Ellen Marqusee

Long-term Assessment of a Multidisciplinary Approach to Thyroid Nodule Diagnostic Evaluation

The diagnostic evaluation of patients with thyroid nodules is imprecise. Despite the benefits of fine‐needle aspiration (FNA), most patients who are referred for surgery because of abnormal cytology prove to have benign disease. Recent technologic and procedural advances suggest that this shortcoming can be mitigated, although few data confirm this benefit in unselected patients.

Hypothyroidism after Sunitinib Treatment for Patients with Gastrointestinal Stromal Tumors

Context Sunitinib, a tyrosine kinase inhibitor, has recently been approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Contribution In a series of imatinib-resistant patients treated with sunitinib for gastrointestinal stromal tumors, 36% developed hypothyroidism during the course of treatment. Incidence of hypothyroidism increased progressively with duration of treatment. Implications Disruption of specific cellular signaling pathways by kinase inhibitors that are intended to interfere with malignant cell growth may have profound and unanticipated metabolic consequences. Patients receiving kinase inhibitors should be closely monitored for the occurrence of adverse effects on other organ systems. The Editors Tyrosine kinase inhibitors are beneficial for the treatment of numerous malignant conditions. Although each small molecule is modeled to block the activity of selected kinase signaling enzymes, it is increasingly evident that many have overlapping effects on several kinase pathways. Sunitinib malate (Sutent [previously known as SU11248], Pfizer, Inc., New York, New York), a multitargeted small-molecule tyrosine kinase inhibitor with proven antitumor activity against gastrointestinal stromal tumors and renal cell carcinoma, has recently been approved in the United States and Europe for treatment of patients with metastatic or surgically unresectable disease (14). Although the drug is usually well tolerated, patient-reported fatigue noted during clinical trials led to the monitoring of serum thyroid-stimulating hormone (TSH) concentrations to rule out primary hypothyroidism. After the identification of 2 index case-patients who developed primary hypothyroidism, we expanded our observations in patients receiving sunitinib therapy to further define this association. Index case-patient 1, a 39-year-old woman, presented with lower gastrointestinal bleeding and was found to have a gastrointestinal stromal tumor of the stomach wall with several liver metastases. Following surgery to resect the bleeding lesion, she was treated with imatinib mesylate. Within months, serial imaging confirmed disease progression. Imatinib was withdrawn, and she enrolled in a phase I/II clinical study investigating the safety and efficacy of sunitinib. She received sunitinib in repeated 4-week cycles (50 mg/d for 2 weeks, followed by a 2-week washout phase). At initiation of therapy, the patient had an Eastern Cooperative Oncology Group performance status of zero and had no cold intolerance, constipation, fatigue, or other signs of hypothyroidism. Baseline serum TSH concentration was 1.6 mU/L (normal range, 0.5 to 5.0 mU/L). The patient was treated with sunitinib for more than 1 year and had normal serum TSH concentration during this time, except 1 value of 8.8 mU/L at 38 weeks of therapy (Figure 1). During the 60th week of sunitinib therapy, she reported progressive fatigue, confusion, and cold intolerance. Physical examination was notable for myxedema. The results of thyroid function testing showed a serum TSH value of 288 mU/L. l-Thyroxine was administered, and a normal TSH value was achieved, resulting in resolution of symptoms. Figure 1. Biochemical findings of thyroid dysfunction in a patient treated with sunitinib for recurrence of gastrointestinal stromal tumor. The figure depicts sequential thyroid-stimulating hormone (TSH) measurements during 2 years of sunitinib therapy. l-Thyroxine therapy was initiated at week 74. At 92 weeks, the patient was referred from the oncology program to the Division of Endocrinology for consultation at the Brigham and Womens Hospital, Boston, Massachusetts. At that time, the patient appeared clinically euthyroid, and results of thyroid function tests were normal while she was receiving 150 g of l-thyroxine per day. Her thyroid was not palpable, and results on neck ultrasonography showed minimal thyroid tissue. Index case-patient 2, a 38-year-old woman, presented with a metastatic gastrointestinal stromal tumor. She had previously been treated with imatinib for 18 months before developing refractory disease. Imatinib was withdrawn, and the patient began receiving sunitinib in repeated 6-week cycles (50 mg/d for 4 weeks, followed by a 2-week washout period) at a different cancer center. After she developed diarrhea and fatigue, her dose was reduced to 37.5 mg/d. Following 24 weeks of sunitinib therapy, she noted heart palpitations, heat intolerance, dysphagia, and anterior neck pain lasting several weeks. After approximately 30 weeks of therapy, the patient developed progressive fatigue, cold intolerance, hoarseness, and constipation. These symptoms were initially attributed to direct