M. Regina Castro

Approach to the patient with nontoxic multinodular goiter.

Thyroid nodules are very common, and although the majority are benign, approximately 5% may harbor malignancy. The evaluation of the patient with solitary thyroid nodule is generally straightforward and will typically include measurement of serum TSH to assess thyroid function and fine-needle aspiration biopsy of the nodule, with or without ultrasound (US) guidance. The approach to the patient with nontoxic multinodular goiter represents a more difficult problem for the clinician. All patients should have serum TSH measured to assess functional thyroid status and US examination to evaluate the number, size, and sonographic features of the nodules and assist in the selection of nodules that may need fine-needle aspiration biopsy. Patients with nodules yielding malignant cytology should be referred for surgery. Given the lack of reliable markers to predict biological behavior of nodules with suspicious (indeterminate) cytology, patients with such nodules are generally advised to have surgery, unless autonomous function of these nodules can be confirmed by scintigraphy. Most of these patients, however, will ultimately prove to have benign follicular tumors. Many patients with benign but large goiters may experience clinical symptoms of pressure, such as dysphagia, choking sensation, or airway obstruction. Such patients will often require surgery for alleviation of symptoms. In the absence of malignancy, asymptomatic patients may be observed. Radioactive iodine, commonly used in many parts of Europe, is safe and effective and may be a reasonable option for many patients. Periodic follow-up with neck palpation and US exam is recommended for all patients.

Predictors of Malignancy in Patients with Cytologically Suspicious Thyroid Nodules

BACKGROUND Fine needle aspiration (FNA), although very reliable for cytologically benign and malignant thyroid nodules, has much lower predictive value in the case of suspicious or indeterminate nodules. We aimed to identify clinical predictors of malignancy in the subset of patients with suspicious FNA cytology. METHODS We reviewed the electronic medical records of 462 patients who had FNA of thyroid nodules at our institution with a suspicious cytological diagnosis, and underwent surgery at Mayo Clinic between January 2004 and September 2008. Demographic data including age, gender, history of exposure to radiation and use of thyroid hormone was collected. The presence of single versus multiple nodules by ultrasonography, nodule size, and serum thyroid-stimulating harmone (TSH) level before thyroid surgery were recorded. Analysis of the latter was limited to patients not taking thyroid hormone or antithyroid drugs at the time of FNA. RESULTS Of the 462 patients, 327 had lesions suspicious for follicular neoplasm (S-FN) or Hürthle cell neoplasm (S-HCN), 125 had cytology suspicious for papillary carcinoma (S-PC) and 10 had a variety of other suspicious lesions (medullary cancer, lymphoma and atypical). Malignancy rate for suspicious neoplastic lesions (FN+HCN) was ∼15%, whereas malignancy rate for lesions S-PC was 77%. Neither age, serum TSH level, or history of radiation exposure were associated with increased malignancy risk. The presence of multiple nodules (41.1% vs. 26.4%, p=0.0014) or smaller nodule size (2.6±1.8 cm vs. 2.9±1.6 cm, p=0.008) was associated with higher malignancy risk. In patients with cytology suspicious for neoplasm (FN, HCN) malignancy risk was higher in those receiving thyroid hormone therapy than in nonthyroid hormone users (37.7% vs. 16.5%, p=0.0004; odds ratio: 3.1), although serum TSH values did not differ significantly between thyroid hormone users and nonusers. CONCLUSION In patients with cytologically suspicious thyroid nodules, the presence of multiple nodules or smaller nodule size was associated with increased risk of malignancy. In addition, our study demonstrates for the first time, an increased risk of malignancy in patients with nodules suspicious for neoplasm who are taking thyroid hormone therapy. The reason for this association is unknown.

Thyroglobulin (Tg) Testing Revisited: Tg Assays, TgAb Assays, and Correlation of Results With Clinical Outcomes.

