Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 5161

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Best Practice & Research Clinical Endocrinology & Metabolism

journal homepage: www.elsevier.com/locate/beem

Assessment of nodular goitre

Massimo Tonacchera, Associate Professor of Endocrinology *, Aldo Pinchera, Professor of Endocrinology, Paolo Vitti, Professor of Endocrinology
Department of Endocrinology, University of Pisa, Pisa Italy

Keywords: non-toxic goitre toxic multinodular goitre toxic adenoma TSH receptor TSH receptor mutations thyroid nodules hyperthyroidism ne-needle aspiration ultrasound elastography TSH receptor

Nodular goitres are enlargements of the thyroid gland. In the absence of thyroid dysfunction, autoimmune thyroid disease, thyroiditis and thyroid malignancy, they constitute an entity described as non-toxic nodular goitre, which occurs both endemically and sporadically. In the early phase of goitrogenesis, goitres are diffuse and, with time, such goitres tend to become nodular. Concomitantly, thyroid function often becomes autonomous, and therefore the patients gradually develop hyperthyroidism. Some non-toxic goitre patients have no symptoms at all, or just complaints of cosmetic disgurement. In the diagnostic evaluation protocol, neck palpation and several imaging methods are available: ultrasonography (US), the new developed US elastography, scintigraphy, computed tomography (CT) scan and magnetic resonance imaging (MRI). Fine-needle aspiration biopsy (FNAB) provides the most direct and specic information about a thyroid nodule. Recently, a combination of cytology and molecular testing has shown signicant improvement in the diagnostic accuracy and allowed for better prediction of malignancy in thyroid nodular disease. 2009 Elsevier Ltd. All rights reserved.

Nodular goitres (NGs) are clinically recognisable enlargements of the thyroid gland. In the absence of thyroid dysfunction, autoimmune thyroid disease, thyroiditis and thyroid malignancy, they constitute an entity described as non-toxic NG.1 NG occurs both endemically, mainly related to iodine deciency when goitre prevalence in children 612 years of age within a population is more than 5%, and sporadically, when this number is 5% or less. In the early phase of goitrogenesis, goitres are diffuse and, with time, diffuse goitres tend not only to grow but also to become nodular. In general, NG can be

* Corresponding author. Tel.: 39 050 995048; Fax: 39 050 578772. E-mail address: mtonacchera@hotmail.com (M. Tonacchera). 1521-690X/$ see front matter 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.beem.2009.08.008

