Hossein Gharib

Fine-needle aspiration biopsy of the thyroid: an appraisal.

Nodular thyroid disease, indicated by the presence of single or multiple nodules within the thyroid gland, remains a common clinical problem. Epidemiologic studies suggest that the prevalence of palpable thyroid nodules is 4% to 7% among adults in North America [1, 2]. It is estimated that new nodules develop, or at least become clinically recognizable, at a rate of about 0.1% per year [2, 3]. Although the mechanism underlying thyroid nodule formation and growth is poorly understood, nodules are more common in women [2-4], in older persons [2-5], in persons exposed to ionizing radiation [6], and in persons living in areas endemic for iodine deficiency [7]. The presence of a thyroid nodule raises the question of malignancy, although fewer than 5% of nodules are actually malignant [2, 3]. The development and application of radionuclide scanning, sensitive ultrasonography, and needle biopsy have been helpful in distinguishing benign from malignant nodules and in selecting patients for surgery [2, 3, 8, 9]. During the last decade, confidence in fine-needle aspiration biopsy as a reliable test has grown considerably, and it has emerged as the most direct, accurate diagnostic procedure in the management of nodular thyroid disease, gaining worldwide acceptance [10-14]. Considerable data on fine-needle aspiration biopsy have been reported during the past few years [15-45]. We examine the utility and limitations of fine-needle aspiration biopsy in the evaluation and management of thyroid nodules by reviewing studies reported in the literature from 1982 to 1991. Relying on these data and our own 12 years of experience with more than 11 000 biopsies, we hope to offer a reasoned approach to the management of thyroid nodules. Fine-Needle Aspiration Biopsy Procedure Fine-needle aspiration biopsy, an office procedure, is relatively simple and is described in detail elsewhere [10, 13, 17]. In brief, after careful thyroid palpation, the nodule or nodules to undergo biopsy are identified. The procedure is usually done with the patient in the supine position; the patients neck is flexed backward, allowing maximal exposure of the thyroid lesion. The skin is cleaned with alcohol; usually, no local anesthesia is necessary. A 23- or 25-gauge needle attached to a 10-mL disposable syringe is used. Following the recommendation of Lowhagen and colleagues [10], most aspirators use a mechanical syringe-holder (Cameco-syringe pistol, Precision Dynamics Corporation, Burbank, California), but some prefer to manipulate the syringe directly with the fingers. Use of the syringe-holder allows one hand to be free for nodule identification and continuous palpation. With one hand holding the pistol-grip holder and the other hand palpating the nodule, the aspirator places the needle into the nodule, applies suction, and moves the needle back and forth within the nodule. Suction is then released and the needle is withdrawn; aspirated material is expelled on glass slides and prepared in a manner similar to that for blood smears. Slides are either air-dried and stained using the May-Grunwald-Giemsa technique or immediately wet-fixed in 95% ethyl alcohol and stained using a modified Papanicolaou method [17]. Most cytologists trained in the United States prefer Papanicolaou staining because it is more similar to other cytologic preparations. Two to four aspirations are usually done. Hamburger and Hamburger [26] found that as the number of aspirations increased, false-negative results decreased, and they suggested doing a minimum of six aspirations. If cystic fluid is obtained, it may be concentrated by filtration (8-micron Nucleopore filter; Nucleopore Corp., Pleasanton, California) and stained using the same technique. After the procedure is completed, the patient is observed for a few minutes and then allowed to depart. Serious complications have not been reported; minor pain and local hematomas are transient and tolerable. Cytodiagnosis Cytodiagnoses can be divided into four categories [10, 29, 31, 40]: benign (negative), suspicious (indeterminate), malignant (positive), and nondiagnostic (unsatisfactory) (Table 1). A satisfactory smear contains five or six groups of well-preserved cells; each group consists of at least 10 to 15 cells [11, 17]. Patients with a benign cytodiagnosis do not have malignancy and may have a normal thyroid, a colloid nodule, lymphocytic thyroiditis, subacute thyroiditis, or other benign conditions. Colloid is often, but not invariably, present, and foam cells indicating degeneration are often noted [17, 22, 32]. Patients with a suspicious (indeterminate) cytodiagnosis have specimens showing hypercellularity and a pattern suggestive of follicular- or Hurthle-cell neoplasms or atypical features suggestive of, but not diagnostic for, malignancy [44]. Hypercellularity may represent non-neoplastic lesions, and Hurthle-cell changes may be seen in patients with lymphocytic thyroiditis. Patients