Is it Worth Suppressing Tsh in low- and Intermediate-Risk Papillary Thyroid Cancer Patients Before the First Disease Assessment?

Objective: Guidelines recommend thyroid-stimulating hormone (TSH) suppression before the first response to treatment assessment in papillary thyroid cancer (PTC) patients. The aim of this study was to assess the rate of structural disease (SD) in low- and intermediate-risk PTC patients according to TSH levels measured 1 year after primary treatment.Methods: A consecutive, prospective series of low- and intermediate-risk PTC patients with 3-years follow-up was collected. TSH, thyroglobulin (Tg), antithyroglobulin antibodies (TgAb), and neck ultrasonography (US) 1 and 3 years after primary treatment were analyzed. Recurrence risk and disease status at 1 year were defined according to the American Thyroid Association (ATA) guidelines and as the presence or absence of SD after 3 years. Patients were grouped according to TSH level at 1 year: group 1, TSH <0.1 μUI/mL; group 2, TSH 0.1 to 0.5 μUI/mL; group 3, 0.5 to 2 μUI/mL; and group 4 >2 μUI/mL.Results: This study included 263 patients (70.9% female, median age 47.2 years) of whom the risk of recurrence was low in 170 (65%), intermediate-low in 63 (24%), and intermediate-high in 30 (11%). The response to initial treatment at 1 year was excellent in 149 (57%), biochemical incomplete in 18 (7%), indeterminate in 84 (32%), and structural incomplete in 12 (4%). Group 1 consisted of 53 (20%) patients, group 2 of 85 (32%), group 3 of 61 (23%), and group 4 of 64 (24%). The rate of SD at 1 and 3 years from primary treatment was not significantly different between TSH groups.Conclusion: TSH suppression before the first response to treatment assessment does not appear to influence the rate of SD evaluated 1 and 3 years after primary treatment.Abbreviations: ATA = American Thyroid Association; DTC = differentiated thyroid cancer; FTC = follicular thyroid cancer; LT4 = levothyroxine; PTC = papillary thyroid cancer; SD = structural disease; Tg = thyroglobulin; TgAb = antithyroglobulin antibodies; TSH = thyroid-stimulating hormone; US = ultrasonography     

Implementing Key Changes in The American Thyroid Association 2015 Thyroid Nodules/Differentiated Thyroid Cancer Guidelines Across Practice Types

Objective: This article provides suggestions to help clinicians implement important changes in the 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Carcinoma (“ATA 2015”) across diverse settings.Methods: Key ATA 2015 changes are summarized regarding: (1) thyroid nodule management; (2) lobectomy versus thyroidectomy for differentiated thyroid carcinoma (DTC); and (3) surveillance following primary treatment of DTC. Advice to facilitate implementation is based on clinical experience and selected literature.Results: Strategies are described to enhance acquisition of high-quality information that helps identify patients who may possibly avoid fine-needle aspiration (FNA) of thyroid nodules or total thyroidectomy for DTC, or undergo less intense postoperative surveillance. Sonographic imaging of nodules may improve if sonograms are obtained by clinicians ordering or performing FNA or trusted high-volume sonographers. Cytopathologic assessment and reporting can be improved by working with regional or national experts. Pre-operative evaluation by endocrinologists is important so that patients are referred to experienced, proficient surgeons and assisted with well-informed decision-making regarding surgical radicality. Endocrinologists and surgeons should ensure performance of pre-operative neck ultrasonography, voice/laryngeal evaluation, and contrast-enhanced cross-sectional imaging when appropriate. Findings should be disseminated to all healthcare team members, ideally through a comprehensive medical record accessible to the entire team.Conclusion: Optimization of the sequence of specialist visits and assembly of interactive multidisciplinary teams coupled with intensified interdisciplinary and patient communication may enable clinicians to more effectively implement ATA 2015, which calls for more individualized, and often, less “invasive” management of thyroid nodules and DTC.Abbreviations: ATA 2009 = 2009 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Carcinoma; ATA 2015 = 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Carcinoma; DTC = differentiated thyroid carcinoma; FNA = fine-needle aspiration; PET/CT = positron emission tomography/computed tomography     