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divided into solitary nodular and multinodular thyroid disease.1 Concomitantly, thyroid function often becomes autonomous, that is, thyroid hormone secretion becomes independent of thyreotropin secretion, and therefore the patients gradually develop subclinical hyperthyroidism and eventually overt hyperthyroidism.1 Thus, the natural history of NG is characterised clinically by thyroid growth, nodule formation and the development of functional autonomy. The clinical forms include toxic multinodular goitre (TMNG) and toxic thyroid adenoma (TA). Epidemiology of NG Epidemiological studies of nodular goitre are hampered by problems such as selection criteria (e.g., age and sex), inuence of environmental factors (e.g., iodine and drug intake and smoking and drinking habits), evaluation of size and morphology (i.e., palpation, sonography and scintigraphy) and determination of thyroid function.2 The clinical grading of thyroid size is subjective and imprecise. More recently, ultrasonography (US) has been used in epidemiologic studies to assess thyroid size.3 A pattern of increased thyroid volume and nodularity in areas with iodine deciency is the rule.25 A recent cross-sectional study using modern technologies on the spectrum of thyroid disorders occurring in a community with mild-to-moderate iodine deciency in the south of Italy5, clearly showed that the prevalence of goitre and thyroid nodularity increased with age. The prevalence of goitre increased from 16% in children to 60% in adults. NG was negligible in the 15- to 25-year age class, but increased up to 29% in the 56- to 65-year age class.5 In the Whickham survey of a representative sample of the adult population from a geographic area with adequate iodine supply of the United Kingdom, 15.5% of the participants had a palpable goitre (8.6% had a small goitre), with a female-to-male ratio of 4.5:1.6 There was a weak association between goitre and thyroid autoantibodies and no correspondence with urinary iodine excretion. In Framingham, Massachusetts, where iodine intake was also sufcient, 1% of persons between 30 and 59 years of age had multinodular goitre by palpation.7 In Connecticut, 2% of the adults were reported to have nodular glands.8 In Denmark, palpable goitre was demonstrated in 9.8% of a mildly iodine-decient population and 14.6% of a moderately iodine-decient population.4 This frequency increased to 15.0% and 22.6%, respectively, when goitre was dened by sonographic determination of thyroid volume.4 There are a vast number of such studies underscoring the inaccuracy of and also the large observer variation in the determination of goitre and thyroid size by clinical examination.9 In the Whickham survey6, solitary thyroid nodules were estimated to be present in 5.3% of women and 0.8% of men (ratio, 6.6:1). No details were provided about nodule size, function or their association with goitre. In Framingham, this frequency was 4.6% in all (6.4% in women and 1.6% in men).7 However, these numbers are markedly changed if sonography is used. Then, the prevalence of thyroid nodules, even if dened as more than 10 mm in diameter, is usually 2030% in unselected populations10 and even higher in older age groups and in areas with insufcient iodine intake.11 Natural history of NG and epidemiology of functional autonomy The natural history of NG is characterised clinically by thyroid growth, nodule formation and the development of functional autonomy. Non-autoimmune hyperthyroidism is usually encountered in subjects with long-standing nodular goitre and is a major cause of morbidity in iodine-decient areas.5,12 The clinical forms include TMNG and TA. Thyrotoxicosis is usually preceded by a long phase of subclinical hyperthyroidsm (abnormally low serum thyroid-stimulating hormone (TSH), with normal circulating thyroid hormones) due to the secretion of thyroid hormones independent from TSH regulation (thyroid autonomy). Toxic or autonomous multinodular goitre has a multifaceted clinical presentation, spanning from a single hyperfunctioning nodule within a goitre where several non-functioning nodules also coexist with NG where multiple hyperfunctining areas, not conned to distinct nodules, are barely distinguishable from non-functioning nodules. TMNG is the most common cause of thyrotoxicosis in iodine-decient areas. The critical role of iodine deciency in the development of iodine-induced hyperthyroidism is demonstrated by the decreased incidence of this disease that occurred in several countries13 after institution and implementation of iodine prophylaxis. The incidence of different types

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of hyperthyroidism was investigated in an epidemiologic study, which compared east Jutland, an area of low iodine intake, with Iceland, a country with adequate iodine intake.14 The incidence of hyperthyroidism was signicantly higher in Jutland (38.7/100 000 per year) than in Iceland (23.6/100 000 per year). It was also shown that the different incidence of hyperthyroidism incorporated a more fundamental difference in the causes of hyperthyroidism. In the area of low iodine intake, TMNG was the most common cause of hyperthyroidism, while it was infrequent in Iceland, where Graves disease was the dominant cause of hyperthyroidism. The age distribution of new cases of hyperthyroidism also demonstrated large differences between the two regions. In Iceland, the majority of the cases of hyperthyroidism were observed in people aged 2060 years. The typical thyrotoxic patient was a young- to middle-aged woman with Graves disease. In Jutland, there was a peak of hyperthyroidism in the elderly, the typical patient being an elderly woman with TMNG.14 A recent cross-sectional study using modern technologies on the spectrum of thyroid disorders occurring in a community with mild-to-moderate iodine deciency in the south of Italy5 clearly showed that the thyroid functional autonomy (dened by the nding of normal serum free T4 (FT4), free T3 (FT3) and subnormal serum TSH concentrations) was rare in children and progressively increased with age to reach 15% in the older age group. Thyrotoxicosis was mainly due to toxic NG and was more frequent in aged people. These data indicate that, in its natural history, NG develops functional autonomy eventually evolving to thyrotoxicosis. The few longitudinal studies in patients with multinodular goitres conrm these cross-sectional data. Aetiopathogenesis Non-toxic NG Non-toxic NG is a complex genetic disease where environmental factors interact with a genetic predisposition.15 Familial clustering of simple goitre has long been recognised, but classical genetic analysis based on Mendelian principles has shown no simple mode of transmission. It is generally accepted that iodine deciency is a major environmental factor contributing to both endemic and sporadic simple goitres.15 In fact, thyroid size is negatively correlated to urinary iodine excretion.15 Constitutional factors such as gender are clearly implicated in the aetiology, because the ratio of females to males in non-endemic goitre regions may range from 5:1 to 10:1. Other suggested risk factors include cigarette smoking15, naturally occurring goitrogens15, increased body mass index16 and certain drugs.15 A strong genetic predisposition has been indicated by family and twin studies: family studies have shown that children of parents with goitre have a signicantly higher risk of goitre compared with the risk for children of healthy parents. Several twin studies from Greece and Denmark1517 have shown a higher concordance rate for monozygotic than dizygotic twins. Furthermore, a study of 5479 same-sex monozygotic and dizygotic twin pairs revealed that the genetic predisposition to developing euthyroid goitre is 82% in women in a Danish population.17 Studies assessing the role of specic candidate genes in the aetiology of simple goitre have provided conicting results. Corral et al.18 demonstrated a thyroglobulin (Tg) gene point mutation in chromosome 8 associated with non-endemic goitre, which could, however, not be conrmed by others.15 Using classic linkage analysis in combination with a genomewide screening in a large FrenchCanadian pedigree, Bignell et al.19 identied a region of interest on chromosome 14, multinodular goitre 1 (MNG-1). Two other studies20,21 have examined the role of MNG-1 and other possible candidate genes/ markers, including Tg, TSH receptor (TSHR) and sodium iodide symporter (NIS), in the aetiology of simple goitre, with conicting results. Recently, Capon et al.22 mapped a dominant form of MNG to chromosome Xp22. Aetiopathogenesis of functional autonomy In 1989, Dumont et al.23 hypothesised that relative hyperactivity of the cyclic adenosine monophosphate (cAMP) system could account for some of the benign tumours, and any molecular lesion leading to constitutive activity of the cAMP cascade (TSH receptor, G protein, cyclase and protein kinase) could be responsible for the growth and hyperfunction typical of TA.24 In the rst study