effects of sunitinib in conjunction with systemic effects of her tumor. After 51 weeks of sunitinib therapy, she was referred to the Dana Farber Cancer Institute, Boston, Massachusetts, and her persistent symptoms suggesting hypothyroidism prompted an endocrine consultation. She was extremely hypothyroid, with dry skin, nonpitting edema, absence of palpable thyroid tissue, and delayed relaxation of deep tendon reflexes. The results of a neck ultrasonography showed no visible thyroid tissue (Figure 2). Her TSH level was 101 mU/L; serum thyroxine concentration was 21 nmol/L (1.6 g/dL) (normal range, 64 to 142 nmol/L [5 to 11 g/dL]), her thyroid hormone binding ratio was 0.48 (normal range, 0.8 to 1.2), her free thyroxine index was 0.8 (normal range, 5 to 11), and her thyroid peroxidase antibody was 17.6 U/mL (normal range, 0 to 20 U/mL). The patient was treated with l-thyroxine, 88 g/d, resulting in complete resolution of her symptoms. On the basis of these initial findings in 2 patients receiving sunitinib, we sought to prospectively evaluate thyroid function in patients enrolled in a phase I/II study investigating sunitinib as a treatment for patients with imatinib-resistant gastrointestinal stromal tumors at the Dana Farber Cancer Institute. Methods Patients Between April 2002 and December 2004, 79 patients were treated in a phase I/II trial investigating sunitinib therapy for the treatment of imatinib-resistant gastrointestinal stromal tumors. Most received 50 mg of sunitinib per day in repeated 4- or 6-week cycles, each consisting of 2 to 4 weeks of sunitinib followed by 2 weeks with no therapy. Patients enrolled in this study had stopped receiving imatinib therapy at least 14 days before starting sunitinib therapy. Between April 2002 and September 2002, thyroid function tests were performed only if there was a clinical suspicion of hypothyroidism. Beginning in October 2002, the study protocol was modified to include measurements of serum TSH at the beginning of each sunitinib treatment cycle. In December 2004, the Endocrinology Division began collaborative evaluation of this population. Serum TSH values were available for 69 of 79 patients (87%), 20 of whom were excluded from primary analysis because of abnormal thyroid function or l-thyroxine therapy preceding initiation of sunitinib or because baseline data were not available. Of these 20 patients, 8 patients were receiving l-thyroxine therapy at study entry (6 had begun l-thyroxine therapy before either imatinib or sunitinib therapy, and 3 patients were first tested for thyroid function after treatment with 5 cycles of sunitinib; 9 other patients had abnormal baseline thyroid function (7 had elevated TSH concentrations, and 2 had suppressed TSH concentrations). Seven additional patients with normal baseline thyroid function received sunitinib therapy for less than 3 cycles because of progressive disease or drug intolerance and were also excluded. No participants received medications known to cause thyroid dysfunction, such as iodinated compounds, lithium, or interferon. Thus, we evaluated results in 42 patients with normal baseline thyroid function treated with sunitinib for at least 3 cycles. These 42 patients were treated for a median of 37 weeks (range, 10 to 167 weeks). Biochemical Evaluation and Treatment Patients were screened for thyroid dysfunction by monitoring serum TSH concentration (5, 6). A TSH concentration greater than 5.0 mU/L was considered abnormal. Patients with substantial increases in TSH were further evaluated, and treatment with l-thyroxine was initiated as indicated. Role of the Funding Source The phase I/II trial of sunitinib was funded in part by Pfizer, Inc., and the results of the trial have been reported elsewhere. There was no separate industry funding source for this investigation, and funding played no role in the collection, analysis, and interpretation of these data or in the decision to submit this paper for publication. The institutional review board of the Dana Farber Cancer Institute granted permission to perform these investigations. Results During the phase I/II trial of sunitinib, 15 of 42 (36%) patients developed hypothyroidism after an average of 50 weeks of therapy (range, 12 to 94 weeks) (Table). Of these, 9 had TSH concentrations more than 20 mU/L (mean maximal serum TSH concentration, 100 mU/L) and 6 had TSH concentrations between 7.0 and 20 mU/L. Seven additional patients (17%) had at least 1 TSH concentration between 5.0 and 7.0 mU/L while receiving sunitinib that subsequently normalized. Four patients developed TSH suppression while receiving sunitinib but discontinued the study protocol before repeated thyroid function studies could be performed. In summary, abnormal serum TSH values were documented in 26 of 42 (62%) patients receiving sunitinib. Eastern Cooperative Oncology Group functional status was similar in patients with normal thyroid function and in those who were hypothyroid, suggesting that acute illness did not selectively influence thyroid function in affected patients. Table. Serum Thyroid-Stimulating Hormone Concentrations in 15 Patients Who Developed Hypothyroidism during Sunitinib Therapy for the Treatment of Gastrointestinal Stromal Tumors Six of the 15 (40%

