ "identificador" => "sec0040" "titulo" => "New molecular markers" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Immunocytochemical markers" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Genetic markers" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Micro-RNA" ] ] ] 5 => array:2 [ "identificador" => "sec0060" "titulo" => "New forms of clinical management" ] 6 => array:2 [ "identificador" => "sec0065" "titulo" => "Future vision" ] 7 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflict of interests" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-06-19" "fechaAceptado" => "2015-07-07" "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Díez JJ, Iglesias P. Actualización en el diagnóstico de la enfermedad nodular tiroidea. Med Clin (Barc). 2016;146:86–91." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2324 "Ancho" => 3100 "Tamanyo" => 317994 ] ] "descripcion" => array:1 [ "en" => "Algorithm suggested for the differential diagnosis of thyroid nodular disease considering the possible location of the novel diagnostic techniques (elastography, immunocytochemical markers and molecular markers). MTC: medullary thyroid carcinoma; PTC: papillary thyroid carcinoma; MEN: multiple endocrine neoplasm; FNA: fine-needle aspiration. a Classification system of the British Thyroid Association (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<a class="elsevierStyleCrossRef" href="#bib0200">9</a> b Microcalcifications, hypoechogenicity, irregular margins, absence of halo, solid content, intranodular vascularization and anteroposterior diameter>transverse diameter.<a class="elsevierStyleCrossRef" href="#bib0215">12</a> c C1-C6, Bethesda system (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0185">6,15,16</a> d Mutation panel, gene expression classifier and miRNA expression." ] ] 1 => array:9 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Campanella et al.<a class="elsevierStyleCrossRef" href="#bib0190">7</a>, Perros et al.<a class="elsevierStyleCrossRef" href="#bib0200">9</a> and Yeh et al.<a class="elsevierStyleCrossRef" href="#bib0210">11</a>." "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Feature \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Suggestive of benignity \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Suggestive of malignity \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Content \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Purely cystic, predominantly cystic spongiform \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Solid \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Echogenicity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Isoechoic or moderately hyperechoic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypoechoic \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Margins \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Well-defined \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Irregular, lobulated, spiculated \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shape \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Anteroposterior diameter larger than the transverse diameter \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Halo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypoechoic, regular, continuous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Absent, irregular or incomplete \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vascularization \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Absent or predominantly peripheral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Central and irregular \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Calcifications \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Peripheral or eggshell Intranodular coarse \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Intranodular microcalcifications \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lymphadenopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oval morphology Hyperechoic central fatty hilum Hilar vascular flow pattern \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Solid, rounded (long axis/short axis <2) Punctate calcifications Peripheral vascularization \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1062200.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Sonographic features of thyroid nodules commonly associated with benignity and malignancy." ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "BTA: British Association Thyorid; MTC: medullary thyroid carcinoma; PTC: papillary thyroid carcinoma; TIRADS: Thyroid Imaging Reporting and Data System.Adaptaded from Perros et al.<a class="elsevierStyleCrossRef" href="#bib0200">9</a> and Horvath et al.<a class="elsevierStyleCrossRef" href="#bib0225">14</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">System \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Category \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Description \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="6" align="left" valign="top">TIRADS</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Anechoic lesion with hyperechoic spots, not vascularized Unencapsulated, mixed, non-expandable lesion, with hyperechoic, vascularized, spongiform spots Unencapsulated nodule, mixed with solid portions, isoechogenic, expandable, vascularized, with hyperechoic spots \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hyper-, iso- or hypoechoic nodule, partially encapsulated with peripheral vascularization in Hashimoto's thyroiditis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Solid or mixed hyper-, iso- or hypoechoic nodule with thin capsule. Hypoechoic lesion with ill-defined margins, without calcification. Hyper-, iso- or hypoechoic encapsulated nodule, hypervascularized, with thick capsule, with calcifications (microcalcifications or coarse) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypoechoic nodule, unencapsulated, irregular shape and margins, with penetration into vessels, with or without calcifications \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Iso- or hypoechoic nodule, unencapsulated with multiple peripheral microcalcifications and hypervascularisation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unencapsulated nodule, isoechoic mixed hypervascularized, with or without calcifications, without hyperechoic spots \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top">BTA</td><td class="td" title="table-entry " align="left" valign="top">U2 Benign \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Presence of halo, isoechoic, moderately hyperechoic Cystic changes with or without signet ring (colloid) Microcystic, spongiform Eggshell calcification Peripheral vascularization \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">U3 Undetermined/equivocal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Homogeneous, markedly hyperechoic, solid, halo (follicular lesion) Hypoechoic (?), equivocal echogenic foci, cystic change Central/mixed vascularization \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">U4 Suspected \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypoechoic solid Very hypoechoic solid Interrupted peripheral calcification Lobulated contour \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">U5 Malignant \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Solid, hypoechoic, lobulated/irregular contour, microcalcification (PTC?) Solid, hypoechoic, lobulated/irregular contour, microcalcification (PTC?) Intranodular vascularization Anteroposterior>transverse diameter Characteristic lymphadenopathies associated \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1062199.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Classification systems of thyroid nodules according to their ultrasound features." ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "FNA: fine-needle aspiration.Adapted from Gharib et al.<a class="elsevierStyleCrossRef" href="#bib0185">6</a>, Ali et Cibas<a class="elsevierStyleCrossRef" href="#bib0230">15</a> and Baloch et al.<a class="elsevierStyleCrossRef" href="#bib0235">16</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnostic category \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk of malignancy (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical management recommended \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1. Nondiagnostic or unsatisfactory \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3–10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Repeat ultrasound-guided FNA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2. Benign \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60–80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0–3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Clinical followup \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3. Atypia/follicular lesion of undetermined significance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10–20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5–15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Correlate clinically (repeat FNA in most; lobectomy if sonographic malignancy or clinical features) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4. Follicular neoplasm or suspected follicular neoplasm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10–20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15–30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lobectomy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">5. Suspected malignancy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.5–10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60–75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Total thyroidectomy or lobectomy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">6. Malignant \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.5–10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">97–99 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Total thyroidectomy \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1062201.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Diagnostic terminology recommended in the interpretation of cytology through FNA of thyroid nodules." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:31 [ 0 => array:3 [ "identificador" => "bib0160" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epidemiology of thyroid nodules" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "D.S. 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Diagnosis and treatment

Diagnosis of nodular thyroid disease: An update

Actualización en el diagnóstico de la enfermedad nodular tiroidea

Juan J. Díeza,b,

Corresponding author

juanjose.diez@salud.madrid.org

Corresponding author.

, Pedro Iglesiasa

a Servicio de Endocrinología, Hospital Universitario Ramón y Cajal, Madrid, Spain

b Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá de Henares, Alcalá de Henares, Madrid, Spain