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from the group of Vassart, nine out of 11 tissues studied were shown to harbour an activating thyroid-stimulating hormone receptor (TSHr) mutation.24 Other studies have conrmed this observation, describing mutations in other residues.25,26 All the mutations found are heterozygous, as expected from gain-of-function mutations with dominant effect, and conned to the adenomatous tissue. Gainof-function mutations of the TSH receptor have been studied after transient expression from recombinant constructs in COS cells and result in constitutive stimulation of cAMP accumulation.26 Subsequent studies conrmed that activating TSHr mutations are the main cause of thyroid toxic adenomas. A total of 73% of toxic thyroid adenomas considered in our rst study in Italy27 were found to harbour an activating TSHr mutation, conrming the notion that this genetic anomaly is the major cause of the disease.27 Similarly, a high prevalence of TSHr mutations have been identied in patients with toxic adenomas living in areas of moderate iodine deciency. In the Belgium series of 33 toxic adenomas studied, 82% were found to harbour a somatic mutation in the TSHr gene and 5% in the Gsa.28 Somatic gain-of-function mutations were identied in 15 out of 31 toxic adenomas in Germany28 and in six out of seven toxic adenomas in Brazil.29 Similar results have been obtained by Georgopolous et al.30 in Greece and by Palos-Paz et al. in Spain.31 A much lower frequency of TSHr mutations was found in toxic thyroid adenoma by other authors.28 This discrepancy might be due to racial differences in the population studied (Caucasian vs. Japanese), or to different criteria used to dene toxic thyroid adenoma. Failure to entirely sequence exon 10 of the TSHr gene or the use of less sensitive techniques, such as single-strand conformation polymorphism (SSCP), might also explain the lower frequency of TSHr gene mutations reported in other studies.28 Despite sequencing the entire transmembrane domains encoded in exon 10 of TSHr, Gabriel et al.32 failed to nd mutations in any of the seven toxic adenomas from patients living in an area with adequate iodine intake. Similar ndings were reported by Takeshita et al.33 in Japan, since only one out of 34 toxic adenomas was found to harbour a TSHr gene mutation. Hyperfunctioning thyroid nodules showing no TSHr mutation may result from alterations of other proteins involved in the activation of the cAMP pathway. In this respect, it is interesting to note that Gs-alfa mutations (gsp oncogene) were reported in about 30% of toxic thyroid adenomas.28 We34 reported that, similarly to solitary toxic thyroid adenoma, activating TSHr mutations are present in single hyperfunctioning nodules (either adenomas or hyperplastic nodules) within TMNGs in which non-functioning nodules also co-exist. The presence of activating TSHr mutations in a few cases of multiple adenomatosis has also been reported. However, in areas of iodine deciency, most patients with toxic or autonomous MNG show thyroid scintigraphic patterns in which hyperfunctioning areas are not superimposable onto nodules found at physical and ultrasound examination. This implies that the boundaries of scintigraphic areas with increased radioiodine uptake do not necessarily correspond to the anatomic boundaries of thyroid nodules. We34 and another group35 have shown that activating TSHr mutations are present in the majority of non-adenomatous hyperfunctioning nodules scattered throughout the gland in patients with toxic or functionally autonomous MNG coming from an area of iodine deciency. Most hyperfunctioning areas corresponded to aggregates of micro-macrofollicular structures not dened by a capsule.34,35 Most areas were separated by irregular strands of apparently normal micro-macrofollicular parenchyma, but in a few cases, nodules were in intimate contact. These data would indicate that TSHr mutations might be implicated in the genesis of the majority of hyperfunctioning areas of TMNG. Signs, symptoms and diagnosis Signs and symptoms Several non-toxic goitre patients have no symptoms at all, or just complain of cosmetic disgurement. Local discomfort in the neck is very common. Obstructive symptoms range from very slight to severe caused by compression of upper airways, the recurrent laryngeal nerve, the oesophagus and the great veins in the thoracic inlet. There may be dysphagia, cough and hoarseness. Paralysis of a recurrent laryngeal nerve may occur when the nerve is stretched taut across the surface of an expanding goitre, but this event is very unusual. When unilateral vocal cord paralysis is demonstrated, the presumptive diagnosis is cancer. Pressure on the superior sympathetic ganglions and nerves may produce Horners