with a malignant cytodiagnosis have cytologic findings indicating the presence of malignant cells consistent with primary or metastatic thyroid carcinoma [17, 20]. In patients with nondiagnostic (unsatisfactory) cytologic results, specimens are found to be inadequate for proper cytopathologic interpretation, usually because of the presence of cystic fluid or hemorrhagic material. Aspirates with too few cells are regarded as nondiagnostic and not as negative for malignancy. A repeat aspiration may provide diagnostic smears in up to 50% of cases [17]. It is clear that proper cytologic interpretation requires specific training in cytology and considerable familiarity with the pathology of thyroid diseases. Table 1. Cytodiagnostic Categories for Thyroid Fine-Needle Aspiration Results Data presented in Table 2 are from seven recent, large series of patients who underwent fine-needle aspiration [17, 19, 24, 30, 35, 40, 46]. Altogether, 18 183 specimens were obtained and examined cytologically. In the seven series, the rate of benign cytologic results ranged from 53% to 90% (average, 69%), and the rate of malignant cytologic findings ranged from 1% to 10% (average, 3.5%). The rate of suspicious or indeterminate cytologic results ranged from 5% to 23% (average, 10%). The rate of nondiagnostic cytologic results varied from 2% to 21% (average, 17%). Caruso and Mazzaferri [11] recently reported similar average rates from 10 series including 9119 patients: benign, 74%; malignant, 4%; and inadequate or suspicious, 22%. With the exception of one study [24], it appears that in most institutions, the rate of nondiagnostic results varies from 15% to 20%. Although the number of nondiagnostic aspirates decreases with experience, it is clear that even with repetitive aspirations, a residual 10% of the smears remain unsatisfactory [12, 17]. However, in more than two thirds of all patients (approximately 75% to 80%), a definitive diagnosis of either benign or malignant disease is suggested by the biopsy results. Table 2. Comparison of Diagnostic Cytologic Categories in Seven Series Yield of Cancer Yield is defined as the ratio of the total number of patients with carcinoma to the total number of cases operated. Detection of malignancy in the nodular thyroid on the basis of clinical evaluation, thyroid scanning, and ultrasonography resulted in a 10% to 15% incidence of malignancy at surgery [2, 3, 9, 12, 14]. For example, Ashcraft and Van Herle [8], in a review of 22 series, reported that the use of thyroid scanning resulted in detection of malignancy in 16% of cold nodules. The application of fine-needle aspiration biopsy resulted in an increased frequency of carcinoma in excised thyroid nodules. As shown in Table 3, 3144 of 18 183 patients (17%) were referred to surgery and 995 patients (32%) proved to have malignancy. The yield of cancer varied from 17% to 51% in the series summarized in Table 3. These results correlate well with the findings of recent studies in which fine-needle aspiration biopsy increased the yield of thyroid cancer to 20% to 50% [11-14]. The increased yield of thyroid cancer is not attributable to the presence of small malignant tumors found incidentally in the thyroid gland at the time of surgery. Table 3. Yield, False-Negative and False-Positive Rates, Sensitivity, and Specificity of Thyroid Fine-Needle Aspiration Biopsy* False-Negative Diagnosis False-negative errors are worrisome because they imply missed malignant lesions. False-negative diagnoses may occur because of sampling error [17, 46] or interpretive mistakes [17, 26, 46]. Regardless of the cause, for fine-needle aspiration biopsy to be considered a useful and reliable diagnostic technique, false-negative results must be acceptably low. It is essential that this problem be carefully reviewed. The false-negative rate is defined as the percentage of patients with benign cytologic findings who are confirmed to have malignant lesions of the thyroid. The true frequency of false-negative results is available only in series in which all patients screened by fine-needle aspiration had subsequent surgery with histologic review [8, 12, 14, 47]. Reported false-negative rates in the seven series summarized in Table 3 ranged from 1.3% to 11.5%, with an average rate of 5.2%. However, when data from the series are combined, only 10% of patients with benign cytologic findings underwent thyroid surgery. Caruso and Mazzaferri [11] found an identical false-negative rate of 5% based on pooled data from 10 series (range, 1% to 6%) in which only 14% of nodules were excised. Campbell and Pillsbury [14], analyzing combined data from 912 patients with benign cytologic results who had a histologic examination, found a false-negative rate between 0.5% and 11.5%, with a pooled rate of 2.4%. Ashcraft and Van Herle [8] noted that false-negative results varied in reported series from 2% to 50% and that among 1330 patients, all of whom had a histologic examination, the false-negative rate was 1.7%. It is cle