Usefulness of Ultrasonography in the Management of Nodular Thyroid Disease

Thyroid nodules are a common diagnostic challenge encountered in clinical medicine. Approximately 4% to 7% of adults have palpable thyroid nodules, and up to 70% have thyroid nodules visible on ultrasonography, many of which are less than 1 cm in diameter (1-5). Fine-needle aspiration biopsy is the standard diagnostic test for evaluating a palpable thyroid nodule in euthyroid patients. Previous studies have shown that the diagnostic accuracy of fine-needle aspiration biopsy is improved with ultrasonography guidance compared with palpation alone (6-9). In addition, ultrasonography guidance is required for aspiration of nonpalpable thyroid nodules (10-12). The objective of our study was to determine whether the routine use of ultrasonography in all patients with suspected thyroid nodules changed clinical management compared with palpation alone. Methods Patients The study sample consisted of all patients referred to the Brigham and Womens Hospital dual-discipline (endocrinology and radiology) Thyroid Nodule Clinic (Boston, Massachusetts) for suspected nodular thyroid disease or suspected recurrent thyroid cancer between October 1995 and March 1997. Clinicians were instructed to refer patients with suspected or diagnosed nodular thyroid disease and a normal serum thyrotropin level to the Thyroid Nodule Clinic. If patients had a suppressed thyrotropin level and were not taking thyroid hormone, a radionuclide scan was suggested. The clinic visit included thyroid ultrasonography performed by a radiologist, an evaluation by an endocrinologist, and ultrasonography-guided fine-needle aspiration biopsy of all nodules measuring at least 1 cm in maximum diameter (up to a maximum of four nodules). A cutoff of 1 cm was selected on the basis of recommendations in the literature (13). For patients seen more than once, only the initial visit was analyzed. Measurements Medical records were reviewed for the specialty of the referring clinician, the referring clinicians examination of the thyroid before referral, and the indication for referral. Sonography was performed by using 5- to 10-MHz transducers. Nodules were measured in three dimensions. Fine-needle aspiration was performed with a 25-gauge needle. Ultrasonography guidance was used to confirm placement of the needle in the nodule or to direct sampling into solid portions of partially cystic nodules. Four to six passes were made per nodule. The needles were rinsed and pooled in a single vial containing CytoLyt solution (CytoLyt Corp., Boxborough, Massachusetts). Two ThinPrep slides (Cytyc Corp., Marlborough, Massachusetts) were stained by using a modified Papanicolaou method and were read by a cytopathologist at the Brigham and Womens Hospital as benign, atypical, suspicious for a follicular or Hrthle cell neoplasm, suspicious or positive for papillary cancer, or nondiagnostic. Aspirates were considered nondiagnostic if they contained fewer than six groups of benign follicular cells. The atypical category was applied to cases in which a mild degree of cellular or architectural atypia precluded a benign diagnosis but was insufficient for a suspicious or positive diagnosis. Cytology reports were reviewed for all patients who had fine-needle aspiration biopsy, and histologic reports were reviewed for all patients who had surgery. Two endocrinologists reviewed the charts to compare the referring physicians findings on thyroid physical examination with the ultrasonography findings. If a discrepancy existed between the referring physicians clinical thyroid examination and the number of nodules requiring fine-needle aspiration biopsy based on ultrasonography ( 1 cm), ultrasonography was considered to have altered the clinical management. Role of the Funding Sources The funding sources had no role in the collection, analysis, and interpretation of the data or in the decision to submit the paper for publication. Results Characteristics of the Study Group A total of 223 patients (203 women and 20 men [mean age, 46.3 15.3 years]) were evaluated at the Thyroid Nodule Clinic between October 1995 and March 1997. Sixty-one percent were referred by primary care physicians, 37% were referred by endocrinologists, and 2% were referred by surgeons. The indication for referral was abnormal findings on thyroid physical examination in 173 of 223 patients (78%); 114 were referred for a suspected solitary nodule, 33 were referred for diffuse or asymmetric goiter, and 26 were referred for multinodular goiter (Table 1). Ultrasonography-guided fine-needle aspiration biopsy was performed on 209 nodules in 156 patients. Sixty-seven patients had no aspirations, 112 had one aspiration, and 44 had two or more aspirations. Table 1. Indication for Referral to the Thyroid Nodule Clinic in 223 Patients Sonographic Findings Ultrasonography revealed solitary nodules in 33% of patients, a multinodular goiter (>1 nodule on ultrasonography) in 50%, and no nodules in 