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Division of Medical Sciences (K.B., J.C.W., M.C.S., J.A.F.), The Medical School, Department of Primary Care and General Practice (R.L.H.), University of Birmingham, Birmingham B15 2TT, United Kingdom; and Department of Medicine (J.H.), Charles University (Prague), Faculty of Medicine and University Hospital, CZ-50005 Hradec Kralove, Czech Republic
Address all correspondence and requests for reprints to: Professor J. A. Franklyn, Division of Medical Sciences, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom. E-mail: j.a.franklyn{at}bham.ac.uk; or Dr. K. Boelaert, Division of Medical Sciences, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom. E-mail: k.boelaert{at}bham.ac.uk.
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Abstract |
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Objective: The objective of the study was to assess whether simple clinical and biochemical parameters can predict the likelihood of thyroid malignancy in subjects undergoing FNAB.
Design: The design was a prospective cohort.
Setting: The study was conducted at a single secondary/tertiary care clinic.
Participants: One thousand five hundred consecutive patients without overt thyroid dysfunction (1304 females and 196 males, mean age 47.8 yr) presenting with palpable thyroid enlargement between 1984 and 2002 were evaluated by FNAB of the thyroid.
Intervention(s): There were no interventions.
Main Outcome Measures: Goiter type was assessed clinically and classified as diffuse in 183, multinodular in 456, or solitary nodule in 861 cases. Serum TSH concentration at presentation was measured in a sensitive assay in patients presenting after 1988 (n = 1183). The final cytological or histological diagnosis was determined after surgery (n = 553) or a minimum 2-yr clinical follow-up period (mean 9.5 yr, range 2–18 yr).
Results: The overall sensitivity and specificity of FNAB in predicting malignancy were 88 and 84%, respectively. The risk of diagnosis of malignancy rose in parallel with the serum TSH at presentation, with significant increases evident in patients with serum TSH greater than 0.9 mU/liter, compared with those with lower TSH. Binary logistic regression analysis revealed significantly increased adjusted odds ratios (AORs) for the diagnosis of malignancy in subjects with serum TSH 1.0–1.7 mU/liter, compared with TSH less than 0.4 mU/liter [AOR 2.72, 95% confidence interval (CI) 1.02–7.27, P = 0.046], with further increases evident in those with TSH 1.8–5.5mU/liter (AOR 3.88, 95% CI 1.48–10.19, P = 0.006, compared with TSH < 0.4 mU/liter) and greater than 5.5 mU/liter (AOR 11.18, 95% CI 3.23–8.63, P < 0.001, compared with TSH < 0.4 mU/liter). Males (AOR 1.8, 95% CI 1.04–3.1, P = 0.04), younger patients (AOR 1.1, 95% CI 1.01–1.15, P = 0.025), and those with clinically solitary nodules (AOR 2.53, 95% CI 1.5–4.28, P = 0.001) were also at increased risk. Based on these findings, a formula to predict the risk of the diagnosis of thyroid malignancy in individual patients, taking into account their gender, age, goiter type determined clinically, and serum TSH, was calculated.
Conclusions: The risk of malignancy in a thyroid nodule increases with serum TSH concentrations within the normal range. In addition to patient’s gender, age, and goiter type, the serum TSH concentration at presentation is an independent predictor of the presence of thyroid malignancy. We propose that these simple clinical and biochemical factors can serve as an adjunct to FNAB in predicting risk of malignancy.
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Introduction |
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Thyroid cancer, in contrast, is rare, accounting for approximately 1% of all new malignant disease (0.5% of cancers in men and 1.5% in women) (4), although the annual incidence is reported to be rising (4). Most patients with thyroid enlargement can be managed conservatively after malignancy is ruled out, the challenge to the clinician being to identify the minority of patients with thyroid cancer who therefore require surgical intervention (5).
In most cases, thyroid glands harboring malignancy are clinically indistinguishable from those that do not, and physical examination is therefore deemed largely unhelpful in identifying those patients with thyroid cancer (5). A major aim of clinical evaluation of patients presenting with thyroid enlargement is to minimize the risk of overlooking thyroid cancer. Recognized clinical parameters raising the suspicion for malignancy include young (<20 yr) or old age (>70 yr), male gender, large (>4 cm) or rapidly growing nodules (especially during thyroid hormone therapy), and radiation exposure history (5, 6). It has been widely perceived that rates of malignancy are higher in subjects with solitary nodules than in those with multinodular goiters (5, 7), although some have reported similar rates in these two groups (8). Our own previous studies have also reported the presence of malignancy in subjects with clinically diffuse as well as those with multinodular goiters (9, 10). Although virtually all patients with thyroid carcinoma are euthyroid, the presence of a suppressed serum TSH concentration (generally indicative of subclinical or overt thyrotoxicosis) does not rule out the presence of malignancy (5).
