| | Thyroid nodules: Does the suspicion for malignancy really justify the increased thyroidectomy rates?Abstract Thyroid nodules are frequently diagnosed today, mainly due to the wide use of neck ultrasonography (US). The majority of these are benign; suspicion for malignancy is an indication for surgery, while benign thyroid nodules may be managed conservatively. There is evidence that a large percentage of patients with thyroid nodules (many diagnosed incidentally) are over-treated. Careful and accurate identification of patients with thyroid nodules highly suspicious for underlying malignancy would allow a more reasonable therapeutic approach and would result in a reduction of the number of unnecessary thyroidectomies. Fine-needle aspiration cytology (FNAC), in conjunction with high-resolution thyroid US, are currently the most accurate and cost-effective diagnostic approach for the evaluation of patients with nodular thyroid disease. Radionuclide thyroid scanning should be used selectively. By increasing the use of FNAC, it is expected that the number of unnecessary thyroidectomies will be further diminished, thereby avoiding over-treatment, without exposing the patients to the risk of under-treatment for a highly curable cancer. However, accurate preoperative diagnosis of thyroid cancer within a thyroid nodule is not always possible and, although the problem of unnecessary surgery can further be diminished, it cannot be completely eliminated. 1. Introduction  Thyroid nodules are very common. In fact, it has been estimated that 4–7% of the adults in the USA have a palpable thyroid nodule, and autopsy and high-resolution ultrasound studies suggest that up to 50% of the general population may have thyroid nodule(s) [1], [2], [3]. While thyroid nodules are common, only a minority (<10%) are malignant [4]. Obviously, the clinician who is faced with a patient with a thyroid nodule must determine clinical significance of the lesion and whether it may be malignant. Thyroid cancer should be managed aggressively (thyroidectomy), while the much more common benign thyroid nodules may be managed conservatively (observation) [5]. The management of thyroid nodules has changed significantly during the last two decades, mainly as a result of the widespread application of modern diagnostic strategies. Neck ultrasonography (US) and Fine-needle aspiration cytology (FNAC) are currently the most powerful diagnostic tools for the evaluation of thyroid nodules and the assessment of the risk of malignancy. This current diagnostic approach has resulted in a sharp decrease in the number of unnecessary operations, while increasing the yield of thyroid cancers found after thyroidectomy for thyroid nodule(s). However, unnecessary thyroidectomies are still performed in a large percentage of patients with thyroid nodules because of the fear of underlying malignancy. The aim of this paper is to discuss the hypothesis that thyroidectomy can be performed more selectively for the management of thyroid nodules. Our intention is to focus on critical factors that can help physicians distinguish between benign (common!) and malignant (rare!) nodules. Rational and cost-effective management of thyroid nodules will help avoid over-treatment (i.e. surgery) of patients with clinically insignificant thyroid nodules and avoid under-treatment of highly curable thyroid cancers. 2. The extent of the problem Thyroid nodules are common in clinical practice and their prevalence depends on the method used for screening and the population evaluated [5], [6]. The lifetime risk for developing a palpable thyroid nodule ranges from 5–10% [7]. In North America, the incidence of thyroid nodules detected by palpation is estimated to be 0.1%/year, with a prevalence between 4% and 7% in the general population [4], [7]. The prevalence of thyroid nodules increases steadily with advancing age [6]. Thyroid nodules were found in only 0.05–1.8% of children not exposed to irradiation in two large series [9], [10]. Conversely, more than 50% of men and women in the sixth decade, and more than 80% of women, and 65% of men in the ninth decade, had thyroid nodules at autopsy [11]. The prevalence of thyroid nodules is higher in women than in men (female-to-male ratio: 1.2/1–4.1/1) [6], [11], [12]. Moreover, the prevalence of thyro id nodules is increased in areas of iodine deficiency (×2.5) and after exposure to external irradiation [8], [13], [14]. In the Framingham, Massachusetts’ population study, palpable nodules were present (or previously removed) in 6.5% of women and 1.5% of men between 30 and 59 years of age [15]. Careful follow-up of this cohort revealed a nodular accrual rate of 1.3% at 15 years, or 0.09% per year [15]. In 1955, Mortensen et al. [11] examined thyroid glands removed during autopsy from 821 patients at the Mayo Clinic. These glands had all been found to be normal on clinical examination. The authors reported that 406 glands (49.5%) contained one or more nodules; 306 of these (37.3% of 821) were multinodular, and 100 (12.2% of 821) contained single nodules. Of the 406 thyroid glands, 144 (35.5%) had nodules that were larger than 20 mm in diameter. Most of these nodules were benign and only 4.2% (n=17) contained malignant nodules [11]. In another autopsy study of 200 patients with nodular goiter, Hermanson et al. [16] compared the clinical evaluation of the thyroid nodularity with the results of pathologic examination in 190 patients. Of 137 patients who had solitary nodules found on clinical examination, 43 (31%) had several nodules found on pathological examination. In an autopsy series of 215 patients who did not have thyroid disease, Furmanchuk et al. [17] documented nodules in the thyroid glands of 70 patients (32.5%). Others have reported in older autopsy