17% (excluding those with a history of thyroid cancer). Ultrasonography findings in the 173 patients referred for abnormal findings on thyroid physical examination are given in Table 2. Table 2. Sonographic Findings in 173 Patients Referred to the Thyroid Nodule Clinic for Abnormal Results on Physical Examination Management of Nodular Thyroid Disease Ultrasonography changed management in 44% (50 of 114) of the patients referred for a solitary nodule on physical examination. In 27 patients, an additional nonpalpable nodule at least 1 cm in diameter was found on ultrasonography and more than one nodule required aspiration. Eighteen patients had no nodules, and 5 patients had only small nodules (<1 cm); therefore, despite the results of the physical examination, no aspiration was required. For the remaining 64 patients referred for a solitary nodule (46 with a solitary nodule 1 cm and 18 with multiple nodules but only one nodule 1 cm), clinical management was not affected because the palpated nodule was the only nodule that was at least 1 cm in diameter on ultrasonography. Among the 33 patients referred for a diffuse or asymmetric goiter, 55% (18 of 33) had one or more nodules at least 1 cm in diameter on ultrasonography, which suggests that the examining physician recognized an abnormality but could not detect a discrete nodule. Among the 26 patients referred for a multinodular goiter, 5 did not require an aspiration based on the ultrasonography findings and 21 required one or more aspirations for discrete nodules at least 1 cm in diameter. In summary, ultrasonography altered clinical management in 109 of the 173 patients (63%) referred for abnormal findings on physical examination. It was needed for guidance of nonpalpable nodules that were at least 1 cm in diameter in 66 patients (27 referred for a solitary nodule with additional nodules 1 cm on ultrasonography, 21 referred for a multinodular goiter, and 18 referred for a diffuse or asymmetric goiter with discrete nodules 1 cm on ultrasonography) and documented no nodules that were at least 1 cm in diameter in 43 patients. In the 48 patients referred for other indications, ultrasonography helped 1) evaluate growth in patients with previous benign cytologic findings, 2) direct sampling of lymph nodes in patients with thyroid cancer, 3) direct sampling of nonpalpable nodules found incidentally on other radiology studies, and 4) screen for nodules in patients with previous exposure to radiation. Cytologic Findings after Fine-Needle Aspiration In the 153 patients with no history of thyroid cancer who had fine-needle aspiration, 130 of the 205 nodules aspirated (63%) were benign. Seven nodules (3%), all confirmed histologically, were positive for papillary cancer. Nine (4%) were suspicious for papillary cancer. Five of these (56%) were histologically confirmed as papillary cancer, and 2 were benign. One patient with 2 suspicious nodules sought a second opinion and was lost to follow-up. Seventeen nodules (8%) were suspicious for follicular or Hrthle cell neoplasm, of which 9 were excised; 1 was a follicular carcinoma and the others were benign. Nine nodules (4%) were characterized as atypical. Of these, 2 were found to be benign after surgery. Thirty-three nodules (16%), of which 13 were more than 50% cystic, had nondiagnostic cytologic characteristics. In 1 patient, surgery for papillary carcinoma in 1 nodule revealed papillary carcinoma in a second nodule whose cytologic characteristics were nondiagnostic. The occurrence of malignancy was similar in patients with solitary nodules and those with multiple nodules. Cancer was found in 4 of 60 patients with solitary nodules (6.7%) and 8 of 90 patients with multiple nodules (8.9%). In 4 of the 12 patients who received a diagnosis of thyroid cancer, the malignant nodule was not palpated by the referring physician. One patient was referred for a solitary palpable nodule, which was benign, but a nonpalpable malignant nodule in the contralateral lobe was detected on ultrasonography. In another patient, who was referred for follow-up of a benign nodule, a second nonpalpable nodule was found to be malignant. The malignant nodule was also nonpalpable in the other 2 patients who had either a multinodular or diffuse goiter on the referring clinicians examination. Fine-needle aspiration biopsies of 4 nonpalpable lymph nodes in the 3 patients with a history of thyroid cancer were all positive for recurrent papillary cancer. Discussion We routinely use ultrasonography and ultrasonography-guided fine-needle aspiration in patients referred to our Thyroid Nodule Clinic for suspected thyroid nodules. Almost half of the patients referred for a solitary nodule on physical examination (a group previously not thought to benefit from ultrasonography) were found to have multiple nodules, and many (27 of 48) required additional aspiration of a nonpalpable nodule. More than 50% of patients (18 of 33) with suspected diffuse or asymmetric goiter had discrete nodules requiring fi