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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Algorithm suggested for the differential diagnosis of thyroid nodular disease considering the possible location of the novel diagnostic techniques &#40;elastography&#44; immunocytochemical markers and molecular markers&#41;&#46; MTC&#58; medullary thyroid carcinoma&#59; PTC&#58; papillary thyroid carcinoma&#59; MEN&#58; multiple endocrine neoplasm&#59; FNA&#58; fine-needle aspiration&#46;</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">a</span> Classification system of the British Thyroid Association &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">9</span></a></p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">b</span> Microcalcifications&#44; hypoechogenicity&#44; irregular margins&#44; absence of halo&#44; solid content&#44; intranodular vascularization and anteroposterior diameter<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>transverse diameter&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">12</span></a></p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">c</span> C1-C6&#44; Bethesda system &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">6&#44;15&#44;16</span></a></p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">d</span> Mutation panel&#44; gene expression classifier and miRNA expression&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">A thyroid nodule is the result of an abnormal growth of thyroid cells &#40;benign or malignant&#41; within the gland&#46; It is estimated that 4&#8211;8&#37; of subjects have nodular thyroid disease when using palpation as a detection method&#46; But this percentage rises up to 13&#8211;67&#37; with ultrasound&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">1</span></a> In necropsy studies over half of subjects aged over 60 years have thyroid nodules&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">2</span></a> The annual incidence is about 0&#46;1&#37;&#47;year&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">3</span></a> which implies that in Spain about 46&#44;500 new nodules are diagnosed every year&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The use of imaging tests&#44; such as ultrasound&#44; computed tomography and positron emission tomography&#44; has led to finding thyroid nodules during the study of thyroid-unrelated diseases&#46; The term <span class="elsevierStyleItalic">incidentaloma</span> has been coined to refer to these nodes&#46; Its significance is not negligible&#44; since they represent up to 20&#37; of thyroid nodules studied at the endicronologist&#39;s office&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">4</span></a> The aim of this paper has been to highlight the developments with impact on clinical practice that have occurred in the last decade in the area of diagnosis of thyroid nodules&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Risk factors</span><p id="par0015" class="elsevierStylePara elsevierViewall">Although most thyroid nodules are benign&#44; the greatest challenge that the clinician faces is to discern between benign or malignant&#46; To this purpose&#44; the clinical data are still important&#46; The standard risk factors for thyroid cancer are&#58; nodules in patients with a history of cervical radiation in childhood&#44; family history of papillary thyroid carcinoma &#40;PTC&#41;&#44; medullary thyroid carcinoma &#40;MTC&#41;&#44; multiple endocrine neoplasm&#44; Cowden&#44; Carney and Werner syndrome&#44; extreme ages of life &#40;&#60;14 years or &#62;70 years&#41;&#44; male&#44; rapid growth&#44; firm consistency&#44; binding to neighboring structures&#44; presence of cervical lymphadenopathy or persistent dysphonia&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">5&#44;6</span></a> However&#44; most patients with thyroid cancer have none of these risk factors&#46; A recent meta-analysis of 41 studies&#44; including 29&#44;678 nodules&#44; has shown that the risk of thyroid cancer is higher in patients with previous head and neck irradiation&#44; family history of thyroid cancer and in males&#46; However&#44; subjects under 18 or over 65 do not show higher risk&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The thyroid-stimulating hormone &#40;TSH&#41; has been considered a risk factor for thyroid cancer following a study of 1183 euthyroid patients with palpable goiter&#46; Benignity of the nodule was judged by histology or monitoring of at least 2 years with repeated punctures&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">8</span></a> The authors found an increased risk of thyroid cancer as TSH levels increased&#44; even within the normal range&#46; Other studies have failed to reproduce these data<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">7</span></a>&#46; Therefore&#44; currently no scientific evidence of sufficient quality is available to include serum TSH in diagnostic algorithms or for risk assessment of thyroid cancer&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Diagnostic assessment</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Analytical assessment</span><p id="par0025" class="elsevierStylePara elsevierViewall">Regardless of its potential value as a predictor of cancer&#44; TSH levels should be quantified in all patients&#46; Most of them showed normal levels&#46; If TSH levels are below the lower limit of normal range&#44; the risk of malignancy is minimal and potential hyperthyroidism should be assessed&#46; In cases of high TSH&#44; hypothyroidism study should be completed&#46; In the absence of hypothyroidism&#44; thyroid antibody determination should be limited to patients with suspected chronic lymphocytic thyroiditis&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The determination of thyroglobulin is not useful in the study of thyroid nodules&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">5&#44;9</span></a> The usefulness of calcitonin has been discussed&#46; The prevalence of MTC in these cases is 0&#46;4&#8211;1&#46;4&#37; and high levels of calcitonin may be false positives&#46; Therefore&#44; the guidelines consider that the determination of calcitonin may be useful if MTC is suspected&#44; but it should not be determined routinely&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">9</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Imaging tests</span><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Thyroid scintigraphy</span> with <span class="elsevierStyleSup">99m</span>Tc or <span class="elsevierStyleSup">123</span>I is not a useful test to distinguish between benign and malignant thyroid nodules&#46; Most