studies that approximately 50% of 60-year-old persons have thyroid nodules [18], [19], [20]. Underlying thyroid cancer was found in only a minority of these nodules (3–5%) [16], [21]. The application of high-resolution US to neck examination (often for unrelated conditions, such as carotid stenosis or parathyroid disease) has revealed unsuspected subclinical thyroid nodules (so-called thyroid incidentalomas) in 18–67% of healthy individuals (women>men) [2], [13], [14]. These incidentalomas create a diagnostic problem and therapeutic dilemma (conservative management vs. surgery). Additionally, patients suspected clinically as having solitary nodules, in fact had one or more additional nodules in 15–48% of cases as assessed by preoperative ultrasound [22], [23] and in 29–48% of thyroid specimens based on careful histologic examination [6], [24]. Witterick et al. [25] in a study of patients undergoing thyroidectomy for apparently solitary nodules showed that palpation alone missed 58% and 78% of additional nodules in partial and total thyroidectomy specimens, respectively, and that even preoperative ultrasound missed between 41% and 58% of nodules ultimately detected with careful histologic evaluation [25]. Although thyroid nodules are common, malignant nodules remain relatively rare. Only 5% of clinically identified nodules are malignant [1], [4], [26]. Malignant thyroid nodules represent only 1% of all cancer [3], [26] which gives rise to 17200 new cases of thyroid cancer each year in the US. There is evidence that benign thyroid nodules remain benign for a long time and rarely become malignant [2], [27], [28], [29]. Since the natural history and the management differ between benign and malignant thyroid nodules, ideally a physician should be able to differentiate these two types from one another. If such were possible, then he/she could apply a selective approach (thyroidectomy) in patients with a high risk for underlying malignancy. However, despite the availability of modern diagnostic tools, this is not an easy task. Indeed, the physician must balance the certainty of thyroidectomy against the safety and frugality of conservative management [6]. To select optimal management he/she should take into account a combination of factors, such as patient preference, clinical and laboratory indicators of malignancy, as well as a current understanding of the benefit and potential harm inherent in conservative (i.e., non surgical management) “treatment” The patient should be actively involved in this decision-making process. 3. Differential diagnosis In the patient with thyroid nodule(s), the most common diagnoses are colloid nodules/thyroiditis (80%), benign follicular neoplasms (“adenomas” 10–15%), cysts, and thyroid carcinoma (5%). Other, less common, diagnoses are listed in Table 1 [5].  | Neoplastic thyroid diseasesBenignThyroid (follicular/ Hürthle cell) adenoma MalignantThyroid cancerPrimary (papillary, follicular [including Hürthle cell carcinoma], medullary, anaplastic, lymphoma) Metastatic Inflammatory thyroid disease (thyroiditis) Riedel disease Infectious thyroid disease Granulomatous disease Developmental abnormalitiesThyroglossal duct cyst Teratoma Other benign thyroid diseasesColloid (adenomatoid) nodule Thyroid cyst Graves’ disease | | | | |
4. Assessment of the risk for malignancy 4.1. Clinical examination History and physical examination cannot reliably diagnose thyroid cancer within a nodule; moreover, when nothing in the history favors a malignant nodule, a small but disturbing number of patients still have thyroid cancer. However, findings from the clinical examination may provide useful clues to recognize high-risk patient in whom further investigation is needed. 4.2. History of head and neck irradiation Prior neck irradiation is a risk factor for the development of thyroid nodules and thyroid cancer [30]. Many studies have documented the increased risk of carcinoma within nodules in individuals exposed to low-level irradiation [31], [32], [33], [34], [35], [36], [37]. A thyroid nodule in an individual with a history of head or neck irradiation in childhood carries a 32–57% likelihood of being malignant (most commonly papillary carcinoma and often microcarcinoma) [8], [31], [32], [33]. The risk of thyroid cancer development is dose-dependent and its incidence is higher in young women [34], [36]. The increase in prevalence of thyroid cancer between the 1930s and the s is—at least in part—attributable to the widespread use of irradiation for the management of a variety of head and neck diseases (most commonly for thymus, acne, or tonsil/adenoid hypertrophy) in the first part of this century [38]. The importance of radiation as a risk factor for thyroid carcinoma has been underscored by the dramatic increase in the incidence of thyroid carcinoma (especially in children) following the Chernobyl nuclear disaster in the Ukraine in 1986 [30]. 4.3. Age and gender Although an uncommon clinical entity, a pediatric patient with a solitary thyroid nodule requires a thorough assessment. The risk of carcinoma doubles in this population [38], [39], [40]. The incidence of thyroid cancer increases with age in adults, and elderly patients (>60 years) have a similarly higher prevalence of malignancy within thyroid nodules compared to their younger adult counterparts [39], [40], [41]. Although nodules are less frequent in men, a greater (×2–3) proportion of them in males are malignant [39]. 4.4. Family history There is increasing evidence that genetic factors may play a role in a small (∼3%) percentage of differentiated thyroid carcinomas [30], [41]. A family history of thyroid carcinoma, especially medullary carcinoma, and other endocrine diseases, such as multiple endocrine neoplasia (MEN 2 A or B) or familial medullary thyroid cancer (FMTC) syndrome increases the likelihood that a thyroid nodule is malignant [32], [42], [43]. The risk of cancer within thyroid nodules is also higher in patients with Gardner syndrome (familial adenomatous polyposis) [44], [45] and Cowden disease (familial goiter and skin hamartomas) [46], [47]. 