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syndrome. Roentgenographic examination is useful in dening the extent of tracheal deviation and compression. Compression is frequently seen but is rarely functionally signicant. Two aspects are important in the differentiation from malignancy. First, the clinical presentation if the goitre is longstanding, showing little or no growth, absence of a dominant node, familial, while there is no neck irradiation in the past, especially in childhood, no hoarse voice and no suspicious lymphnodes in the neck, there is little fear of carcinoma.Second, if suspicion of the above symptoms is present, ne-needle aspiration (FNA) cytology may be helpful. Clinical examination The evaluation of a patient with NG comprises initially a careful history and physical examination focussing on inspection of the neck (including regional lymph nodes) and the upper thorax and palpation of the goitre to determine its size and nodularity. NG does not include thyroid cancer, but one of the main aims of the clinical evaluation is to exclude the risk of overlooking thyroid cancer. Table 1 lists the most important factors suggesting thyroid malignancy. A family history of benign goitre usually suggests a benign disorder. The risk of harbouring thyroid cancer is highest in the young and the old, and therefore, the diagnostic approach should be more aggressive in these age groups. Nodular thyroid disease is 510 times more common in females, whereas the rates of thyroid carcinoma are nearly equal in men and women. Therefore, NG in a man is more likely to be a carcinoma. Head and neck irradiation in infancy or childhood, for a number of benign conditions, is strongly associated with a subsequent occurrence of carcinoma.36 The possibility that many naturally occurring thyroid carcinomas may be due to radiation fallout from various radiation sources or the natural background radiation is strengthened by the observed epidemic of childhood papillary thyroid cancer seen in Belarus and Ukraine after the Chernobyl nuclear accident.37 A growth observed during thyroid hormone therapy is particularly worrisome. Sudden growth is most likely a thyroid cyst or a previously undetected nodule in which a haemorrhage has occurred. Rapid enlargement is also encountered in cases of anaplastic carcinoma or the development of lymphoma in a patient with previous chronic autoimmune thyroiditis. The presence of discomfort in the neck, jaw or ear and dysphagia, hoarseness or dyspnoea can occur in patients with benign thyroid nodules, particularly in those with large MNGs, and may also indicate thyroid carcinoma. A hard and xed nodule is suggestive of thyroid carcinoma, as is paralysis of the vocal cords and ipsilateral lymphadenopathy. Laboratory investigations In any patient with cervical goitre, serum TSH is by far the most used test in the initial evaluation of NG.38,39 If the serum TSH concentration is low, measurement of serum-free thyroxine is indicated to determine if the patient has subclinical or overt thyrotoxicosis. In patients with low serum TSH and normal serum-free FT4 concentrations, serum-free T3 should be measured. If the TSH concentration is high, chronic autoimmune thyroiditis or ingestion of an antithyroid compound such as lithium should be considered. Antithyroid peroxidase (anti-TPO) and anti-Tg antibodies should also be measured.38,39 This seems relevant because thyroid antibodies are found in approximately 10% of the population, and consequently, autoimmunity may well co-exist within a goitre. On the other hand, diffuse or focal lymphocytic inltrates in an enlarged gland may represent chronic autoimmune thyroiditis and not merely simple goitre. Although serum Tg correlates with the iodine status and/or the size of the thyroid gland, this marker is too inaccurate at the individual level to have any