Can Color Doppler Sonography Aid in the Prediction of Malignancy of Thyroid Nodules

Objective. To determine whether color Doppler interrogation of a thyroid nodule can aid in the prediction of malignancy. Methods. We obtained color Doppler images of thyroid nodules undergoing sonographically guided fine‐needle aspiration. The color Doppler appearance of each nodule was graded from 0 for no visible flow through 4 for extensive internal flow. The size, sonographic appearance, results of fine‐needle aspiration, and surgical pathologic findings, if available, were recorded for each nodule. Results. There were 254 nodules sampled, of which 32 were malignant (all confirmed at surgery) and 177 were benign. Fourteen (43.8%) of the 32 malignant nodules were color type 4, compared with only 26 (14.7%) of the 177 benign nodules (P = .0004, Fisher exact test). Thirteen (40.1%) of the 32 malignant nodules were solid, as were 18 (10.2%) of the 177 benign nodules (P = .006, Fisher exact test). Among solid nodules, the prevalence of malignancy was greater when the nodule was hypervascular (13 [41.9%] of 31) than when the color type was less than 4 (11 [14.7%] of 77; P = .004, Fisher exact test). Conclusions. Solid hypervascular thyroid nodules have a high likelihood of malignancy (nearly 42% in our series). The color characteristics of a thyroid nodule, however, cannot be used to exclude malignancy, because 14% of solid nonhypervascular nodules were malignant