benign and almost all malignant nodules concentrate both radiotracers less avidly than the adjacent healthy tissue&#46; Scintigraphy is a useful test in patients with low TSH to differentiate an autonomous nodule of a hyperactivemultinodular goiter&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">6</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">CT and MRI are not tests of choice for evaluating thyroid nodules&#44; while useful for assessing the size&#44; extension and compression of airway in the intrathoracic goiter&#46; These tests will be needed only in a minority of patients&#46; Discovered by positron emission tomography&#44; thyroid incidentalomas are of clinical interest since fluorodeoxyglucose hyperuptake may indicate the possibility of malignancy&#44; which occurs in 35&#8211;46&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">10</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Thyroid ultrasound is undoubtedly the imaging test of choice for the study of all thyroid nodules&#46; It reports on the morphology&#44; number&#44; size and characteristics of each nodule&#46; Its usefulness is questionable for diagnosis&#44; differential diagnosis&#44; guidelines for the fine-needle aspiration &#40;FNA&#41; and patient followup&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">9</span></a> Given the high prevalence of thyroid nodules in the general population&#44; this test is not recommended as a screening test in patients with normal cervical palpation and low risk of thyroid cancer&#46; Its indications are limited to patients with palpable nodule or multinodular goiter&#44; lymphadenopathy suggestive of malignancy or at high risk of thyroid cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">6</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The ultrasound report is vital for malignancy risk stratification &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">7&#44;9&#44;11</span></a> A recent meta-analysis<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">7</span></a> found that the nodule features most associated to cancer were&#58; anteroposterior diameter larger than the transverse diameter&#44; absence of halo&#44; microcalcifications&#44; irregular edges&#44; hypoechogenicity&#44; solid nodule and intranodular vascularization&#46; The positive predictive values reported for each of these individual characteristics have ranged from 9 to 70&#37;&#46; Therefore&#44; today ultrasound is considered to obtain only acceptable predictive levels for malignancy when multiple features are present simultaneously in a thyroid nodule&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">12&#44;13</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">In recent years attention has also been focused on the negative predictive value of ultrasound&#44; in order to avoid unnecessary aspiration in benign nodules&#46; Therefore&#44; in 2009 the Thyroid Imaging Reporting and Data System &#40;TIRADS&#41;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">14</span></a> defined the following categories according to their likelihood of malignancy &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#58; TIRADS 2 &#40;0&#37;&#41;&#44; TIRADS 3 &#40;&#60;5&#37;&#41;&#44; TIRADS 4 &#40;5&#8211;80&#37;&#41;&#44; TIRADS 5 &#40;&#62;80&#37;&#41; and TIRADS 6 &#40;100&#37;&#41;&#46; The negative predictive value in the baseline study that included 1007 nodules was 88&#37;&#46; The guidelines of the British Thyroid Association<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">9</span></a> also include a nodule classification system &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; so that benign nodules &#40;U2&#41; would not require needle aspiration&#44; while those confusing&#44; indeterminate or suspicious for malignancy &#40;U3&#8211;U5&#41; should be aspirated&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Cytologic evaluation</span><p id="par0060" class="elsevierStylePara elsevierViewall">Current recommendations include FNA in nodules with any of the following characteristics<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">6</span></a>&#58; &#40;1&#41; diameter &#62;1<span class="elsevierStyleHsp" style=""></span>cm&#44; solid and hypoechoic&#44; &#40;2&#41; of any size with ultrasound findings suggestive of extracapsular growth or lymph node metastases&#44; &#40;3&#41; of any size in patients with a history of cervical radiation&#44; PTC&#44; MTC or type 2 multiple endocrine neoplasm in first-degree relative&#44; previous thyroid cancer surgery&#44; or increased calcitonin in the absence of interference&#44; and &#40;4&#41; diameter &#60;1<span class="elsevierStyleHsp" style=""></span>cm with findings associated with malignancy&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The nodules with increased uptake on scintigraphy should not be aspirated&#46; The size is not specific for the detection of malignancy&#46; Therefore&#44; in multinodular goiters&#44; the nodules should be selected by ultrasound criterion&#44; not by size&#46; The solid component should always be biopsied in mixed nodules&#46; Thus&#44; the cytologic diagnosis is more reliable and the rate of nondiagnostic samples is lower when the FNA is ultrasound-guided&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">6</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Extensions must be studied by cytopathologists experienced on thyroid disease&#46; A minimum of 6 groups of well-preserved thyroid epithelial cells should be available&#44; with at least 10 cells per group&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">15</span></a> The diagnosis must use a standardized classification system such as Bethesda &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">6&#44;15&#44;16</span></a> FNA has an excellent diagnostic performance&#44; with a 0&#8211;7&#37; false