4.5. History of benign thyroid disease Hashimoto thyroiditis has been associated with thyroid lymphoma [48], [49]. Thyroid nodules are frequently found in association with Graves’ disease and thyroid cancer may arise from these nodules. Some evidence suggests “cold” (hypofunctional) nodules [6], [50] may carry greater risk of malignancy while the risk of thyroid cancer is not increased in patients with autonomous thyroid (“hot”) nodules [14]. Of note, the risk of malignant activity is similar in uninodular and multinodular thyroid glands [51]. 4.6. Rapid growth of the nodule Rapid growth of the tumor, especially when the patient is under treatment with L-thyroxine, indicates a greater likelihood of underlying cancer [4], [28], [52], [53], [54]. Kuma et al. [28], [54] found malignancy in 26% of previously unbiopsied nodules that increased in size over a 10- to 30-year period . A follow-up study 2 years later reported a malignancy rate of 4.5% among nodules that were previously found to be benign on FNAC and subsequently grew (although no definition of growth was provided) [28]. The risk of underlying malignancy is substantially higher in larger nodules (at baseline) that rapidly increase their size [52]. However, rapid nodule enlargement can be seen when hemorrhage occurs within a benign thyroid adenoma or cyst [55], [56]. In contrast, the stability in the size of the nodule cannot rule out the diagnosis of thyroid cancer. Indeed, nodules known to be present for decades have ultimately been discovered to be malignant [6]. Finally, most benign thyroid nodules do, in fact grow over time [52]. 4.7. Physical examination The development of hoarseness, progressive dysphagia, or shortness of breath suggests growth or invasiveness, and should raise the index of suspicion of malignancy. Factors favoring the diagnosis of a benign process include sudden or gradual onset of pain or tenderness (that would suggest either hemorrhage into a benign adenoma or cyst, or subacute granulomatous thyroiditis, respectively); symptoms of hypothyroidism (suggestive of chronic autoimmune [Hashimoto] thyroiditis); and a family history of benign thyroid nodular disease, Hashimoto thyroiditis, or other autoimmune disease. Thyroid cancer is rarely painful or tender. During physical examination, vital signs (including pulse rate and blood pressure) should be obtained, since a rapid pulse rate may suggest hyper-or hypothyroidism, and hypertension may occur in the context of multiple endocrine neoplasia, type 2 (MEN 2). Other manifestations of a possible MEN 2 syndrome should also be noted, such as mucosal neuromas (“bumpy” lips and tongue) and marfanoid body habitus (MEN 2B), or localized pruritus due to cutaneous lichen amyloidosis (MEN 2A) [6]. In this case, medullary thyroid cancer (MTC) is highly possible, and before thyroidectomy is offered, the physician should exclude the possibility of pheochromocytoma and hyperparathyroidism. The thyroid gland should be carefully palpated to identify the clinical characteristics (location, size, shape, consistency, number, and mobility) of the nodule(s) and the presence or absence of tenderness. Although not definitive in the diagnosis of thyroid cancer, the findings on palpation can be strongly suggestive of thyroid cancer in exceptional cases. A firm to hard, irregular, fixed, nontender nodule is more likely to be a thyroid malignancy, although some thyroid cancers are smooth and not particularly hard; conversely, some benign nodules can be very hard because of calcifications [7], [57]. A smooth, soft, easily mobile nodule suggests benignancy, as does the presence of tenderness. Deviation of the trachea, which suggests a mass, should be noted. Next, the neck should be carefully palpated for regional lymphadenopathy. While the presence of ipsilateral enlarged lymph nodes strongly suggests thyroid cancer, their absence in no way rules out malignancy. Multinodularity, especially if the nodules all have the same consistency, is consistent with a benign multinodular goiter. A nodule or mass that is dominant in size or has a different consistency than other nodules within the gland should be evaluated by employing the same criteria as those outlined for single nodules. A midline nodule over the hyoid bone that moves cephalad with protrusion of the tongue is likely to be a thyroglossal duct cyst. Clinical examination has, however, many limitations. Only a minority of patients with malignant thyroid nodules have suggestive findings, which often also occur in patients with benign thyroid disorders. Although most nodules >1cm can be palpated in thin patients with a long neck, even larger nodules may be difficult to detect by palpation when located within or on the posterior surface of the gland and/or when the patient has a short, fat neck [57], [58], [59]. In the study by Brander et al. [59], one-half of the nodules discovered on US had escaped detection on clinical examination; approximately one-third of the nodules that had not been detected by palpation were larger than 2cm in diameter. Christensen et al. [60] reported a sensitivity of palpation of the thyroid gland (in terms of size and nodularity) of roughly 40%. Moreover, a prominent, but normal thyroid gland in a patient with a thin neck may be perceived clinically as an abnormality [61]. Clearly, experience is required on the part of the examiner, and this can explain the observed inter-observer variation in evaluating thyroid nodules, a finding that may