CONTEXT Measurement of thyroglobulin (Tg) by mass spectrometry (Tg-MS) is emerging as a tool for accurate Tg quantification in patients with anti-Tg autoantibodies (TgAbs). OBJECTIVE The objective of the study was to perform analytical and clinical evaluations of two Tg-MS assays in comparison with immunometric Tg assays (Tg-IAs) and Tg RIAs (Tg-RIAs) in a cohort of thyroid cancer patients. METHODS A total of 589 samples from 495 patients, 243 TgAb-/252 TgAb+, were tested by Beckman, Roche, Siemens-Immulite, and Thermo-Brahms Tg and TgAb assays, two Tg-RIAs, and two Tg-MS assays. RESULTS The frequency of TgAb+ was 58%, 41%, 27%, and 39% for Roche, Beckman, Siemens-Immulite, and Thermo-Brahms, respectively. In TgAb- samples, clinical sensitivities and specificities of 100% and 74%-100%, respectively, were observed across all assays. In TgAb+ samples, all Tg-IAs demonstrated assay-dependent Tg underestimation, ranging from 41% to 86%. In TgAb+ samples, the use of a common cutoff (0.5 ng/mL) for the Tg-MS, three Tg-IAs, and the USC-RIA improved the sensitivity for the Tg-MSs and Tg-RIAs when compared with the Tg-IAs. In up to 20% of TgAb+ cases, Tg-IAs failed to detect Tg that was detectable by Tg-MS. In Tg-RIAs false-high biases were observed in TgAb+ samples containing low Tg concentrations. CONCLUSIONS Tg-IAs remain the method of choice for Tg quantitation in TgAb- patients. In TgAb+ patients with undetectable Tg by immunometric assay, the Tg-MS will detect Tg in up to 20% additional cases. The Tg-RIA will detect Tg in approximately 35% cases, but a significant proportion of these will be clinical false-positive results. The undetectable Tg-MS seen in approximately 40% of TgAb+ cases in patients with disease need further evaluation.

Extending Association Rule Summarization Techniques to Assess Risk of Diabetes Mellitus

Early detection of patients with elevated risk of developing diabetes mellitus is critical to the improved prevention and overall clinical management of these patients. We aim to apply association rule mining to electronic medical records (EMR) to discover sets of risk factors and their corresponding subpopulations that represent patients at particularly high risk of developing diabetes. Given the high dimensionality of EMRs, association rule mining generates a very large set of rules which we need to summarize for easy clinical use. We reviewed four association rule set summarization techniques and conducted a comparative evaluation to provide guidance regarding their applicability, strengths and weaknesses. We proposed extensions to incorporate risk of diabetes into the process of finding an optimal summary. We evaluated these modified techniques on a real-world prediabetic patient cohort. We found that all four methods produced summaries that described subpopulations at high risk of diabetes with each method having its clear strength. For our purpose, our extension to the Buttom-Up Summarization (BUS) algorithm produced the most suitable summary. The subpopulations identified by this summary covered most high-risk patients, had low overlap and were at very high risk of diabetes.

Diagnostic accuracy of thyroid nodule growth to predict malignancy in thyroid nodules with benign cytology: Systematic review and meta-analysis

Thyroid ultrasound to assess for nodular growth is commonly performed during the follow‐up of patients with benign thyroid nodules, with the goal of identifying patients with a missed diagnosis of thyroid cancer. The objective of this study was to summarize the evidence regarding the diagnostic accuracy of growth during follow‐up of benign thyroid nodules for thyroid cancer.

The value of repeat thyroid fine-needle aspiration biopsy in patients with a previously benign result: How often does it alter management?

BACKGROUND Thyroid nodules are prevalent and mostly benign, being present in up to 67% of the population when assessed by ultrasound. Due to the variable diagnostic performance of ultrasound-guided fine-needle aspiration biopsy (USFNA) of the thyroid and the possibility of a false-negative result, current clinical guidelines recommend ultrasonographic follow-up of benign thyroid nodules. The objective of this study was to evaluate the clinical relevance of a repeat fine-needle aspiration (rFNA) in patients with an initial benign fine-needle aspiration biopsy (iFNA). METHODS A retrospective review was conducted of medical records of patients seen at the Mayo Clinic between January of 2003 and December of 2013 who had undergone rFNA of a nodule with benign iFNA. The outcome measured was the result of the rFNA and histopathological correlation, when available. RESULTS Three hundred and thirty-four nodules with benign iFNA underwent rFNA during the 10-year study period. The rFNA was most commonly reported as benign (85.3%), followed by suspicious (7.2%), nondiagnostic (5.7%), and malignant (1.8%). The rFNA changed clinical management in 9.5% of the cases. The prevalence of thyroid malignancy ranged from 4.1% to 1.2% based on the gold standard used (histology vs. long-term follow-up, 4.0 ± 2.3 years). CONCLUSION In the majority of patients with a benign iFNA, results of the rFNA were unchanged. However, in a small group of patients, the rFNA may differ from the initial results, and alter management. Even so, the prevalence of malignancy remains very low, ranging from 1.2% to 4.1% depending on the gold standard.