Although several imaging modalities are available, fine-needle aspiration biopsy (FNAB) remains the gold standard in the evaluation of patients presenting with thyroid enlargement as stated in recent guidelines published by the American Thyroid Association (ATA) (11) and other authorities (12, 13, 14). FNAB has a reported diagnostic sensitivity and specificity ranging between 65 and 98% and 72 and 100%, respectively (4, 7, 15). Diagnostic FNAB results are obtained in approximately 80% of cases, and repeat aspiration can augment the accuracy of the procedure (15, 16). Several studies have demonstrated that ultrasound guidance, compared with palpation-guided FNAB, reduces the number of nondiagnostic aspirates, and some, but not all, studies suggest that it increases diagnostic sensitivity and specificity (16, 17, 18).
We set out to explore the hypothesis that simple clinical or biochemical criteria might predict the likelihood of thyroid malignancy in patients presenting with thyroid enlargement, thereby identifying those at greatest risk of harboring thyroid malignancy. Having previously undertaken a similar analysis in a cohort of 1005 patients (10), we reexamined this hypothesis in a larger prospectively collected cohort of 1500 patients who underwent FNAB between 1984 and 2002 in our clinic. We performed a detailed investigation of which parameters of clinical and laboratory assessment might predict the diagnosis of thyroid cancer. We also used these parameters to derive a formula to predict the risk of diagnosis of malignancy in individual subjects undergoing FNAB.
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Subjects and Methods |
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We prospectively collected data on 1500 patients presenting consecutively to the Multidisciplinary Thyroid Clinic at the University Hospital Birmingham National Health Service Trust, Birmingham, UK, between 1984 and 2002. This study was performed with the approval of the Trust Research and Development Directorate. The cohort included 1304 females and 196 males with a mean age of 47.8 yr (range 6–88 yr). All patients included were clinically and biochemically euthyroid [defined as normal serum concentrations of free T4 (fT4) and free T3 (fT3)]. Patients were followed up in the clinic for a minimum duration of 2 yr (mean duration of follow-up since presentation 9.5 yr, range 2–19 yr). A final histological diagnosis was made in 553 patients who underwent surgery, and a final cytological diagnosis was made after a minimum 2-yr follow-up period in the remainder. The goiter type was assessed by physical examination of the neck by one of four senior clinicians and classified as diffuse in 183, multinodular in 456, and solitary nodule in 861 subjects as we have previously described (10).
All 1500 patients had FNAB of their thyroid performed at initial presentation, the clinic protocol being to perform this investigation at first visit in all subjects with goiter or nodules and without overt thyroid dysfunction, in keeping with guidelines from the ATA and British Thyroid Association (BTA) (11, 19). The aspirate was performed on the dominant nodule in subjects with multinodular goiters, whereas those with large diffuse goiters had multiple aspirates from different sites at a single sitting. In patients with nondiagnostic aspirates as well as those with changing clinical symptoms and signs, FNAB was repeated at subsequent visits, typically after 3–6 months. A minimum follow-up period of 2 yr was designated to allow clinical reevaluation of the neck over an extended period. Any change in symptoms or signs at 3- to 6-month review prompted repeat FNAB, a policy in agreement with the recently published ATA guidelines, which state that easily palpable nodules do not require sonographic monitoring but that patients should be followed up clinically at 6- to 18-month intervals (11).