explain why an increasing number of thyroid specialists use imaging as part of the evaluation [59], [62], [63], [64]. Clinical palpation is therefore not a precise tool for assessing abnormalities of the thyroid gland (including thyroid nodules), and its reliability depends on the size and location of the nodule, the size and shape of the neck, and the experience of the examiner. Moreover, some clinical findings indicative of malignancy may be observed in patients with benign thyroid nodules. For example, hemorrhagic or calcified adenomas may feel hard, and many papillary cancers are pliable. The thyroid gland in patients with Hashimoto thyroiditis may seem adherent to local neck structures, and Riedel thyroiditis is characterized by local tissue infiltration. As a result, clinical examination has a low sensitivity and specificity in differentiating between benign and malignant thyroid nodules. Despite its limitations, clinical evaluation (history and physical examination) remains the diagnostic cornerstone in managing the patient with a thyroid nodule (Table 2, Table 3). The more risk factors that are identified, the higher the likelihood of underlying cancer [65]. | Family history of Hashimoto thyroiditis or autoimmune thyroid disease | | | Family history of benign thyroid nodule or goiter | | | Symptoms of hypothyroidism or hyperthyroidism | | | Pain or tenderness associated with the nodule | | | Soft, smooth, mobile nodule | | | Multinodular goiter without a dominant nodule | | | | |
4.8. Thyroid suppression therapy Thyroid suppression therapy has been used as a diagnostic test in differentiating benign from malignant nodules [3]. Thyroid suppressive therapy, although frequently used, has not been shown to cause a statistically significant decrease in the size of nodules (even benign) when compared with placebo in recent studies [66], [67]. Even some malignant thyroid nodules have decreased in size during suppressive therapy [51]. Therefore, the role of thyroid suppression therapy in the diagnostic evaluation of a thyroid nodule is limited. Nonetheless, in clinical practice, most physicians consider growth of a nodule under thyroid suppressive therapy as an indication for underlying malignancy and refer these patients for surgery [6]. 5. Laboratory evaluation and imaging In an attempt to preoperatively distinguish benign from malignant thyroid nodules, many studies and procedures can be performed; however, indiscriminate application of tests in all patients with nodules would be an extraordinary burden to the health-care system. A few studies are necessary in most instances, and for some patients one may be enough. 5.1. Laboratory investigations TSH, thyroxine and triiodothyronine levels.—In patients with a thyroid nodule, a sensitive thyroid-stimulating hormone (TSH) assay should be obtained to determine the presence of hyperthyroidism (TSH suppressed) or hypothyroidism (TSH elevated) [1]. Approximately 10% of patients with a solitary nodule have a suppressed level of serum thyrotropin, which suggests that the thyroid nodule is benign [26], but an iodine 123-labeled scan should be performed to confirm the presence of a hyperfunctioning (“hot”) nodule, since a hypofunctioning nodule may coexist in the context of underlying hyperthyroidism. Measurements of the serum thyroxine and triiodothyronine levels may also be helpful [7]. Abnormal thyroid function does not exclude thyroid cancer, but may make it less likely or offer another indication for thyroidectomy [6]. An abnormal TSH level may decrease suspicion, but does not eliminate the possibility of malignancy in a thyroid nodule [7]. It should be noted that nearly all patients with medullary cancer are euthyroid [4]. Antithyroid peroxidase/antithyroglobulin antibody levels.—With thyroid nodular disease, serum antithyro-peroxidase (antimicrosomal) antibody and antithyroglobulin antibody levels are helpful for diagnosing Hashimoto disease (chronic thyroiditis), especially if the serum TSH level is increased. These antibodies are positive in more than 85% of patients with this disease. Often in Hashimoto thyroiditis, the thyroid gland may have a size and consistency that simulate a solitary nodule or bilateral nodules [7]. Evidence for thyroiditis, however, does not preclude the presence of cancer in the thyroid gland. Antithyro-peroxidase and antithyroglobulin antibody titers do not distinguish benign from malignant thyroid nodules [6]. Serum thyroglobulin (Tg) levels.—In thyroid diseases, serum thyroglobulin levels are generally increased, and therefore a serum assay of Tg levels is not useful for the preoperative differential diagnosis between benign or malignant thyroid nodules [68]; however, if these levels are dramatically elevated in a patient with a small thyroid nodule, metastatic thyroid carcinoma should be considered [7]. The value of the thyroglobulin level lies in serial determinations after thyroid cancer has been diagnosed and resected [69]. Serum calcitonin levels.—Basal calcitonin measurement is routinely performed in patients with a thyroid nodule to detect medullary carcinoma [70]. However, since MTC is present in only 1 of 250 patients with a thyroid nodule, the value of calcitonin levels in patients with a solitary thyroid nodule but without suspicion of MTC or MEN 2 has been questioned [71]. Measurements of basal and stimulated (with pentagastrin and calcium) serum calcitonin levels are indicated in patients after total thyroidectomy for MTC and for screening family members for C-cell hyperplasia or MTC if there is a history of FMTC or MEN 2 [71], [72]. 