Table 1 Factors suggesting thyroid malignancy in NG. Presence of a dominant growing node Presence of thyroid carcinoma in the family Neck irradiation in the past Hoarse voice Suspicious lymphnodes in the neck

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independent value in the diagnosis of goitre. A test giving rise to much discussion during recent years is serum calcitonin. This hormone is a marker of medullary thyroid carcinoma (MTC), and the serum levels correlate with the tumour burden.40 MTC accounts for less than 10% of all thyroid cancers and is supposed to be present in less than 0.5% of all thyroid nodules.41 Of particular interest is its use in the early diagnosis of MTC. A two-site immunometric calcitonin assay should be used, but the presence of heterophilic antibodies may still cause falsely elevated values. With modern assays, serum calcitonin is found to be below 10 pg ml1 in 99% of healthy subjects and is slightly higher in men than in women. Raised levels of calcitonin not related to thyroid diseases are seen in conditions such as impaired renal function, pseudohypoparathyroidism or treatment with proton-pump inhibitors. Pentagastrin stimulation may have a role in sporadic cases in which basal calcitonin exceeds 10 pg ml1. Six large-scale studies4247 of the routine use of serum calcitonin in patients with nodular thyroid disease have been published. The studies vary with regard to the diagnostic setup and the fraction of patients with histological verication. The prevalence of MTC was up to 1.4% in a large French study45 in which 41% of 34 patients with an elevated basal calcitonin had MTC, and also included two false-negative cases. In the study of Hahm et al.42, 56 of 1448 patients (3.9%) with nodular thyroid diseases had a serum calcitonin level above 10 pg ml1. Ten patients (0.7%) proved to have MTC. Half of these subjects had a basal serum calcitonin level above 100 pg ml1. Vierhapper et al.43 found three of 1062 patients having a basal calcitonin level exceeding 100 pg ml1. More important, in 10 of 31 patients with basal calcitonin ranging from 10 to 100 pg ml1, a pentagastrin stimulation increased calcitonin above 100 pg ml1.43 MTC was found in three patients and another six had C-cell hyperplasia. Basal or stimulated calcitonin levels were generally more sensitive than FNAB in detecting MTC, and the routine use of serum calcitonin was recommended by all authors of these studies. Diagnostic imaging Neck palpation is notoriously imprecise with regard to both thyroid gland morphology and size determination. For this purpose, several imaging methods are available: US, the newly developed US elastography (USE), scintigraphy, computed tomography (CT) scan and magnetic resonance imaging (MRI). Of these, US clearly has rst priority among clinicians. US The main reasons for the widespread use of thyroid sonography are availability, low cost, limited discomfort to the patient and non-ionising nature. Sonography has many favourable features, such as detection of non-palpable nodules, estimation of nodule size/goitre volume and guidance for FNAB. The possibility of measuring thyroid volume is another highly useful feature of sonography, particularly where diagnosis and monitoring of goitre size are of crucial importance. High-resolution US is very sensitive in the detection of thyroid nodules, for which purpose the interobserver variation is low and distinguishes solid from cystic lesions.48 Sonography detects 5 times as many nodules as thyroid palpation and twice as many when only nodules larger than 2 cm are considered.49 Thus, after the introduction of sonography, it has become clear that nodules in the thyroid gland are very prevalent, ranging from 17% to as much as 67% in a given population.50 As a consequence, the term thyroid incidentaloma has emerged. Sonographic characteristics such as hypoechogenicity, microcalcications and increased nodular ow visualised by Doppler are all, to some extent, predictive of malignancy (Table 2). However, its low accuracy in most studies disqualies sonography in the differentiation between benign and cancerous lesions51, and it is clearly inferior to FNAB in this setting. Recently, USE, a new powerful diagnostic tool, which assesses hardness as indicator of malignancy in thyroid nodules, has been proposed.52 USE has a high specicity and is independent as regards sensitivity from the nodule size, this predictive value being maintained in follicular lesions. Available data suggest that USE is the best available non-invasive tool comparable to FNAB for the evaluation of thyroid nodules, provided that nodule is solid and devoid of coarse calcications. Thus, conventional US maintains its importance for the selection of nodules in which USE is predictive.52