Cytological findings were classified according to accepted guidelines (11, 19) as: nondiagnostic (Thy1 category according to BTA guidelines); benign (BTA Thy2, nonneoplastic category); indeterminate (including BTA categories Thy3 (follicular lesions) and Thy4 (suspicious of malignancy)]; and diagnostic of malignancy (BTA Thy5 category). Patients were assigned to a final diagnostic category for cytology results (true negative, true positive, false negative, or false positive for malignancy) after the minimum 2-yr follow-up period, except for those patients who underwent surgery before the end of this period (and in whom a formal histological diagnosis was obtained earlier). The cytological diagnosis was considered true negative if, after a follow-up period or surgery, a diagnosis of thyroid malignancy had not been made. Cytology indicating indeterminate or frankly malignant findings was considered true positive if malignancy was confirmed histologically after surgery or open biopsy. Cytological results were defined as false negative in subjects with one or more diagnostic aspirates without suspicious or malignant features in whom later cytology and/or surgery provided evidence for malignancy (including those patients harboring a microcarcinoma).
A biochemical evaluation of all patients attending a morning clinic was performed at presentation through measurement of fT4, fT3, and TSH concentrations, in keeping with ATA and BTA guidance (11, 19). Furthermore, 697 patients were investigated by respiratory flow-loop examination to identify those with evidence of upper airway obstruction as described by ourselves previously (20). Serum fT4, fT3, and TSH were measured by automated luminescent immunoassays (ACS 180; Chiron Diagnostics, Halstead, UK) with interassay coefficients of variation of less than 12% over the ranges 6.2–81 pmol/liter, 2.5–20 pmol/liter, and 0.3–39 mU/liter, respectively. A measurement of TSH in this sensitive assay was obtained for all patients who presented after 1988 (n = 1183). A total of 1229 subjects had antibodies to thyroid peroxidase measured by gelatin particle agglutination (Fujirebo Inc., Tokyo, Japan), and a titer of 1:100 or greater was considered positive.
Statistical analysis
The final diagnostic outcome was defined as the presence or absence of malignancy (thyroid cancer). The influence of factors including age, gender, thyroid characteristics on physical examination, serum TSH concentration, and presence of antimicrosomal antibodies at presentation on the final diagnostic outcome was investigated statistically. We used binary logistic regression analyses, using Minitab (version 14.0; Minitab Ltd., Coventry, UK) as the statistical package. The serum TSH concentration was recorded as a categorical variable in this analysis; analysis of the influence of serum TSH measurement was confined to the subgroup (n = 1183) in whom TSH had been measured in a sensitive assay. Examination of the prevalence of malignancy in the different serum TSH categories enabled a judgment to be made on the validity of including TSH as a continuous variable. With a satisfactory outcome to this investigation, a formula could then be proposed to predict the probability of malignancy in an individual patient through binary regression analysis using the serum TSH concentration as a continuous variable.
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Results |
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A total of 697 patients had a respiratory flow loop examination performed, and evidence of significant airways obstruction was detected in 85 patients, all of whom subsequently underwent surgery.
Accuracy of FNAB
Of the cohort of 1500, FNAB was repeated on one occasion in 479 patients and more than once in 177. The final cytological diagnosis reached after a minimum of 2 yr clinical follow-up was benign cytology in 1086 (72.4%), indeterminate cytology in 291 (19.4%), and malignant cytology in 30 (2%) subjects. Nondiagnostic aspirates were initially obtained in 257 subjects (17.1%), but after repeated FNAB, only 93 (6.2%) had cytological features that remained unclassified. Thirty-three of these patients proceeded to surgery, and in the remainder, the thyroid enlargement was no longer evident at follow-up.
A total of 553 patients proceeded to open biopsy or surgery. This group included all those with malignant (n = 30) or indeterminate cytology (n = 291), 85 subjects with upper airways obstruction defined by respiratory flow-loop examination, 31 with recurrent accumulation of cyst fluid, 33 with persistent nondiagnostic cytology, and 83 who requested surgery for cosmetic reasons. The histological diagnoses were compared with the cytological findings before surgery. Those in the cohort not subjected to surgery were followed up in the clinic at 6-month intervals for a minimum of 2 yr to allow identification of those with changing symptoms or signs and the need for repeat FNAB.