Natural History of Benign Solid and Cystic Thyroid Nodules

Context Although benign thyroid nodules are common, we know relatively little about their natural history. Contribution This observational study from a single tertiary care facility used repeated ultrasonography to show that benign thyroid nodules typically increase in volume over a 3- to 5-year period. Solid nodules grew more than cystic nodules, and only 1 of 74 reaspirated nodules was malignant. Implications Nodule growth alone does not predict malignancy. The Editors Thyroid nodules are present in nearly 50% of adults, increasing in prevalence with age (1). The evaluation of thyroid nodules that measure 1 cm or greater in diameter typically includes a screening measure of serum thyroid-stimulating hormone (TSH) levels and fine-needle aspiration (FNA). Most FNA results are benign (90% to 95%), and follow-up examinations are advised. Recommendations include periodic clinical examinations or ultrasonography, with or without suppressive l-thyroxine therapy (1, 2). Nodules that increase in size during follow-up are often regarded as suspicious for malignancy, and repeated FNA or surgery is advised (3-6). Data supporting these recommendations are limited, however, as few reports have evaluated thyroid nodule growth using the most sensitive technique, high-resolution ultrasonography. Furthermore, criteria defining nodule growth are inconsistent; some guidelines use an increase in maximal diameter of greater than 50%, while others suggest an increase in maximal diameter greater than 5 mm or an increase in calculated volume greater than 15% (5-10). We used ultrasonography of thyroid nodules to determine the natural history of cytologically benign thyroid nodules over a 1-month to 5-year follow-up period. Methods We retrospectively reviewed the records of all patients referred to the dual-discipline Thyroid Nodule Clinic at Brigham and Womens Hospital, Boston, Massachusetts, for evaluation of nodular thyroid disease between 1995 and 2000. All patients referred to the clinic underwent ultrasonography of the thyroid by a radiologist and ultrasonography-guided FNA of nodules measuring 1 cm or greater in maximal diameter by an endocrinologist. All ultrasonography evaluations were adequate for review and interpretation. All patients with benign cytology on initial FNA were advised to schedule follow-up ultrasonography 9 to 12 months later. Repeated FNA was performed on the follow-up visit at the discretion of the endocrinologist, usually because of nodule growth. The study sample included all patients with nodules with benign cytologic results on the initial visit who returned for follow-up ultrasonography within the 5-year period. Thyroid ultrasonography was performed by one of three radiologists using a 5- to 15-MHz transducer. The length, width, and depth of each nodule were reported, and each nodule was classified as solid, less than 25% cystic, 25% to 50% cystic, 50% to 75% cystic, or greater than 75% cystic. Nodule volume was calculated by using the formula for a rotational ellipsoid (length width depth /6) (7, 11, 12). Ultrasonography-guided FNA was performed with a 25-gauge needle (three to four aspirations per nodule), and specimens were processed by using the Thin-Prep technique (Cytyc Corp., Boxborough, Massachusetts). All slides were read by a cytopathologist at Brigham and Womens Hospital. Specimens were considered benign when six or more groups of benign follicular cells (each group containing 15 cells) were identified without atypical features. Repeated ultrasonographies were performed, and findings were directly compared with the previous images. Change in nodule size over the interval between examinations was assessed by using three criteria: 1) change in maximal diameter greater than 50% [7, 8, 12, 13]; 2) change in maximal diameter of 3 mm or more; 3) change in calculated volume of 15% or more (11, 14). The latter two criteria are defined by established inaccuracy rates for each method (11, 15). The Investigational Review Board of Brigham and Womens Hospital granted permission to perform this review. Descriptive statistics are presented according to nodule or patient as appropriate. The main outcome for the single-variable and multivariable predictive models was nodule growth, defined as an increase in volume of 15% or greater. Single-variable and multivariable mixed-effects logistic regression was used to predict growth, while accounting for the correlation structure in the data where some patients had more than one nodule (16). Potential predictors were the time between examinations, cystic content (solid, <25% cystic, 25% to 50% cystic, 50% to 75% cystic, or >75% cystic), TSH level (mIU/L), l-thyroxine use, age, and sex. Unadjusted and adjusted odds ratios and 95% CIs were calculated. Time to growth was determined by using life-table methods. Data were analyzed by using SAS software, version 8.2 (SAS Institute, Inc., Cary, North Carolina). The funding sources had no role in the design, conduct, or reporting of the study or the decision to publish the manuscript. Results A total of 1009 patients were examined in the Thyroid Nodule Clinic between 1995 and 2000, and 1358 nodules were biopsied. On initial FNA, 854 nodules (in 700 patients) measured 1 cm or greater in maximal diameter with benign cytologic results. Two hundred sixty-eight patients (38%) with 330 benign thyroid nodules (39%) returned for follow-up ultrasonography, with a mean interval of 20 months (range, 1 to 65 months) between examinations (Appendix Figure). The baseline demographic and ultrasonography characteristics of these 268 patients and their nodules were similar to those of the 432 patients who did not return for follow-up (Table 1). Table 1. Demographic and Ultrasonography Characteristics of Patients with a Benign Thyroid Nodule 1 cm in Maximal Diameter Who Returned for Follow-up Ultrasonography as Recommended Compared with Those Who Did Not Change in nodule size over each patients follow-up period was assessed by three methods to facilitate comparison with previous studies. With use of a greater than 50% change in maximal diameter, 14 nodules (4%) were determined to have increased in size upon repeated ultrasonography. With evaluating change in maximal diameter of 3 mm or greater or change in calculated volume (cm3) of 15% or greater, 86 nodules (26%) and 129 nodules (39%), respectively, were determined to have increased in size on follow-up ultrasonography. The time interval between examinations was significantly correlated with nodule growth (r = 0.22; P < 0.001). Table 2 shows mixed-models logistic regression analysis for prediction of thyroid nodule growth (volume change 15%). Time between examinations and lower cystic content remained statistically significant predictors of growth in the final multivariable model. Each year, the background odds of growth increased by 50%. The estimated median time to achieve volume growth of 15% or greater was 35 months (95% CI, 29 to 41 months). The estimated proportion with growth was 53% (CI, 46% to 61%) at 3 years and 89% (CI, 81% to 97%) at 5 years using life-table methods. The patients age, sex, baseline serum TSH concentration, or l-thyroxine use did not predict nodule growth. Table 2. Single-Variable Predictors and Final Multivariable Model To Predict Thyroid Nodule Growth (Volume Increase 15%) Sixty-one patients underwent repeated FNA at the time of the second ultrasonography. The nodules in this group were larger on initial examination (2.7 cm vs. 2.3 cm; P = 0.001) and had increased in volume by an average of 69% during follow-up compared with 14% in those nodules not rebiopsied (P < 0.001). Patient characteristics were similar except for a longer interval between examinations (28 months vs. 18 months) and younger age (43 years vs. 48 years) noted among the rebiopsied group. One of the 74 repeated FNA samples suggested a follicular neoplasm, and the remainder were benign. The nodule was removed; it was a poorly differentiated papillary carcinoma. It had enlarged from 10.1 cm3 to 18.1 cm3 in volume (an 80% increase) over 38 months. Discussion We used ultrasonography to assess the natural history of 330 benign thyroid nodules measuring 1 cm or more in maximal diameter followed for a mean period of 20 months. Although the 268 patients (with 330 nodules) represent only 39% of the benign nodules seen in the Brigham and Womens Hospital Thyroid Nodule Clinic between 1995 and 2000, they appear to be representative of the whole group with respect to demographic and nodule characteristics. Using the most rigorous criteria ( 15% increase in volume), we documented growth in 39% of benign thyroid nodules during follow-up, which indicates that many such nodules grow. Consistent with our findings, Brander and colleagues (10) found that 35% of benign nodules increased in size over 4.9 to 5.6 years. However, the criteria for growth were not defined, and minimal data on repeated FNA were provided (10). Similarly, Papini and colleagues (15) documented an increase in mean nodule volume among patients in the control group of a 5-year randomized study that assessed the efficacy of l-thyroxine suppression therapy for nodular goiter. Our results also support previous conclusions that more cystic nodules are less likely to grow compared with nodules with a greater solid component (5). Current opinion suggests that increasing nodule size has modest but significant power for predicting thyroid cancer (2). Kuma and colleagues found malignancy in 26% of previously unbiopsied nodules that increased in size over a 10- to 30-year period (5). A follow-up study 2 years later reported a malignancy rate of 4.5% among nodules that were previously found to be benign on FNA and subsequently grew (although no definition of growth was provided) (6). In our study, only 1 of 74 rebiopsied nodules was malignant on repeated FNA biopsy. Although only 22% of nodules seen in follow-up were rebiopsied, this group had s

Clinical outcome for atypia of undetermined significance in thyroid fine-needle aspirations: should repeated fna be the preferred initial approach?