American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules

American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules are systematically developed statements to assist health care professionals in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances.

Thyroid Incidentalomas: Management Approaches to Nonpalpable Nodules Discovered Incidentally on Thyroid Imaging

In North America, the incidence of thyroid nodules detected by palpation is estimated to be 0.1% per year, with a prevalence between 4% and 7% in the general population. Thyroid nodules are more common in women, with advancing age, in areas of iodine deficiency, and after exposure to external radiation [1]. Most thyroid nodules are benign, and nonsurgical diagnostic approaches to the nodules are currently preferred. Fine-needle aspiration biopsy has emerged as the most accurate diagnostic test for differentiating benign from malignant thyroid nodules. Benign nodules are treated medically, but those with a high risk for malignancy are selected for surgical resection [1]. During the past decade, improved technology has increased the sensitivity of many imaging devices, resulting in the discovery of subclinical nodules in the adrenal, pituitary, and thyroid glands [2-4]. The increasing use of sensitive, high-frequency ultrasonography has led to the identification of nonpalpable thyroid nodules during nonthyroidal ultrasonographic examination of the neck [2]. The discovery of one or more nodules within an otherwise clinically normal thyroid gland raises concern about malignancy and creates a difficult treatment decision for clinician and patient. These lesions, which are referred to as incidentalomas, are small and nonpalpable and are incidentally discovered on ultrasonography. Although most authorities recommend fine-needle aspiration biopsy for palpable nodules, the optimal method for treating nonpalpable nodules is a matter of controversy. We review the frequency and clinical significance of incidentally discovered, nonpalpable thyroid nodules and offer a practical approach to their treatment. Data Sources We reviewed relevant articles published in major English-language medical journals during the past 15 years. We included prospective and retrospective studies that evaluated the prevalence of incidental thyroid nodules as determined by neck ultrasonography, by other imaging studies for thyroid and nonthyroid diseases, and by autopsy studies. Search Strategy The MEDLINE and Current Contents, Sciences Edition, computerized databases were used to search the medical literature published in the past 15 years. We used the keywords thyroid nodule and goiter, nodular, and we did keyword and textword searches using the terms occult, incidental, impalpable, and unexpected. We obtained the full text of the articles that met our criteria. We also reviewed articles cited in the articles identified in our database searches. To formulate our algorithm for approaching thyroid incidentalomas, we also searched using the textword thyroid neoplasms in combination with the previous textword searches. Data Extraction We examined each article identified in our search and determined which were eligible. A total of 135 articles and abstracts were reviewed. Three articles reported autopsy findings, and 11 reported ultrasonographic findings, either in comparison with findings on clinical palpation or as part of prospective studies in a given population. One study compared scintigraphic scanning with palpation. Several other reports on the risk for malignancy in irradiated thyroid glands, the natural history of benign thyroid nodules, and the prevalence of occult thyroid cancer were also reviewed. These articles formed the basis of our recommendations for treating thyroid incidentalomas. Data Synthesis Reliability of Clinical Examination Because the thyroid gland is located superficially, it is easily palpated. There is disagreement about whether thyroid palpation is best done from the front or the back of the patient and about which system best describes the size of the thyroid gland-one based on estimated weight or one based on other variables, such as the presence of a visible prominence [5]. However, no study has compared the results of different methods of thyroid examination or size determination, which makes it difficult to recommend the use of one method over another [6, 7]. Most nodules that are 1 cm in diameter or larger can be palpated, especially when they are favorably situated. A careful examination should record the size, shape, and consistency of the gland and the number, dimensions, and consistencies of any nodules. A nodule that is located deep within or on the posterior surface of the gland is more difficult to palpate than is one located on the anterior surface [2]. In patients with short, fat necks, nodules may be extremely difficult to detect. Moreover, even with experience and careful technique, physicians may fail to