An online survey of hypothyroid patients demonstrates prominent dissatisfaction

BACKGROUND Approximately 15% more patients taking levothyroxine (LT4) report impaired quality of life compared to controls. This could be explained by additional diagnoses independently affecting quality of life and complicating assignment of causation. This study sought to investigate the underpinnings of reduced quality of life in hypothyroid patients and to provide data for discussion at a symposium addressing hypothyroidism. METHODS An online survey for hypothyroid patients was posted on the American Thyroid Association Web site and forwarded to multiple groups. Respondents were asked to rank satisfaction with their treatment for hypothyroidism and their treating physician. They also ranked their perception regarding physician knowledge about hypothyroidism treatments, need for new treatments, and life impact of hypothyroidism on a scale of 1-10. Respondents reported the therapy they were taking, categorized as LT4, LT4 and liothyronine (LT4 + LT3), or desiccated thyroid extract (DTE). They also reported sex, age, cause of hypothyroidism, duration of treatment, additional diagnoses, and prevalence of symptoms. RESULTS A total of 12,146 individuals completed the survey. The overall degree of satisfaction was 5 (interquartile range [IQR] = 3-8). Among respondents without self-reported depression, stressors, or medical conditions (n = 3670), individuals taking DTE reported a higher median treatment satisfaction of 7 (IQR = 5-9) compared to other treatments. At the same time, the LT4 treatment group exhibited the lowest satisfaction of 5 (IQR = 3-7), and for the LT4 + LT3 treatment group, satisfaction was 6 (IQR = 3-8). Respondents taking DTE were also less likely to report problems with weight management, fatigue/energy levels, mood, and memory compared to those taking LT4 or LT4 + LT3. CONCLUSIONS A subset of patients with hypothyroidism are not satisfied with their current therapy or their physicians. Higher satisfaction with both treatment and physicians is reported by those patients on DTE. While the study design does not provide a mechanistic explanation for this observation, future studies should investigate whether preference for DTE is related to triiodothyronine levels or other unidentified causes.

Outcomes of Radiofrequency Ablation Therapy for Large Benign Thyroid Nodules: A Mayo Clinic Case Series

Objective: To assess the effectiveness, tolerability, and complications of radiofrequency ablation (RFA) in patients with benign large thyroid nodules (TNs). Patients and Methods: This is a retrospective review of 14 patients with predominantly solid TNs treated with RFA at Mayo Clinic in Rochester, Minnesota, from December 1, 2013, through October 30, 2016. All the patients declined surgery or were poor surgical candidates. The TNs were benign on fine‐needle aspiration, enlarging or causing compressive symptoms, and 3 cm or larger in largest diameter. We evaluated TN volume, compressive symptoms, cosmetic concerns, and thyroid function. Results: Median TN volume reduction induced by RFA was 44.6% (interquartile range [IQR], 42.1%‐59.3%), from 24.2 mL (IQR, 17.7‐42.5 mL) to 14.4 mL (IQR, 7.1‐19.2 mL) (P<.001). Median follow‐up was 8.6 months (IQR, 3.9‐13.9 months). Maximum results were achieved by 6 months. Radiofrequency ablation did not affect thyroid function. In 1 patient with subclinical hyperthyroidism due to toxic adenoma, thyroid function normalized 4 months after ablation of the toxic nodule. Compressive symptoms resolved in 8 of 12 patients (67%) and improved in the other 4 (33%). Cosmetic concerns improved in all 8 patients. The procedure had no sustained complications. Conclusion: In this population, RFA of benign large TNs performed similarly to the reports from Europe and Asia. It induces a substantial volume reduction of predominantly solid TNs, improves compressive symptoms and cosmetic concerns, and does not affect normal thyroid function. Radiofrequency ablation has an acceptable safety profile and should be considered as a low‐risk alternative to conventional treatment of symptomatic benign TNs.