In the Bethesda System for reporting thyroid fine-needle aspirations (FNAs), atypia of undetermined significance (AUS) is a category with limited reported follow-up and outcome data. We report a retrospective analysis of our institutions experience during nearly 4.5 years with a tiered classification scheme conforming to the Bethesda System in which repeated FNA was recommended for most patients with an initial AUS diagnosis. Of 4,691 thyroid FNAs, 512 (10.9%) had a diagnosis of AUS. Cytologic or histologic outcome data were available for 331 cases (64.6%), of which 240 (72.5%) were benign and 91 (27.5%) were malignant. Of patients with a surgical diagnosis, there was no statistically significant difference in malignancy rate among patients who went directly to surgery after a single AUS diagnosis (37/90 [41%]), patients having 2 successive AUS FNA diagnoses (22/51 [43%]), and patients with a benign aspirate after AUS (2/7 [29%]). Although AUS confers an intermediate risk of malignancy, guidelines recommending repeated FNA for most cases should be reevaluated.

The Impact of Noninvasive Follicular Variant of Papillary Thyroid Carcinoma on Rates of Malignancy for Fine-Needle Aspiration Diagnostic Categories

BACKGROUND Increased recognition of the indolent nature of noninvasive follicular variant of papillary thyroid carcinoma (NFVPTC) along with greater insight into the molecular alterations of these tumors has prompted endocrine pathologists to question whether these tumors warrant a diagnosis of carcinoma. However, a change in terminology would affect the rates of malignancy of fine-needle aspiration (FNA) diagnostic categories. Therefore, the aim of this study was to determine the percentage decrease in associated risk of malignancy for each FNA diagnostic category if NFVPTCs were no longer termed carcinomas. METHODS We evaluated a cohort of 655 FNAs with subsequent resection specimens over a 22-month time period. The diagnoses of the preceding FNAs were recorded according to the Bethesda System for Reporting Thyroid Cytopathology. For cases with more than one preceding FNA, the FNA diagnosis associated with the highest risk of malignancy was identified. Slides for all resection specimens with a diagnosis of FVPTC were reviewed to identify noninvasive tumors. By definition, all of these tumors were encapsulated, partially encapsulated, or well circumscribed and lacked any indication of infiltrative growth, capsular penetration, or lymphovascular invasion. RESULTS Our cohort of 655 FNAs with subsequent resection specimens included 53 (8.1%) nondiagnostic (ND), 167 (25.5%) benign, 97 (14.8%) atypia/follicular lesion of undetermined significance (AUS/FLUS), 88 (13.4%) suspicious for follicular neoplasm (SFN), 94 (14.4%) suspicious for malignancy (SUS), and 156 (23.8%) malignant cases (POS). Surgical resections demonstrated benign findings in 309 (47.2%) and malignant tumors in 346 (52.8%), including 85 NFVPTCs accounting for 24.6% of malignancies. Our rates of malignancy for ND, benign, AUS/FLUS, SFN, SUS, and POS were 18.9%, 13.2%, 39.2%, 45.5%, 87.2%, and 98.7%, respectively. If NFVPTC were no longer termed carcinoma, these rates would drop to 17.0% (10% decrease), 5.4% (59% decrease), 21.6% (45% decrease), 37.5% (18% decrease), 45.7% (48% decrease), and 93.6% (5% decrease), respectively. CONCLUSION Our findings demonstrate that if terminology were changed and NFVPTCs were not considered carcinomas, the rates of malignancy for FNA diagnostic categories would be substantially decreased, with the most clinically significant decrease seen in the SUS category, which demonstrated a relative decrease of nearly 50%.