Overall, the rate of malignancy in our cohort was 8%. Table 1
displays the number of patients with each of the different types of thyroid cancer found. The number of subjects within each clinical goiter classification subgroup and within each cytology diagnostic category are also given. A true-negative cytological diagnosis was made in 1164 (77.6%) patients, whereas 105 (7%) subjects were assigned to the true positive cytological category. Only one of the 216 (14.4%) patients with a false-positive result had an original cytological diagnosis of malignancy, the remainder having indeterminate cytological aspirates. A false-negative cytological diagnosis was found in 15 patients (1%), and three of these harbored a microcarcinoma. Review of the initial cytology in this group did not indicate an error of interpretation in any case, and false-negative cytology results were therefore likely to reflect sampling error. The final histological diagnosis for the 15 patients in this false-negative group was follicular carcinoma in six, papillary carcinoma in seven, and Hürthle cell carcinoma in two subjects. Based on these findings, the overall sensitivity and specificity of FNAB for the diagnosis of malignancy in our series was 88 and 84%, respectively. When analyzing the performance of FNAB for the different goiter types defined clinically, we obtained sensitivities of 80, 77, and 90% and specificities of 90, 84, and 83% for clinically defined diffuse goiters, multinodular goiters, and solitary nodules, respectively.
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The predictive value of the patient’s age and gender, as well as the goiter type as defined by clinical examination, on final diagnostic outcome of malignancy in the total cohort (n = 1500) was investigated. Male subjects (n = 196) presenting with thyroid enlargement had significantly higher rates of malignancy (12.2%) when compared with female patients (n = 1304, 7.4%, P = 0.02). Significant increases in the prevalence of malignancy (P = 0.005) were detected in patients who were aged younger than 30 yr and in those older than 80 yr at presentation (Fig. 1A). The change in prevalence with age was not linear as evidenced by high prevalences at both extremes of age. We therefore incorporated an age squared term in the binary logistic regression analysis to correct for this increase in rates of malignancy in patients younger than 30 yr and older than 80 yr at the time of presentation (P < 0.001).
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Subsequently a binary logistic regression analysis was performed, simultaneously analyzing gender, age, and goiter type to determine which factors could be considered independent risk predictors. Significantly increased adjusted odds ratios for malignancy (Table 2) were detected in male patients, those of younger age, and those presenting with clinically solitary lesions. The calculations also took into account the square of the age to correct for the increased risk in patients of age younger than 30 or older than 80 yr.
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A total of 1183 patients had their serum TSH concentration at presentation measured in a sensitive assay, and of these, 182 were found to have subclinical hyperthyroidism, i.e. TSH concentration less than 0.4 mU/liter (normal range 0.4–5.5 mU/liter) with normal serum fT4 and fT3 concentrations. Nine hundred seventy-four subjects had a serum TSH concentration within the normal range, and these were subdivided into three tertiles of similar size (TSH 0.4–0.9 mU/liter, n = 322; TSH 1.0–1.7 mU/liter, n = 336; TSH 1.8–5.5 mU/liter, n = 316). Twenty-seven patients were noted to display subclinical hypothyroidism, i.e. TSH measurement greater than 5.5 mU/liter with normal serum fT4. Among those who had their TSH concentration measured in a sensitive assay, a total of 92 patients (7.8%) had a final diagnosis of thyroid malignancy.
The prevalence of malignancy (n = 182, 2.8%) was lowest in subjects with serum TSH below the normal range (<0.4 mU/liter). Compared with subjects with below-normal serum TSH, higher rates of malignancy (3.7%, P = NS) were present in those with serum TSH in the lower tertile of the normal range, i.e. 0.4–0.9 mU/liter (n = 322). Even higher rates were found in patients with serum TSH 1.0–1.7 mU/liter (n = 336, 8.3%, P = 0.02), compared with TSH less than 0.4 mU/liter, rising to 12.3% (P = 0.001, compared with low TSH) for those with serum TSH 1.8–5.5 mU/liter (i.e. the highest tertile of the normal range, n = 316). The highest prevalences of malignancy (29.6%, P < 0.001, compared with low TSH) were evident in those with serum TSH above the normal range (>5.5 mU/liter, n = 27, Fig. 1B
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Binary logistic regression analysis simultaneously analyzing gender, age, goiter type, and TSH concentration confirmed significantly increased odds ratios for malignancy in males, those of younger age, those with solitary nodules, and those with serum TSH greater than 0.9 mU/liter (Table 3). A simultaneous likelihood ratio test of the effect of all these factors gives 
28 = 59.8 (P < 0.001), indicating the combination of these factors in the prediction of malignancy to be very valuable.