positive rate and 1&#8211;11&#37; false negatives&#46; However&#44; false negatives are reduced up to 1&#8211;2&#37; when ultrasound-guided FNA is used&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">New imaging techniques</span><p id="par0075" class="elsevierStylePara elsevierViewall">Ultrasound elastography in real time is a new technique that uses ultrasound to assess tissue stiffness&#46; There are two criteria for evaluating an elastography&#58; a qualitative classification using a color scale &#40;score of elasticity&#41; and a quantitative classification by an index of elasticity or strain &#40;strain index&#41; which is obtained by comparing the value of the nodule against the surrounding tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">17</span></a> The shear wave technique is independent of the operator and uses a low-intensity focused ultrasound beam generating mechanical vibrations spreading depending on tissue elasticity&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">18</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Elastography has been used to select benign nodules that do not require FNA&#46; In a prospective study&#44; conducted in 126 malignant lesions and 372 benign lesions&#44; Trimboli et al&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">19</span></a> showed that adding elastography to conventional ultrasound increased test safety in the diagnosis of malignancy&#44; up to a 97&#37; sensitivity and a 97&#37; negative predictive value&#46; Therefore&#44; the selection of the benign nodules that do not need fine needle aspiration is significantly improved with this technique&#46; In other studies the positive predictive values of elastography have ranged 55&#8211;100&#37; and 93&#8211;98&#37; the negative&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">13</span></a> A meta-analysis of 31 studies involving over 5000 nodules analyzed showed that the sensitivity and specificity of elastography to differentiate benign from malignant nodules reached values of 79 and 77&#37;&#44; respectively&#44; when using qualitative assessment by scores of elasticity&#44; and 85 and 80&#37;&#44; respectively&#44; when using quantitative assessment by strain index&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">20</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Elastography can also be a useful procedure in nodules with indeterminate or nondiagnostic cytology for the selection of those which should not undergo surgery&#46; Rago et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">17</span></a> studied 176 patients with one or more nodules with indeterminate or nondiagnostic cytology whose final histology was available after thyroidectomy&#46; Elastography sensitivity in this series was 96&#46;8&#37; and 87&#46;5&#37; in the indeterminate and nondiagnostic cytology nodules respectively while specificity reached 91&#46;8&#37; and 86&#46;7&#37; respectively&#44; for said nodules&#46; Elastography has limited use in predominantly cystic nodules and nodules with coarse calcifications&#46; In the nodules located on isthmus or lower poles&#44; applying proper pressure in order to obtain reliable measures might not be possible&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">New molecular markers</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Immunocytochemical markers</span><p id="par0090" class="elsevierStylePara elsevierViewall">In the differential diagnosis of nodular thyroid disease different immunocytochemical markers have been used&#44; such as galectin-3&#44; cytokeratin-19&#44; fibronectin&#44; human bone marrow endothelial cells&#44; cyclin D1&#44; peroxisome proliferator-activated receptor gamma &#40;PPAR&#947;&#41; and iodine carrier protein&#44; among others&#46; The positive samples for cytokeratin-19 showed a 81&#37; sensitivity and a 73&#37; specificity for the diagnosis of malignancy&#46; In the case of galectin-3&#44; sensitivity and specificity were 82 and 81&#37;&#44; respectively&#44; and 77 and 83&#37;&#44; respectively&#44; for human bone marrow endothelial cells&#46; The combination of the 3 markers was associated with malignancy with a 85&#37; sensitivity and a 97&#37; specificity&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">21</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Genetic markers</span><p id="par0095" class="elsevierStylePara elsevierViewall">The major clinical problem in the interpretation of the cytology is the attitude to indeterminate cytology specimens such as atypia or follicular lesions of uncertain significance&#46; In recent years this problem has been addressed by two types of molecular studies&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">The gene expression classifier is a ruling-out system in which an algorithm analyzes the expression pattern of 142 genes through the analysis of messenger ribonucleic acids &#40;mRNAs&#41; obtained from FNA samples&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">22&#44;23</span></a> The test aims to obtain high sensitivity and minimize the number of false negatives&#46; The negative predictive value in early studies was very high&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">22</span></a> However&#44; this value decreases as the prevalence of cancer increases&#46; Therefore&#44; the gene expression classifier is more reliable when the lower risk of cancer in the patient population&#46; More recent studies<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">23</span></a> have found negative predictive values slightly lower than the baseline &#40;80&#8211;83&#37;&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The gene mutation panel studies gene point mutations such as <span class="elsevierStyleItalic">BRAF</span>&#44; <span class="elsevierStyleItalic">NRAS</span>&#44; <span class="elsevierStyleItalic">HRAS</span>&#44; <span