6. Imaging methods 6.1. Ultrasonography (US) Following palpation, US examination is currently the most common and basic evaluation for patients suspected of having nodular or diffuse thyroid disease [1]. Currently, high-frequency (7–10Hz) US permits high-resolution imaging of the thyroid gland that is more accurate than clinical palpation or other imaging techniques (such as radionuclide scanning, computed tomography (CT), and magnetic resonance imaging (MRI), see below) [8], [73], [74]. US is safe and sensitive and is capable of detecting lesions as small as 1–3mm within the thyroid parenchyma (sensitivity ∼90% and specificity ∼85%) [27]. Subclinical (most <1cm in diameter) thyroid nodules are often detected and may be multiple in a high percentage of cases [27]. The frequency of abnormalities detected with thyroid US in the adult population is consequently much higher than detection by palpation and approaches that of autopsy studies [59], [74], [75]. Thyroid US therefore is exquisitely sensitive in documenting the size and number of nodules. It provides an objective and sensitive indicator of whether a nodule is increasing or decreasing in size over time. A reasonable assumption is that—even without cytologic confirmation—the lack of growth of a lesion during an interval of 5 years may be interpreted as a strong indication that this lesion is probably benign. Thyroid US can also differentiate simple cysts, which have a low risk of being malignant (<1%), from solid nodules or from mixed cystic and solid nodules, which have a 5% risk of being malignant [1]. Another important use of US is in patient follow-up when the decision is made not to operate on a nodule. Obviously, a nodule that is decreasing in size is unlikely to require surgical treatment, whereas a nodule that is enlarging—especially under levothyroxine treatment—should be treated more aggressively. US also provides guidance for diagnostic procedures (e.g., FNA, in patients with complex cysts, those with lesions that are difficult to palpate, or those whose cysts or lesions have been detected incidentally by using other imaging procedures) as well as therapeutic procedures (e.g. cyst aspiration, ethanol injection, or laser therapy) [76]. Lastly, US can be helpful in the long-term follow up of patients with thyroid cancer by detecting small or otherwise inaccessible nodules that could represent recurrence of cancer [7]. The value of thyroid US is highly operator dependent. The experienced examiner can recognize echomorphological findings suggestive of malignancy. Hypoechoic nodules are concerning for malignancy [27], [73], [74], [75], [76]. The malignant potential of mixed and hyperechoic lesions is usually considered low [27]. Pure cysts (anechoic lesions) have no malignant risk [27], [73], [74], [75], [76]. However, pure cysts are very rare (1–1.5% of thyroid nodules) and most cystic lesions have solid elements; these “mixed” cysts have a similar or only slightly decreased risk of malignancy than that for solid nodules [6]. The distinction between a small anechoic vs. a small hypoechoic lesion with thyroid US is sometimes problematic [27]. Other ultrasound features of thyroid nodules suggestive of malignant potential include the presence of microcalcifications, irregular or microlobulated margins, increased intranodular vascularity and blood flow visualized by duplex scanning, absence or irregularity of the peripheral ring or halo, and—especially—the evidence of invasion or regional lymphadenopathy [74]. However, accurate differentiation between benign and malignant thyroid nodules is not always possible by US [7], [73], [74], [75], [76]. The clinical significance of small (<1cm), nonpalpable, single or multiple nodules detected only by US remains uncertain [77]; usually, these nodules have a benign clinical course and generally do not require further evaluation but may be followed with US at periodic intervals [14], [27], [29], [77]. 6.2. Radionuclide scanning Radionuclide scanning, used more commonly in the past and in particular in Europe [20], [62], [63], provides functional information about thyroid nodules and differentiates hyper-functional from hypo-functional nodules. This distinction may help to differentiate between benign and malignant nodules [20], [62], [63], [78]. Optimal thyroid scintigraphy requires an understanding of the embryology, anatomy, and physiology of the thyroid gland, and the properties of the two common imaging agents, technetium-99m pertechnetate (Tc99m) and radioiodine (I131 and I123) [79]. “Hot” or autonomously functioning thyroid nodules, representing about 5% of all thyroid nodules, are identified visually when the area of the thyroid gland on the scan containing the nodule accumulates the isotope more than normal thyroid tissue. The extranodular tissue can also take up the isotope or may be suppressed so that only the nodule is seen [7]. “Warm” or functionally nondelineated nodules (∼10%) have function equivalent to normal thyroid tissue. “Cold” nodules (∼85%), either hypofunctioning or nonfunctioning, are seen as defects on the scan [3], [32]. Cancer is present in approximately 15% of cold nodules, 10% of warm nodules, and 5% of hot nodules [3]. Thus, although not our preference, in the patient with a suppressed level of serum thyrotropin, radionuclide confirmation of a functioning nodule could theoretically obviate the need for biopsy. A scan can also indicate whether a clinically solitary nodule is a dominant nodule in an otherwise multinodular gland and can reveal substernal extension of the thyroid [1]. A scan can be performed with I123, I131, or Tc99m. Iodine isotopes, which are both trapped and bound organically in the thyroid, are preferred, since 3–8% of nodules that appear functioning on Tc99m appear nonfunctioning on radioiodine scanning, and a few of those nodules may be thyroid cancers [80]. For this reason it has been suggested that all nodules that are hot with Tc99m should be rescanned with