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The presence of antibodies to thyroid peroxidase was determined in 1229 patients. A titer of greater than 1:100 was considered to be positive and was evident in 160 patients. The rate of malignancy was significantly higher (11.9 vs. 6.7%, P = 0.02) in patients with detectable thyroid peroxidase antibodies, compared with those in whom antibodies were absent (n = 1069). Binary logistic regression analysis, simultaneously analyzing the presence of antibodies and the serum TSH concentration, did not identify antibody status to be an independent predictor of prognosis for thyroid malignancy (adjusted odds ratio 1.19, 95% confidence interval 0.6–2.35, P = 0.6).
Prediction of risk of thyroid malignancy in individual patients
Based on the independent risk factors identified from the binary logistic regression analysis, we calculated formulae to predict the risk of thyroid malignancy from simple clinical and laboratory markers in individual patients. These calculations were based on the cohort of 1183 patients who had their TSH concentration measured in a sensitive assay; the adjusted odds ratios analyzing serum TSH as a categorical variable suggested that TSH could be satisfactorily used as a continuous variable in these formulae. The risk of malignancy was calculated through the formula: P = 1/(1 + e–x), with e being the antilogarithmic transformation (e = 2.71828) and x representing a calculation taking into account the patient’s age and gender, the goiter type, and serum TSH. For the probability of malignancy, a numeric value for x was obtained through the following calculation: x = –1.266 + 1.029 (type) – 0.662 (gender) – 0.085 (age) + 0.00089 (age2) + 0.247 (TSH concentration). The goiter type was coded as 1 for diffuse or multinodular goiter and 2 for solitary nodule. The patient’s gender was represented by 1 for males and 2 for females. Examples of risk calculations based on this formula are given in Table 5.
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). These results illustrate that the predicted probability of diagnosis of malignancy increases from less than 10% for serum TSH concentrations at the lower end of the normal range up to 25% if the same patient has a TSH concentration at the upper end of the normal range.
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Discussion |
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The sensitivity (88%) and specificity (82%) of FNAB as well as the low false-negative rate for the diagnosis of malignancy (1%) in this large UK cohort compare favorably with other large series (15, 22, 23). Similarly, our rate of nondiagnostic FNAB samples (6.2% after repeated biopsies) was comparable with that reported by others as between 5 and 20% (15, 17, 18).
Measurement of serum TSH, which is a highly sensitive determinant of thyroid dysfunction, is the recommended biochemical test in the initial evaluation of patients presenting with thyroid enlargement (11, 19). A subgroup of 1183 subjects within our cohort had a serum TSH measurement in a sensitive assay performed, and subsequent fT4 (as well as fT3 measurements in subjects with below-normal TSH concentrations) confirmed the absence of overt thyroid dysfunction in those with TSH measurements outside the reference range. Subclinical hyperthyroidism was present in 15% (n = 126) of our patients, a prevalence that is higher than that generally reported (0.5–6.3%) in population-based surveys but consistent with reported prevalences in subjects with nodular thyroid disease (24, 25, 26). The rate of subclinical hypothyroidism in our patients who had sensitive TSH measurements was 2.3% (n = 27), a prevalence that is somewhat lower than that reported by others, again in population-based surveys (2, 24, 27).
We demonstrated for the first time that the risk of diagnosis of malignancy rises in parallel with the serum TSH concentration at presentation, and further analysis indicated significantly increased odds ratios for the presence of malignancy in patients with TSH greater than 1.8 mU/liter after adjustment for patients’ gender, age, and goiter type (Table 3). It is well documented that TSH has a trophic effect on thyroid cancer growth, which is most likely mediated by TSH receptors on tumor cells (28, 29), and furthermore that TSH suppression is an independent predictor of relapse-free survival from differentiated thyroid cancer (30). We propose that the risk increase associated with serum TSH concentrations in the upper half of the normal range, and even more strikingly in those whose TSH measurements were above normal, may at least in part be mediated by this trophic effect of TSH. An alternative explanation is that patients with lower TSH concentrations were developing autonomous function, which is itself associated with lower rates of malignancy (15, 23, 32).
Twenty-seven patients had above-normal serum TSH concentrations (>5.5 mU/liter), and antimicrosomal antibodies were present in 66.6% (n = 18 subjects) of those 27, consistent with the diagnosis of autoimmune thyroiditis in these patients. When we assessed the association between the presence of thyroid antibodies and final outcome, we detected significantly higher rates of malignancy (P = 0.02) in those with detectable antimicrosomal antibodies, although further statistical analysis, taking into account the serum TSH concentration, did not identify patients’ antibody status as an independent risk predictor. Previous studies have found the presence of antithyroglobulin and antithyroid peroxidase antibodies not to be useful in distinguishing benign from malignant lesions (33).