class="elsevierStyleItalic">KRAS</span> and <span class="elsevierStyleItalic">RAS</span>&#44; as well as RET&#47;PTC and PAX8&#47;PPAR&#947;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">24</span></a> rearrangements&#46; In a retrospective analysis of 513 samples of thyroid aspiration of 479 patients undergoing surgery&#44; mutations were found in 22 of the 35 nodules that were ultimately diagnosed with thyroid cancer&#46; The specificity of this test was 99&#44; 97 and 96&#37; for cytology with Bethesda categories 3&#44; 4 and 5&#44; respectively&#46; The positive predictive values ranged 72&#8211;94&#37;&#46; According to these authors the likelihood of cancer was 100&#37; when BRAF mutations and PAX8&#47;PPAR&#947; rearrangements and 84&#37; when mutations in <span class="elsevierStyleItalic">RAS</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">25</span></a> Based on these results diagnostic lobectomy is recommended for nodules with follicular neoplasm cytology or suspected follicular neoplasm or suspected mutation-positive malignancy&#44; while monitoring is recommended for atypia and follicular lesions of uncertain significance with negative mutation panel&#46; However&#44; it should be noted that the sensitivity of this test is low and has a 6&#8211;14&#37; false negative rate&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Micro-RNA</span><p id="par0110" class="elsevierStylePara elsevierViewall">Micro-RNA &#40;miRNA&#41; are small non-coding RNA molecules&#44; generally 21&#8211;23 nucleotides&#44; involved in the regulation of gene expression through suppression of target mRNA&#44; leading to blocking the synthesis of proteins through mRNA destabilization and translational repression&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">26&#8211;28</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Several studies have evaluated the role of miRNAs as diagnostic markers in thyroid cancer&#46; Agretti et al&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">26</span></a> showed that the expression panel of 3 miRNAs &#40;miR-146b&#44; miR-155 and miR-221&#41; in 53 indeterminate FNA samples of thyroid allowed to distinguish between benign nodules and PTCs with a 60&#37; sensitivity and 58&#37; specificity&#46; Kitano et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">27</span></a> reported that miR-7 was the best predictor for distinguishing malignant and benign nodules in 95 thyroid FNA samples&#44; with a 100&#37; sensitivity&#44; but low specificity &#40;29&#37;&#41;&#46; A recent meta-analysis<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">28</span></a> of 7 assays with 361 cytological samples obtained from 341 patients&#44; concluded that three miRNAs &#40;miR-30a-3p&#44; -30d&#44; -7&#41; were significantly downregulated in PTC&#46; Multiple miRNA assays have a higher sensitivity &#40;87&#37; <span class="elsevierStyleItalic">vs</span> 71&#37;&#41; to differentiate malignant from benign thyroid nodules compared to single miRNA assays&#46; However&#44; the former show a lower specificity &#40;75&#37; <span class="elsevierStyleItalic">vs</span> 84&#37;&#41;&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">New forms of clinical management</span><p id="par0120" class="elsevierStylePara elsevierViewall">The study of thyroid nodule has traditionally involved the participation of multiple medical specialties with a large number of visits and poor efficiency of health care&#46; In recent years we have witnessed a shift from the traditional model to one that increases the efficiency by reducing the number of visits at high-resolution consultations &#40;HRCs&#41; or unique consultation&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">There are 2 types of thyroid nodule HRCs currently in our country&#46; One involves thyroid ultrasound &#40;and FNA if necessary&#41; in the radiology department&#44; with subsequent evaluation by the endocrinologist&#44; while the second method involves ultrasound at the endocrinologist&#39;s office&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">4&#44;29</span></a><span class="elsevierStyleSup">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">30</span></a> Including in-office ultrasound at the endocrinologist&#39;s reduces the number of visits and lost work hours&#44; thus obtaining a social benefit&#46; The use of in-office ultrasound by endocrinologists reduces the time required for diagnosis and initiate treatment and decreases the number of visits of patients in different hospital departments&#46; All this leads to cost savings and time delay in diagnosis of thyroid nodular disease&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Recently&#44; Castells et al&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">29</span></a> have shown that the availability of in-offce ultrasound&#44; with the possibility of thyroid nodule aspiration with <span class="elsevierStyleItalic">in situ</span> cytologic specimen evaluation&#44; improves the diagnostic efficiency and quality of healthcare&#46; These authors showed that the number of punctures needed for a diagnosis is reduced with the use of in-office ultrasound since the number of punctures with insufficient material is lower&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">29</span></a> In short&#44; as Arg&#252;elles et Tof&#233;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">31</span></a> point out&#44; the option of ultrasound in the hands of the endocrinologist is simpler&#44; cheaper and therefore more efficient&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Future vision</span><p id="par0135" class="elsevierStylePara elsevierViewall">The positioning of the new procedures&#44; both imaging and molecular studies in the diagnostic algorithm of thyroid nodules has not been defined