I123. I131 is clearly the most effective isotope for thyroid cancer follow-up evaluation, but for routine scanning of the thyroid, I131 exposes the patient to excessive thyroidal irradiation and should be avoided. I123 scanning is recommended because it avoids false-positive technetium scanning and the radiation burden of I131 [7]. Nowadays, radionuclide scans may be helpful in selected cases, such as patients with suppressed TSH levels (i.e., in patients with Graves disease or multinodular goiter) to determine if a nodule is functioning [7]. Functioning thyroid nodules are treated by I131 or by surgery, in particular if serum TSH levels are decreased or overt hyperthyroidism is present (because of adverse effects on bone and the cardiovascular system). Thyroidectomy should be preferred if the nodule is very large or partly cystic or if the patient is young. Radionuclide scans may also be used in patients with multinodular goiter, to differentiate the functional status of the nodules. Patients with nodules found to be benign by FNAC would not benefit from subsequent nuclear imaging unless thyroid hormone suppression is being considered as treatment; then nuclear imaging will identify functioning nodules, for which administration of thyroid hormone could lead to thyrotoxicosis. In nodules found to be follicular neoplasms by FNAC, nuclear imaging might also be diagnostically helpful: if the nodule is cold, then surgery is indicated [7], [81]. The major limitation of radionuclide scanning is its low specificity (∼15%), which—despite a high sensitivity (∼95%)—limits its role as a diagnostic tool [32]. Certainly, nuclear imaging is not required in all patients with thyroid nodules and cannot differentiate benign from malignant lesions. In many centers ultrasound and FNAC have replaced nuclear thyroid imaging as the initial diagnostic approach in the evaluation of a thyroid nodule. Because the vast majority of both benign and malignant solitary thyroid nodules appear hypofunctional relative to adjacent normal thyroid tissue, the finding of a cold nodule has relatively low specificity. Furthermore, small thyroid nodules may not be detected with this technique due to superimposition of uptake from adjacent normal thyroid tissue [6]. Moreover, a scan cannot be used to measure the size of a nodule accurately. Due to these limitations, radionuclide scanning is not routinely recommended in the diagnostic evaluation of thyroid nodule by the American Thyroid Association and the American Association of Clinical Endocrinologists [7], [82], [83]. The physician should use clinical judgment in considering the appropriateness of the thyroid nuclear scan in each individual patient [7], [83]. 6.3. Other imaging methods The role of other imaging methods, such as CT or MRI, in the evaluation of the risk of malignancy in a patient with thyroid nodule is very limited; CT and MRI cannot reliably differentiate between benign and malignant nodules and therefore these costly tests are rarely indicated [57], [83]. However, CT or MRI may be indicated in the diagnosis and evaluation of large (>3cm) or substernal goiters, allowing a more accurate and precise identification of the extent of the goiter (including extension to the mediastinum or retropharyngeal region) and possible compression of adjacent anatomic structures (i.e., trachea) [84], [85]. Evaluation of glucose metabolism by positron-emission tomography (PET) using fluorine-18-fluorodeoxyglucose is a recent option and may be useful in the preoperative assessment of suspicious thyroid nodules [86]. Thyroid cancer, in contrast to benign thyroid nodules, demonstrate significantly increased glucose metabolism; however, [18] F- FDG PET is unlikely to accurately differentiate preoperatively all benign from malignant thyroid nodules [86]. Moreover, the use of [18] F- FDG PET is limited by the high cost and limited availability of the method. 7. Fine-Needle Aspiration Cytology (FNAC) The wide use and perfection of FNAC resulted in a major advance in the diagnostic evaluation of the patient with thyroid nodule(s). FNAC is currently considered the most effective, accurate, safe, and cost-effective method for the preoperative distinction between benign and malignant thyroid nodules [1], [2], [3], [4], [7], [32], [86]. Accurate FNAC will allow optimal management for each patient (surgery for neoplastic disease, potentially conservative management for nonneoplastic disease). Many investigators have suggested its use as the initial diagnostic technique [87], [88]. FNAC is performed on an outpatient basis (F4/1,4,5), is relatively inexpensive, and is easy to learn [4], [62], [63]. Complications are rare and primarily involve local discomfort. The use of anticoagulants or salicylates are not a contraindication for FNAC. FNAC has a reported sensitivity of 83% (range 68–98%), and a specificity of 92% (range 72–100%) [7]. The false-negative rate is <5% and the false-positive rate is <1% [4], [29], [32]. FNAC should be performed liberally in all thyroid nodules when the possibility of malignancy is a concern. FNAC is also indicated even when the suspicion of cancer is very high, since foreknowledge of the cancer cell type aids in the appropriate planning of the surgical procedure [7]. FNAC has been used more widely in recent years (in 50% of patients vs. 10% of patients in the past) [5]. Due to the more common application of FNAC in clinical practice, the number of unnecessary operations for thyroid nodules and nodular goiters (mainly because of the suspicion of underlying malignancy) has decreased sharply (by approximately 50%) in many centers, while at the same time the surgical yield of thyroid cancer after thyroidectomy for thyroid nodule(s) increased dramatically from 15% to 45% [7], [32], [78], [89], [90], [91]. Moreover, as