M. Tonacchera et al. / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 5161 Table 2 US characteristics of malignancy in thyroid nodules. Hypoechogenicity Microcalcications Irregular margins Absent halo sign Solid aspect Increased intranodular ow by Doppler US

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Scintigraphy Radionuclide scintigraphy with iodine-123 or technetium pertechnetate usually visualises the goitre. Scintigraphy is very helpful in the determination of the functionality of the thyroid nodules. Nodules with a high uptake by scintigraphy almost never harbour clinically signicant malignancy, although exceptions have been reported. Radioactive 99mTc used as a tracer may result in falsely positive uptake in 38% of thyroid nodules (the trapping only nodules)53, whereas iodine isotopes are devoid of this problem. Typically, inhomogeneous uptake of the radionuclide will be seen with relatively cold and hot areas in an enlarged thyroid gland, compatible with MNG. TSH suppression by laevothyroxine administration emphasises autonomous nodular function, but is not routinely used. The fraction of inactive or cold lesions constitutes 7794% of nodules in consecutive series of thyroid scintigrams.5456 The a priori risk of malignancy among cold nodules is reported to be 825% or even higher.5558

Other imaging techniques It is often necessary to establish whether thyroid enlargement, particularly nodular, produces any signicant compression and/or displacement of neighbouring structures. X-ray of the neck and the chest on both orthogonal positions should be performed. At the neck level, displacement and/or narrowing of the trachea can be observed and examination with barium may demonstrate displacement of the cervical oesophagus in patients with large goitres. Less penetrating pictures may show intrathyroidal calcication and will also indicate the size of the goitre and its retrosternal extension. For the latter purpose, CT scan and MRI will usually provide a more precise picture of the mediastinal involvement and the relationship between the goitre and the surrounding vascular structures. Laryngoscopy can be performed to assess vocal cord mobility.

FNAB FNAB provides the most direct and specic information about a thyroid nodule. The use of FNAB reduces the number of thyroidectomies by approximately 50%,59,60 roughly doubles the surgical yield of carcinoma and reduces the overall cost of medical care in these patients by 25%.60 Patients with suspicious, malignantand non-diagnostic cytology (after reaspiration)require surgery. Most cytopathologists agree that it is nearly impossible to distinguish benign from malignant follicular neoplasms on the basis of FNA cytology. In a large 3-year prospective study from The Mayo Clinic comprising nearly 2000 patients, 17% had suspicious cytological ndings, and, in 24% of these patients, malignancy was detected.61 If scintigraphy of the cytologically suspicious nodule suggests that it is hyperfunctioning, also indicated by a suppressed TSH, in case of the solitary nodule, such a lesion almost never harbours malignancy. US-guided FNAB dramatically reduces the risk of sampling error, and the rate of adequate material aspirated during the procedure greatly increases.62 In a retrospective Italian study by Danese et al.63, comparing conventional FNAB with US-guided FNAB in 4697 and 9683 patients, respectively, sensitivity, specicity and overall diagnostic accuracy were signicantly improved when using US guidance. In another retrospective study from California, sensitivity and specicity improved to 100%, and the adequacy rate improved from 84% to 93% when compared with conventional FNAB.64