yet&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> is a proposal for the possible location of these new methods in the classical scheme of decision making in patients with nodular thyroid disease&#46; Elastography might be useful in benign nodules to avoid FNA in high-elasticity cases&#46; But it also lays at the point of decision making about surgery or observation in patients with indeterminate or nondiagnostic FNA&#46; The use of different immunocytochemical techniques can become an attractive tool to increase the diagnostic value of thyroid cytology&#46; Similarly&#44; molecular genetics techniques might constitute a useful tool for selecting patients for surgery more accurately and therefore improve the diagnostic yield of the samples obtained through thyroid FNA&#46; The experience with these techniques is still limited&#46; Thus&#44; further studies are required to establish their actual clinical usefulness&#46; Finally&#44; it is expected that thyroid nodule HRC will be increasingly implemented in the immediate future in specialized care centers&#44; which will contribute to the optimization of resources&#44; streamlining diagnosis and improved clinical outcomes&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflict of interests</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors report no conflict of interest regarding the contents of this article&#46;</p></span></span>"
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              "titulo" => "Immunocytochemical markers"
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          "titulo" => "New forms of clinical management"
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    "fechaRecibido" => "2015-06-19"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; D&#237;ez JJ&#44; Iglesias P&#46; Actualizaci&#243;n en el diagn&#243;stico de la enfermedad nodular tiroidea&#46; Med Clin &#40;Barc&#41;&#46; 2016&#59;146&#58;86&#8211;91&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Algorithm suggested for the differential diagnosis of thyroid nodular disease considering the possible location of the novel diagnostic techniques &#40;elastography&#44; immunocytochemical markers and molecular markers&#41;&#46; MTC&#58; medullary thyroid carcinoma&#59; PTC&#58; papillary thyroid carcinoma&#59; MEN&#58; multiple endocrine neoplasm&#59; FNA&#58; fine-needle aspiration&#46;</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">a</span> Classification system of the British Thyroid Association &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">9</span></a></p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">b</span> Microcalcifications&#44; hypoechogenicity&#44; irregular margins&#44; absence of halo&#44; solid content&#44; intranodular vascularization and anteroposterior diameter<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>transverse diameter&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">12</span></a></p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">c</span> C1-C6&#44; Bethesda system &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">6&#44;15&#44;16</span></a></p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">d</span> Mutation panel&#44; gene expression classifier and miRNA expression&#46;</p>"
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        "fuente" => "Adapted from Campanella et al&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">7</span></a>&#44; Perros et al&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">9</span></a> and Yeh et al&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">11</span></a>&#46;"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Feature&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Suggestive of benignity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Suggestive of malignity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Content&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Purely cystic&#44; predominantly cystic spongiform&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Solid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Echogenicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Isoechoic or moderately hyperechoic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypoechoic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Margins&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Well-defined&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Irregular&#44; lobulated&#44; spiculated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shape&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anteroposterior diameter larger than the transverse diameter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Halo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypoechoic&#44; regular&#44; continuous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Absent&#44; irregular or incomplete&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vascularization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Absent or predominantly peripheral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Central and irregular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Calcifications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Peripheral or eggshell<br>Intranodular coarse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Intranodular microcalcifications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lymphadenopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oval morphology<br>Hyperechoic central fatty hilum<br>Hilar vascular flow pattern&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Solid&#44; rounded &#40;long axis&#47;short axis &#60;2&#41;<br>Punctate calcifications<br>Peripheral vascularization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">BTA&#58; British Association Thyorid&#59; MTC&#58; medullary thyroid carcinoma&#59; PTC&#58; papillary thyroid