detect many nodules smaller than 1 cm in diameter [8]. In a study by Brander and colleagues [2], one half of the nodules discovered on ultrasonography had escaped detection on clinical examination; approximately one third of the nodules that had not been detected by palpation were larger than 2 cm in diameter. However, a prominent but normal thyroid gland in a patient with a thin neck may be perceived by an examiner as an abnormality of the thyroid [5]. The accuracy of thyroid palpation depends greatly on the experience of the examiner. Interobserver variation in nodule examination has been assessed in two studies. Brander and colleagues [2] discovered a good correlation among examiners in the assessment of thyroid size and classification of nodularity. Most of the examinations were done by internists, but some were done by residents. In contrast, Veith and coworkers [9] found that in one third of cases, examiners disagreed about the number of nodules present. In another study [10], interobserver variation was shown to be less among examiners who had more experience than among those who had different levels of training. We found no study that compared the accuracy of palpation done by thyroidologists or endocrinologists with that of palpation done by general internists. Clinical palpation is thus not a precise tool for assessing abnormality of the thyroid gland, and its reliability is influenced by the size and location of the nodule, the size and shape of the neck, and the experience of the examiner. In one study [11], the sensitivity of palpation of the thyroid gland in terms of size and nodularity was 38%. Autopsy Data In 1955, Mortensen and colleagues [12] 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 nodular glands, 144 (35.5%) had nodules that were larger than 2.0 cm in diameter. In an autopsy study of 200 patients with nodular goiter, Hermanson and associates [13] compared the clinical evaluation of 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 pathologic examination. In an autopsy series of 215 patients who did not have thyroid disease, Furmanchuk and coworkers [14] documented nodules in the thyroids of 70 patients (32.5%). Thyroid Imaging Studies Current ultrasonographic technology permits high-resolution imaging of the thyroid gland that is more accurate than clinical palpation or other imaging techniques [8, 15, 16]. Ultrasonography is safe and sensitive and is capable of detecting lesions as small as 1 to 3 mm in the thyroid parenchyma [17]. Katz and colleagues [18] reviewed the accuracy of thyroid ultrasonography in 28 thyroid glands examined at autopsy. The correlation between the ultrasonographic finding of thyroid nodules and the pathologic finding of adenomatous goiter was good; ultrasonography thus had a sensitivity of 89% and a specificity of 84%. Tan and associates [8] recently reported that in 151 patients with a clinical diagnosis of a solitary thyroid nodule, ultrasonography showed that 73 (48%) had other nodules (Table 1). Among the patients in whom subclinical nodules were discovered on ultrasonography, 49 (67%) had two nodules and the other 24 (33%) had three or more nodules that had escaped clinical detection. In that report [8], 89% of clinically palpable nodules were 1 cm in diameter or larger. In 72% of patients with more than one nodule, nodules that had not been identified by palpation were smaller than 1 cm in diameter. Table 1. Frequency of Discovery of Additional Thyroid Nodules on Ultrasonography in Patients in Whom Solitary Nodules Were Detected on Palpation In a retrospective analysis, Brander and colleagues [2] compared results of clinical examination with those of ultrasonography and found that only 12 of 32 (38%) clinically solitary nodules were truly solitary on ultrasonographic examination; 15 patients (47%) had several nodules, and 5 had normal glands. As did Tan and associates [8], Brander and colleagues also found that most nonpalpable nodules were smaller than 1 cm in diameter. Walker and coworkers [19] reported that of 200 patients with nodules that appeared to be solitary on clinical examination, 39 (20%) had more than one nodule found on ultrasonography. The sensitivity of thyroid scintigraphy done using technetium Tc 99m pertechnetate was evaluated in the diagnosis of nodular glands. Arnold and colleagues [20] showed that among patients who had clinically normal thyroid glands or equivocal findings, 40% had evidence of one or more lesions on scintigraphy. From these studies, it is clear that thyroid incidentalomas are common in apparently normal glands and in glands with solitary nodules and that they are detected on thyroid ultrasonography, scintigraphy, or both. A nodule smaller than 1 cm in diameter often escapes clinical palpation unless it is located superficially. Prevalence Studies In 1982, Carroll [21] found at least one incidental thyroid nodule in 13% of patients who had carotid ultrasonography (Table 2). In anot