A Standardized Assessment of Thyroid Nodules in Children Confirms Higher Cancer Prevalence Than in Adults

CONTEXT Thyroid cancer is the most common endocrine malignancy, but due to its rare occurrence in the pediatric population, the cancer risk of childhood thyroid nodules is incompletely defined, and optimal management of children with suspected nodules is debated. OBJECTIVE The aim was to study the presenting features and cancer risk of sporadic childhood thyroid nodules using a standardized clinical assessment and management plan. DESIGN AND SETTING Boston Childrens Hospital and Brigham and Womens Hospital collaborated to create a multidisciplinary pediatric thyroid nodule clinic and implement a standardized assessment plan. Upon referral for a suspected nodule, serum TSH was measured and hypothyrotropinemic patients underwent (123)I scintigraphy. All others underwent thyroid ultrasonography, and if this confirmed nodule(s) ≥ 1 cm, ultrasound-guided fine-needle aspiration was performed. Medical records were retrospectively reviewed and compared to a control population of 2582 adults evaluated by identical methods. PATIENTS AND RESULTS Of 300 consecutive children referred for the initial evaluation of suspected thyroid nodules from 1997 to 2011, 17 were diagnosed with autonomous nodules by scintigraphy. Neck ultrasonography performed in the remainder revealed that biopsy was unnecessary in over half, either by documenting only sub-centimeter nodules or showing that no nodule was present. A total of 125 children met criteria for thyroid biopsy, which was performed without complication. Their rate of cancer was 22%, significantly higher than the adult rate of 14% (P = .02). CONCLUSIONS Neck ultrasonography and biopsy were key to the evaluation of children with suspected thyroid nodules. Although the relative cancer prevalence of sonographically confirmed nodules ≥ 1 cm is higher in pediatric patients than adults, most children referred for suspected nodules have benign conditions, and efforts to avoid unnecessary surgery in this majority are warranted.

Thyroid Dysfunction from Antineoplastic Agents

Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated with thyroid dysfunction. These include tyrosine kinase inhibitors, bexarotene, radioiodine-based cancer therapies, denileukin diftitox, alemtuzumab, interferon-α, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide. Primary hypothyroidism is the most common side effect, although thyrotoxicosis and effects on thyroid-stimulating hormone secretion and thyroid hormone metabolism have also been described. Most agents cause thyroid dysfunction in 20%-50% of patients, although some have even higher rates. Despite this, physicians may overlook drug-induced thyroid dysfunction because of the complexity of the clinical picture in the cancer patient. Symptoms of hypothyroidism, such as fatigue, weakness, depression, memory loss, cold intolerance, and cardiovascular effects, may be incorrectly attributed to the primary disease or to the antineoplastic agent. Underdiagnosis of thyroid dysfunction can have important consequences for cancer patient management. At a minimum, the symptoms will adversely affect the patients quality of life. Alternatively, such symptoms can lead to dose reductions of potentially life-saving therapies. Hypothyroidism can also alter the kinetics and clearance of medications, which may lead to undesirable side effects. Thyrotoxicosis can be mistaken for sepsis or a nonendocrinologic drug side effect. In some patients, thyroid disease may indicate a higher likelihood of tumor response to the agent. Both hypothyroidism and thyrotoxicosis are easily diagnosed with inexpensive and specific tests. In many patients, particularly those with hypothyroidism, the treatment is straightforward. We therefore recommend routine testing for thyroid abnormalities in patients receiving these antineoplastic agents.

Thyroid Nodule Size and Prediction of Cancer

CONTEXT Thyroid nodule size is routinely measured, although its impact on thyroid cancer risk is unclear. OBJECTIVE Our objective was to evaluate the association of nodule size upon cancer risk. DESIGN, SETTING, AND PATIENTS We conducted a retrospective cohort analysis at an academic hospital with 4955 consecutive patients evaluated between 1995 and 2009. INTERVENTION Ultrasound and ultrasound-guided fine-needle aspiration of nodules >1 cm was done. Indeterminate and malignant nodules were referred for surgery, and histopathology was reviewed. MAIN OUTCOME MEASURE The presence and histological subtype of cancer was evaluated. RESULTS Of 7348 evaluated nodules, 927 (13%) were cancerous. Of those 1.0 to 1.9 cm in diameter, 10.5% were cancerous. In contrast, of those >2.0 cm, 15% were cancerous (P < .01). However, nodules 2.0 to 2.9, 3.0 to 3.9, and >4 cm were cancerous in 14%, 16%, and 15% of cases (P = .14), respectively, demonstrating no graded increase in risk beyond the 2-cm threshold. When malignant, the proportion of papillary carcinoma decreased (nodules 1.0-1.9 cm, 92% of cases; 2.0-2.9 cm, 88%; 3.0-3.9 cm, 83%; >4 cm, 74% [P < .01]), while follicular carcinoma increased (1.0-1.9 cm, 6%; 2.0-2.9 cm, 7%; 3.0-3.9 cm, 12%; >4 cm, 16% [P < .01]) as nodules enlarged. Nodules size did not influence cytology distribution or risk of false-negative aspirates. CONCLUSIONS Increasing thyroid nodule size impacts cancer risk in a nonlinear fashion. A threshold is detected at 2.0 cm, beyond which cancer risk is unchanged. However, the risk of follicular carcinomas and other rare thyroid malignancies increases as nodules enlarge.