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The risk of malignancy in thyroid nodules occurring within an MNG has not been completely claried, but some authors nd a similar frequency in uni- and multinodular goitres.11,65The possibility of thyroid malignancy should be considered in all patients with MNG, and the use of US guidance has been shown to enhance the diagnostic efcacy of FNAB.66 It has been recommended that nodules less than 10 mm, detected incidentally, do not require an FNAB.67 However, in the recent study by Papini et al.67, thyroid malignancy was found in 6% of non-palpable lesions of 815 mm in size in MNGs (9% in solitary thyroid nodules). The risk was similar in nodules smaller or larger than 10 mm. A similar independency of size with regard to malignancy in non-palpable nodules was found in an earlier study.62 However, whether carcinomas found in nodules other than the index nodule constitute clinically signicant cancers or just incidental microcarcinomas remains an unsolved issue, leaving the clinician with no clear-cut guidelines for management. Sonographic features and the recently introduced elastography57 may guide the clinician to include FNAB in nodules other than the index nodule. So far, results clearly indicate that FNAB remains superior to other diagnostic tests. The most frequent type of thyroid malignancy is papillary carcinoma, which constitutes more than 80% of all cases and follicular carcinoma.68 Thyroid tumours, especially those of the papillary type, frequently have genetic alterations, leading to activation of the mitogen-activated protein kinase (MAPK) signalling pathway.68 The molecular alterations identied involve genes coding for the receptor tyrosine kinase, RET, and two intracellular effectors of the MAPK pathway, a GTP-binding protein RAS and a serinethreonine kinase, v-raf murine sarcoma viral oncogene homologue B1 (BRAF). Activation of the RET gene through chromosomal rearrangements is one of the most common molecular event in papillary carcinoma. The RET proto-oncogene codes for a cell membrane receptor tyrosine kinase. In the thyroid gland, RET is expressed in parafollicular C cells but not in follicular cells, in which it can be activated by chromosomal rearrangement, resulting in the fusion of the 30 portion of the RET gene to the 50 portion of several unrelated genes, known as receptor tyrosine kinase (RET)/ papillary thyroid carcinoma (PTC) rearrangements. The two most common rearrangements types are RET/PTC 1 and RET/PTC 3, which account for the vast majority of all rearrangements found in papillary carcinoma. BRAF belongs to the family of RAF proteins, which are intracellular effectors of the MAPK signalling cascade. Upon activation triggered by RAS binding and protein recruitment to the cell

Practice points  NG is usually associated with a normal thyroid function.  NG can progress to subclinical hyperthyroidism.  Subclinical hyperthyroidism in the elderly patients can cause rhythm disturbances, including atrial brillation and heart failure.  NG is a complex disease.  Iodine deciency is the major environmental factor contributing to NG.  A strong genetic predisposition has been shown.  The role of specic candidate genes has given conicting results.  In patients with NG serum TSH, FT4, FT3, antibodies against thyroglobulin (AbTG), antithyroperoxidase antibodies (AbTPOs) and calcitonin should be measured.  Serum TG correlates with the iodine status and/or the size of the thyroid gland, but this marker is inaccurate at the individual level in the diagnosis of goitre.  Thyroid US is a rst-line diagnostic procedure in thyroid nodular disease.  The great majority of nodules in NG are benign.  If serum TSH is low, a thyroid scintigraphy should be performed.  Signicant compression and/or displacement of neighbouring structures can be assessed by X-ray of the neck or a CT scan.  Conventional US is important for: estimation of goitre volume, detection of non-palpable nodules, guidance for FNAB; a combination of cytology and molecular testing has increased the diagnostic accuracy and allowed better prediction of malignancy in the nodules with indeterminate cytology

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membrane, these serinethreonine kinases phosphorylate and activate MAPK/ERK kinase, which, in turn, activates ERK and consequent effectors of the MAPK cascade. A high prevalence of BRAF mutations have been found in papillary carcinomas. RAS mutations and a recently reported chromosomal translocation fusing the thyroid transcription factor paired box gene 8 (PAX 8) and the nuclear receptor peroxisome proliferators-activated receptor gamma (PPARg) were found in some follicular thyroid cancers. Recently, a combination of cytology and molecular testing showed signicant improvement in the diagnostic accuracy and allowed better prediction of malignancy in the nodules with indeterminate cytology. In fact, in a recent prospective study of 470 FNA samples of thyroid nodules, a small part of the material was tested for BRAF, RAS, RET/PTC, paired box gene 8 (PAX8)/PPARg.69 The presence of any mutation was a strong indicator of cancer. The molecular testing of thyroid nodules for a panel of mutations can be effectively performed in a clinical setting. It enhances the accuracy of FNAB cytology and is of particular value in cases of thyroid nodules with indeterminate cytology.

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