Fine-Needle Aspiration Biopsy of Thyroid Nodules: Advantages, Limitations, and Effect

BACKGROUND The efficacy of fine-needle aspiration (FNA) biopsy and its role in the management of a nodular goiter are clearly established. The accuracy of cytologic diagnosis approaches 95%. FINDINGS FNA biopsy is a reasonable approach to thyroid nodules; it has decreased costs substantially because it facilitates selection of patients who need to undergo surgical excision. Selecting patients for operation on the basis of results of FNA biopsy has more than doubled the yield of carcinoma. The limitations of cytologic examination, nondiagnostic results, and cellular follicular neoplasms should be remembered but need not negate continued use of FNA biopsy. Negative (benign) and positive (malignant) cytologic results are conclusive; careful clinical follow-up of benign nodules and surgical excision of malignant nodules are recommended. Nondiagnostic results are inconclusive; further evaluation by repeated FNA biopsy, ultrasound-guided biopsy, or radionuclide scanning is necessary. Suspicious cytologic results are also inconclusive and are associated with a 20% chance of malignant involvement; surgical treatment is necessary for clarification. The role of levothyroxine therapy remains uncertain and is not recommended until compelling data are available. CONCLUSION FNA biopsy is a safe, simple, reliable, and cost-effective means of detecting benign nodules. FNA biopsy, not thyroid scanning or ultrasonography, is the preferred initial diagnostic test in all patients with thyroid nodules.

American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: Executive Summary of recommendations.

American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules are systematically developed statements to assist health care professionals in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances.

Clinical Practice Guidelines for Hypothyroidism in Adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association

OBJECTIVE Hypothyroidism has multiple etiologies and manifestations. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions. This paper describes evidence-based clinical guidelines for the clinical management of hypothyroidism in ambulatory patients. METHODS The development of these guidelines was commissioned by the American Association of Clinical Endocrinologists (AACE) in association with American Thyroid Association (ATA). AACE and the ATA assembled a task force of expert clinicians who authored this article. The authors examined relevant literature and took an evidence-based medicine approach that incorporated their knowledge and experience to develop a series of specific recommendations and the rationale for these recommendations. The strength of the recommendations and the quality of evidence supporting each was rated according to the approach outlined in the American Association of Clinical Endocrinologists Protocol for Standardized Production of Clinical Guidelines-2010 update. RESULTS Topics addressed include the etiology, epidemiology, clinical and laboratory evaluation, management, and consequences of hypothyroidism. Screening, treatment of subclinical hypothyroidism, pregnancy, and areas for future research are also covered. CONCLUSIONS Fifty-two evidence-based recommendations and subrecommendations were developed to aid in the care of patients with hypothyroidism and to share what the authors believe is current, rational, and optimal medical practice for the diagnosis and care of hypothyroidism. A serum thyrotropin is the single best screening test for primary thyroid dysfunction for the vast majority of outpatient clinical situations. The standard treatment is replacement with L-thyroxine. The decision to treat subclinical hypothyroidism when the serum thyrotropin is less than 10 mIU/L should be tailored to the individual patient.