a result of a more reasonable management of these patients, the overall cost of medical care was reduced by 25% as compared with surgery performed on the basis of clinical findings alone [1], [2], [92]. FNAC is a relatively simple diagnostic procedure and is generally performed with 21–29 gauge needles (depending on the vascularity or fibrous consistency of the nodule), making three to five passes of the needle and aspirations of the nodule. Care should be taken to avoid excessive blood dilution and crush artifact. When feasible, microscopic evaluation during the procedure provides immediate information on adequacy of the aspirate and results in lower rates of unsatisfactory specimens [7]. The smears are then alcohol fixed and air dried. Papanicolaou's and Giemsa (Diff-Quik) stains are performed, and smears containing 6–8 medium-sized fragments of follicular epithelium on at least two slides are defined as adequate [3]. Despite its technical simplicity, a major limitation diminishing the potential benefit of FNAC is the unskilled physician performing the biopsy. FNA of a thyroid nodule, although a relatively simple procedure, should be performed preferentially by an experienced operator. Ultrasound-guided FNA is extremely helpful for accurate sampling in difficult cases (i.e., non palpable, small, posteriorly located lesions, or nodules in patients with a fat, short neck or when sampling of the solid component of complex cystic nodules is needed) [87], [93]. As a result, ultrasound-guided FNA decreases the number of inadequate biopsy specimens and increases both the sensitivity and the specificity of the procedure [94]. Poor technique leads to a higher proportion of unsatisfactory (“nondiagnostic” or insufficient) biopsy specimens and probably a higher rate of surgical procedures [7]. When the biopsy specimen is insufficient or non-diagnostic, FNA should be repeated (preferentially under ultrasound guidance), because a 10% incidence of malignancy has been reported in this population, and repeat FNA can provide diagnostic smears in as many as 50% of cases [89], [93]. If repeat aspiration still yields non-diagnostic cytologic findings, management should be based on the data available from the clinical evaluation. Another problem may be the difficulty of interpretation of the results of FNAC of small (<1cm) or large (>4cm) thyroid nodules. Small nodules are difficult for biopsy and the possibility of sampling error is high. Ultrasound-guided FNA may be helpful in this case. Conversely, nodules of 4cm or larger readily yield diagnostic material, but are subject to inadequate sampling with hemorrhage and cellular necrosis. If more than one discrete nodule is present within the thyroid, FNAC should be performed on all accessible nodules and not only on the largest [7]. Cystic nodules, representing 10–25% of all thyroid nodules, present additional diagnostic challenges [6]. Cystic degeneration may be observed in both benign and malignant thyroid nodules. The malignancy rate within cystic thyroid nodules is ∼10% [95]. However, conventional FNAC for cystic thyroid nodules has a high rate of non-diagnostic and false-negative results [96]. The few thin-walled cysts will collapse completely with needle evacuation [95], [96]. Most cysts, however, have a partially solid component, and these cysts should be aspirated for residual tumor. Initially, the cystic fluid, if not excessively viscous, should all be aspirated and sent for cytopathologic evaluation. Ultrasound-guided FNAC can then be performed to sample the suspicious solid component; US permits direct sampling of the wall and/or the solid portion of the cystic thyroid nodule, thereby increasing the possibility of a representative sample [96], [97]. However, due to difficulties both in obtaining adequate tissue sampling, and in accurately detecting enlargement of the solid portions of these nodules, surgery should be considered for persistent or recurrent complex cystic nodules for both diagnostic and therapeutic reasons [6]. Surgery is indicated especially for cystic thyroid nodules ⩾4cm, since the risk of malignancy is higher in large cystic lesions [97]. For accurate risk estimation in cystic thyroid nodules, other characteristics should also be taken into account, such as male sex and findings of local invasion in imaging [97]. Experience is also required from the cytopathologist who interprets the specimen. Inexperienced cytopathologists may report a very high proportion of follicular lesions or suspicious biopsy specimens, perhaps from lack of confidence in interpreting those nodules that are benign. The endocrinologist should closely cooperate with the cytopathologist, especially on difficult cases [7]. The cytopathologist should adhere to appropriate criteria for specimen adequacy (⩾6–8 clusters smeared on slides) and he/she should report the cellularity of the specimen and whether it is sufficient for the diagnosis. Such teamwork will avoid the problem of a report such as “no malignant cells seen” in a specimen that is hypocellular or even acellular, resulting in a false conclusion of a benign FNA biopsy specimen [7]. With the exception of calcitonin immunostaining for medullary carcinoma, there are no reliable immunohistologic or molecular tests for distinguishing between benign and malignant nodules based on cytopathology findings [20]. In general, one of four types of interpretation may be reported (despite nomenclature variability between institutions [32], [89]): (a) benign (∼70%), (b) malignant (∼5%), (c) suspicious or indeterminate (∼10%) (for follicular or Hürthle cell carcinoma), and (d) insufficient for a diagnosis (∼15%). Assuming an adequate specimen is obtained, the experienced cytopathologist can recognize the following by thyroid FNAC [7]: Hashimoto thyroiditis, colloid nodule (nodular goiter), subacute (granulomatous) thyroiditis, papillary carcinoma, follicular carcinoma, medullary carcinoma, anaplastic carcinoma, malignant lymphoma, and carcinoma metastatic to the thyroid. Most of the cytologic specimens interpreted as suspicious are follicular and Hürthle cell neoplasms. This diagnosis requires further evaluation and management, since the cytologic features of benign follicular or Hürthle cell tumors and low-grade follicular or Hürthle cell cancer are similar [4], [89]. The two entities can only be distinguished by the presence or absence of capsular, lymphatic, or vascular invasion on histologic examination of surgical specimens. Follicular and Hürthle cell tumors, diagnosed by using FNAC, have a malignancy rate of 10–30% [98]. At the present time, the most useful approach for the treatment of indeterminate follicular and Hürthle cell lesions involves assessing the likelihood of malignancy by examining various clinical parameters. Several studies have demonstrated an improved, but not perfect, ability to predict malignant potential using the size of the lesion and the age of the patient [3], [98]. Indeterminate follicular or Hürthle cell neoplasms in patients over 50 years of age with nodules >4cm in diameter have a 40–60% incidence of being malignant compared with an incidence of 10% in individuals with smaller nodules (<4cm), or under the age of 50 (3). Patients with follicular neoplasms and a suppressed TSH can be screening using radionuclide scanning. If the patient's scan shows a hot nodule, the likelihood of malignancy is very low (see above, 3). Nevertheless, our bias is to offer thyroidectomy for most patients with follicular or Hürthle cell neoplasms. 8. Comments Thyroid nodules are very common in the general population and represent the number one disorder presenting to endocrine surgeons. Most nodules are benign, but the principal problem facing the physician is that of identifying the relatively few malignant neoplasms requiring surgery [26]. Obviously, an indiscriminate performance of surgery because of the fear of malignancy will result in over-treatment of thousands of patients, exposing them to the potential morbidity (and even mortality) of an unnecessary surgical procedure, adding at the same time a significant burden to the health-care system and increasing health-care costs. Of course, some patients with even benign thyroid nodules will need to be operated on for other indications (e.g. pressure of adjacent structures from a large nodule, discomfort, or cosmetic reasons); obviously, in these cases surgery is not considered “unnecessary”. A systematic diagnostic approach to the evaluation of thyroid nodules is important to avoid unnecessary surgery [99] (Fig. 1). Experience on the part of the physician (or early referral to an experienced endocrinologist) results in significant savings in cost of evaluation, lessens patient time and anxiety, and increases diagnostic precision [100]. Findings from the history and physical examination should be used as significant factors in the estimation of the likelihood of underlying cancer, in the decision-making process, and in directing the use of available diagnostic studies. Recent advances in our diagnostic armamentarium enable us to accurately estimate the risk of underlying malignancy within a thyroid nodule. A carefully thought-out management plan can help reduce the risk of unnecessary surgery in these patients [101]. FNAC, in conjunction with US, is the single most important procedure for differentiating preoperatively benign from malignant thyroid nodules, and its role in evaluation and management of nodular thyroid disease cannot be overemphasized. When cytology is benign, repeated FNAC is rarely indicated and in this case periodic follow up may be a reasonable option for the majority of patients. FNAC has a high negative predictive value, which is useful to reassure the majority of patients with thyroid nodules [102]. The wide application of FNAC (often under ultrasound guidance) resulted in a significant reduction of the number of unnecessary thyroidectomies (by approximately 50%), a sharp increase of the surgical yield of malignancy within these nodules, and a reduction of the cost of the management of thyroid nodules (see above). However, despite its accuracy, a negative FNAC cannot exclude malignancy if there is a strong clinical suspicion [102]. The role of radionuclide scanning is limited today, and it should be performed selectively (see above) (Fig. 1). While the use of FNAC has significantly increased during the last decade, there is evidence that FNAC is still under-utilized in the management of patients with thyroid nodules [5]. A significant potential to apply a more rational approach in added patients is likely by increasing the use of FNAC. From a practical point of view, FNAC is indicated in patients with thyroid nodules exceeding 10mm in diameter [14]. This approach is based on the fact that smaller (<10mm) nodules, even if malignant (the so-called “papillary thyroid microcarcinomas”) [77], have an excellent prognosis. A more rigorous approach (FNA of all nodules) will not increase survival and will add a huge burden to health-care providers, and would likely result in a substantial increase in the number of unnecessary thyroidectomies in patients with false-positive FNAC results or with benign follicular or indeterminate lesions [14]. Experience is needed to appropriately perform FNAC and interpret the results of cytology. Poor technique or inadequate experience on the part of the cytopathologist will result in unsatisfactory results and probably will increase the number of unnecessary thyroidectomies[7]. 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