Ethanol Ablation for the Treatment of Cystic and Predominantly Cystic Thyroid Nodules

Objective: To determine the efficacy and safety of percutaneous ethanol injection (PEI) for the treatment of symptomatic cystic thyroid nodules. Patients and Methods: Retrospective analysis of patients with benign cystic thyroid nodules treated with PEI from February 1, 2000, through October 31, 2016. The main outcomes were efficacy, defined as symptom relief or reduction in nodule volume of 50% or more, and safety, defined as no or minor adverse events. Results: Twenty patients had PEI. Mean age at the time of PEI was 50 years, and 13 (65%) were women; all patients were euthyroid. Twelve patients (60%) had complex cystic thyroid nodules (>50% cystic component), with the rest being purely cystic. The median largest diameter of the thyroid cyst was 4.5 cm (interquartile range [IQR], 3.2‐5.3 cm; range, 2.3‐8.0 cm); the median volume pre‐PEI was 19.6 mL (IQR, 10.4‐48.5 mL; range, 2.8‐118.1 mL). The median amount of cystic fluid drained before PEI was 13.5 mL (IQR, 6.8‐32.3 mL), and the median amount of ethanol administered was 3 mL (IQR, 2‐5 mL; range, 0.5‐20 mL). After median follow‐up of 2 years, 17 of 19 patients (89%) were asymptomatic. Of 10 patients with available imaging on follow‐up, 7 (70%) had a 50% or greater reduction in nodule volume (median volume decrease, 75.64% [IQR, 41.40%‐91.99%]). Adverse effects occurred in 4 patients (20%) and were mild and temporary (slight pain, vagal reaction, and bleeding into the cyst). Conclusion: Percutaneous ethanol injection seems to be a safe and effective alternative to surgical resection for patients with purely or predominantly cystic thyroid nodules and compressive symptoms who decline surgery or are not good surgical candidates.

Physical exam in asymptomatic people drivers the detection of thyroid nodules undergoing ultrasound guided fine needle aspiration biopsy

Understanding epidemiology and the factors leading to thyroid nodule diagnosis might help alter the course of the thyroid cancer epidemic. Population-based study using the Rochester Epidemiology Project database between 2003 and 2006. Patients with thyroid nodules who underwent ultrasound guided fine needle aspiration biopsy were included. We identified 453 patients with 520 thyroid nodules undergoing ultrasound guided fine needle aspiration. Patients were mostly women (n: 349, 77 %) with a mean age of 52 (standard deviation 17) years. The age-adjusted and sex-adjusted incidence of ultrasound guided fine needle aspiration-thyroid nodules between 2003 and 2006 was 89 (95 % confidence interval, 80–97) per 100,000 person-years; the incidence in women was 130 (95 % confidence interval, 117–144), and for men 43 (95 % confidence interval, 35–52) per 100,000 person-years. The incidence of ultrasound guided fine needle aspiration-thyroid nodules increased by 42 %, from 68 (95 % confidence interval, 54–82) in 2003 to 97 (95 % confidence interval, 80–113) per 100,000 person-years in 2006. The group with the highest incidence was patients between 70 and 79 years of age, 258 per 100,000 person-years. Most ultrasound guided fine needle aspiration-thyroid nodules were found in asymptomatic patients (n: 371, 82 %) by physical examination (n: 197, 43 %) or on imaging studies performed for non-thyroid issues (n: 108, 24 %). Women were more likely to have nodules detected by palpation (45 %), whereas imaging and physical examination contributed similarly in men (39 and 38 %). There is a large and rapid increase in the ultrasound guided fine needle aspiration-thyroid nodules, particularly among women and elderly patients which mirrors the trends observed in thyroid cancer. Most thyroid nodules were found in asymptomatic patients as a result of routine physical examination or imaging.