An increased risk of underlying malignancy in men, compared with women, has been demonstrated previously (5, 7, 23), although a few smaller studies indicated patients’ gender not to be helpful in predicting risk of carcinoma (34, 35). More recently, a retrospective case series of 1009 patients evaluating the natural history of cytologically benign thyroid nodules using ultrasonography indicated that patient’s gender did not predict nodule growth (36). In our series, significantly increased rates of malignancy were detected in men, regardless of age and goiter type, and logistic regression analysis identified patients’ gender as an independent predictor of thyroid malignancy (adjusted odds ratio 1.63, P = 0.046, Table 2). We also identified patients’ age as an independent risk predictor for malignancy (P = 0.004, Table 2) after correcting for gender and clinically determined goiter type, in accord with previous studies (5, 21, 23, 37).
Notably, we found that goiter type assessed by physical examination alone was significantly associated with final diagnosis. It is well recognized that examination of the neck is poorly specific in the classification of goiter, and ultrasound examination often reveals the presence of multiple nodules in patients judged clinically to have a single nodule or diffuse thyroid enlargement (5, 23, 38). Because ultrasonography was not routinely performed in our practice [or that of many other centers (13, 14)] at the time of data collection and because the aim of this study was to identify simple clinical or biochemical predictors of risk of malignancy, we chose to analyze findings with respect to clinical examination alone. Strikingly, our results indicate that the presence of a clinically solitary lesion was associated with increased malignancy rates, compared with those patients presenting with clinically diffuse or multinodular goiters. Moreover, regression analysis confirmed the goiter type assessed clinically to be an independent predictor of risk (odds ratio 2.77, P < 0.001, Table 2) after correcting for patients’ age and gender. Previous studies performed by us and others have indicated increased cancer risk in nodules deemed solitary by palpation (5, 9, 23, 31, 39), although others have found similar rates of malignancy when comparing solitary lesions and multinodular goiters defined clinically (8).
Experts advocate thyroidectomy, regardless of cytology results in subjects with a high clinical suspicion of malignancy (5, 21, 23). However, few studies have attempted to integrate clinical or laboratory parameters systematically with the results of FNAB into the selection process of patients who need surgery. One previous report (31) aimed to develop clinical criteria capable of predicting malignancy in 149 patients with an FNAB diagnosis of follicular neoplasm and concluded that features such as gender, nodule size, and character of the gland by palpation can be systematically integrated into the decision analysis before surgical referral (31). We demonstrate that the presenting TSH concentration is an additional useful parameter in the prediction of probability of underlying malignancy. The results displayed in Table 6 illustrate that the calculated risks based on our formula rise dramatically with increasing TSH concentrations if the other parameters (patients’ age, gender, and goiter type) remain constant.
We acknowledge the following limitations to this study: 1) the final diagnosis of benign or malignant disease was not confirmed histologically in all but was based on a minimum of 2 yr of clinical follow-up and repeat FNAB in the majority; 2) we did not analyze serum TSH measurements for the whole cohort because the sensitive TSH assay became available only after 1988; and 3) patients’ goiter types were classified clinically based on findings obtained by physical examination alone.
Based on our findings, we have, for the first time, been able to calculate a formula predicting a diagnosis of thyroid malignancy, taking into account patient’s age, gender, goiter type evaluated clinically, and the serum TSH concentration at presentation, factors that we found to be independently associated with likelihood of diagnosis of thyroid malignancy. This risk prediction, based on simple clinical and biochemical parameters, can be used as an adjunct to results of FNAB to identify those who require further investigation and/or surgical intervention. Prospective studies are required to define the role of this risk prediction in refining clinical management of the larger patient population.
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Footnotes |
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K.B., J.H., R.L.H., J.C.W., M.C.S., and J.A.F. have nothing to declare.
First Published Online July 25, 2006
Abbreviations: ATA, American Thyroid Association; BTA, British Thyroid Association; FNAB, fine-needle aspiration biopsy; fT3, free T3; fT4, free T4.
Received March 9, 2006.
Accepted July 18, 2006.
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