carcinoma&#59; TIRADS&#58; Thyroid Imaging Reporting and Data System&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Adaptaded from Perros et al&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">9</span></a> and Horvath et al&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">14</span></a></p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">System&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Category&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Description&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="6" align="left" valign="top">TIRADS</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anechoic lesion with hyperechoic spots&#44; not vascularized<br>Unencapsulated&#44; mixed&#44; non-expandable lesion&#44; with hyperechoic&#44; vascularized&#44; spongiform spots<br>Unencapsulated nodule&#44; mixed with solid portions&#44; isoechogenic&#44; expandable&#44; vascularized&#44; with hyperechoic spots&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hyper-&#44; iso- or hypoechoic nodule&#44; partially encapsulated with peripheral vascularization in Hashimoto&#39;s thyroiditis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Solid or mixed hyper-&#44; iso- or hypoechoic nodule with thin capsule&#46; Hypoechoic lesion with ill-defined margins&#44; without calcification&#46; Hyper-&#44; iso- or hypoechoic encapsulated nodule&#44; hypervascularized&#44; with thick capsule&#44; with calcifications &#40;microcalcifications or coarse&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypoechoic nodule&#44; unencapsulated&#44; irregular shape and margins&#44; with penetration into vessels&#44; with or without calcifications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Iso- or hypoechoic nodule&#44; unencapsulated with multiple peripheral microcalcifications and hypervascularisation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unencapsulated nodule&#44; isoechoic mixed hypervascularized&#44; with or without calcifications&#44; without hyperechoic spots&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">BTA</td><td class="td" title="table-entry  " align="left" valign="top">U2<br>Benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Presence of halo&#44; isoechoic&#44; moderately hyperechoic<br>Cystic changes with or without signet ring &#40;colloid&#41;<br>Microcystic&#44; spongiform<br>Eggshell calcification<br>Peripheral vascularization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">U3<br>Undetermined&#47;equivocal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Homogeneous&#44; markedly hyperechoic&#44; solid&#44; halo &#40;follicular lesion&#41;<br>Hypoechoic &#40;&#63;&#41;&#44; equivocal echogenic foci&#44; cystic change<br>Central&#47;mixed vascularization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">U4<br>Suspected&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypoechoic solid<br>Very hypoechoic solid<br>Interrupted peripheral calcification<br>Lobulated contour&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">U5<br>Malignant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Solid&#44; hypoechoic&#44; lobulated&#47;irregular contour&#44; microcalcification &#40;PTC&#63;&#41;<br>Solid&#44; hypoechoic&#44; lobulated&#47;irregular contour&#44; microcalcification &#40;PTC&#63;&#41;<br>Intranodular vascularization<br>Anteroposterior<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>transverse diameter<br>Characteristic lymphadenopathies associated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">FNA&#58; fine-needle aspiration&#46;</p><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Adapted from Gharib et al&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">6</span></a>&#44; Ali et Cibas<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">15</span></a> and Baloch et al&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">16</span></a></p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnostic category&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk of malignancy &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical management recommended&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1&#46; Nondiagnostic or unsatisfactory&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#8211;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2&#46; Benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60&#8211;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#8211;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Clinical followup&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3&#46; Atypia&#47;follicular lesion of undetermined significance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#8211;20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#8211;15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correlate clinically &#40;repeat FNA in most&#59; lobectomy if sonographic malignancy or clinical features&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4&#46; Follicular neoplasm or suspected follicular neoplasm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#8211;20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&#8211;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lobectomy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">5&#46; Suspected malignancy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;5&#8211;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60&#8211;75&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Total thyroidectomy or lobectomy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">6&#46; Malignant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;5&#8211;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">97&#8211;99&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Total thyroidectomy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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