Fine-Needle Aspiration Biopsy of the Thyroid: The Problem of Suspicious Cytologic Findings

Cases in which thyroid nodules yielded suspicious cytologic findings on fine-needle aspiration biopsy were prospectively studied during a 3-year period. Of 1970 patients, 333 (17%) had suspicious cytologic findings; from this group, the cases of 253 patients were studied. The cytologic diagnoses were 96 (38%) H urthle cell neoplasms, 84 (33%) follicular cell neoplasms, and 73 (29%) nonspecific diagnoses. A thyroid scan was obtained in 123 of 203 (61%) patients with a solitary nodule, and the nodules were hypofunctional in 102 (83%). Malignant lesions were found in 60 (24%) of the 253 patients. Our findings are consistent with reports that 20% of patients who have a fine-needle aspiration biopsy will have suspicious cytologic findings and that of these, 20% may have a malignant lesion. Thyroid scanning will not distinguish between benign and malignant thyroid lesions that are suspicious on cytologic examination. Surgical excision of all suspicious lesions seems reasonable.

Long-term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma

Thirty-one patients with persistent hypercalcitoninemia after seemingly adequate primary operation for medullary thyroid carcinoma (MTC) were followed for a mean period of 11.9 years after operation. Ten patients had sporadic MTC and the remaining patients were members of families with multiple endocrine neoplasia (MEN)--either MEN 2A (15 patients) or MEN 2B (six patients). Overall 5- and 10-year survival rates were 90% and 86%, respectively. Only four patients died at the completion of the study: two of MTC and two of unrelated causes. Eleven patients (35.5%) underwent surgical re-exploration after demonstration of recurrent disease clinically or radiologically. In no patient did the calcitonin level return to normal after re-exploration. The presence of more than three metastatic nodes at the time of initial operation was a statistically significant (p = 0.003) predictor for disease recurrence. Factors approaching statistical significance were patients younger than age 35 (p = 0.06) and the percentage of cells in the S phase of cell division (0.07). This data supports a conservative surgical philosophy in the management of the patient with persistent hypercalcitoninemia after resection of MTC.

CHANGING CONCEPTS IN THE DIAGNOSIS AND MANAGEMENT OF THYROID NODULES

Thyroid nodules are extremely common, affecting from 4% to 7% of the population. Fine-needle aspiration biopsy is the most accurate and cost-effective technique for nodule diagnosis. It is simple, safe, and should be the first test used in patient work-up. Routine thyroxine (T4) suppressive therapy is no longer recommended for cytologically benign nodules. T4 suppression can cause or aggravate osteoporosis, especially in postmenopausal women. New data on T4 suppressive therapy, cost analysis, and nodule guidelines are reviewed.

Suppressive therapy with levothyroxine for solitary thyroid nodules. A double-blind controlled clinical study.

Thyroid nodules are present in up to 50 percent of adults in the fifth decade of life. Patients are often treated with thyroxine in order to reduce the size of the nodule, but the efficacy of thyrotropin-suppressive therapy with thyroxine remains uncertain. In this study, 53 patients with a colloid solitary thyroid nodule confirmed by biopsy were randomly assigned in a double-blind manner to receive placebo (n = 25) or levothyroxine (n = 28) for six months. Before treatment, pertechnetate-99m thyroid scanning showed that 22 percent of the nodules were functional, 25 percent hypofunctional, and 53 percent nonfunctional. High-resolution (10-MHz) sonography was used to measure the size of the nodules before and after treatment. Suppression of thyrotropin release was confirmed in the levothyroxine-treated group by the administration of thyrotropin-releasing hormone; thyrotropin release was normal in the placebo group. Six months of therapy did not significantly decrease the diameter or volume of the nodules in the levothyroxine group as compared with the placebo group. We conclude that the efficacy of levothyroxine therapy in reducing the size of colloid thyroid nodules is not apparent within six months, despite effective suppression of thyrotropin.