Can Age at Diagnosis and Sex Improve the Performance of the American Thyroid Association Risk Stratification System for Prediction of Structural Persistent and Recurrent Disease in Patients With Differentiated Thyroid Carcinoma? A Multicenter Study

ObjectiveAlthough the age at diagnosis has been suggested as a major determinant of disease-specific survival in the recent TNM staging system, it is not included in the recent American Thyroid Association (ATA) guidelines to estimate the risk of recurrence. Nevertheless, the effect of sex on differentiated thyroid carcinoma (DTC) recurrence is controversial. Therefore, this multicenter study was conducted to assess whether age at diagnosis and sex can improve the performance of the ATA 3-tiered risk stratification system in patients with DTC with at least 5 years of follow-up.MethodsIn this study, the computer-recorded data of the patients diagnosed with DTC between January 1985 and January 2016 were analyzed. Only patients with proven structural persistent/recurrent disease were selected for comparisons.ResultsThis study consisted of 1691 patients (female, 1367) with DTC. In Kaplan-Meier analysis, disease-free survival (DFS) was markedly longer in females only in the ATA low-risk category (P = .045). Nevertheless, a markedly longer DFS was observed in patients aged <45 years in the ATA low- and intermediate-risk categories (P = .004 and P = .009, respectively), whereas in patients aged <55 years, DFS was markedly longer only in the ATA low-risk category (P < .001). In the Cox proportional hazards model, ages of ≥45 and ≥55 years at diagnosis and the ATA risk stratification system were all independent predictors of persistent/recurrent disease.ConclusionApplying the age cutoff of 45 years in the ATA intermediate- and low-risk categories may identify patients at a higher risk of persistence/recurrence and may improve the performance of the ATA risk stratification system, whereas sex may improve the performance of only the ATA low-risk category.     

Prognostic Value of Lymph Node Uptake on Pretreatment F-18 FDG PET/CT in Patients with N1B Papillary Thyroid Carcinoma

Objective: The aim of this study was to investigate the prognostic value of metabolic characteristics of metastatic lymph node (LN) using pretreatment F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for patients with papillary thyroid carcinoma (PTC) and metastatic lateral LN (N1b).Methods: Ninety-six PTC patients (female:male = 72:24; median age, 44.5 years) with pathologic N1b who underwent pretreatment FDG PET/CT, total thyroidectomy, and radioactive iodine ablation were retrospectively reviewed. To predict responses to initial therapy and recurrence, clinicopathologic factors and metabolic parameters were reviewed, such as sex, age, tumor size, extranodal extension, number and ratio of metastatic LNs, serum thyroglobulin, and maximum standardized uptake value (SUVmax).Results: Among the 96 PTC patients, 81 (84.4%) were classified into the acceptable response (58 excellent; 23 indeterminate) and 15 (15.6%) into the incomplete response (8 biochemical incomplete; 7 structural incomplete) by the 2015 American Thyroid Association management guideline for differentiated thyroid carcinoma. The multivariate analysis showed that SUVmax of N1b (P = .018), pre-ablation stimulated thyroglobulin level (P = .006), and the ratio of metastatic LNs (P = .018) were related to incomplete response. The cutoff value of each variable was determined by receiver operating characteristic analysis. Nine (9.4%) patients experienced recurrences (median follow-up: 50 months). The Kaplan-Meier analysis revealed that SUVmax of N1b (cutoff value: 2.3; P = .025) and ratio of metastatic LNs (cutoff value: 0.218; P = .037) were significant prognostic factors for recurrence.Conclusion: High SUVmax of N1b cervical LN on pretreatment FDG PET/CT could predict incomplete responses to initial therapy and recurrence in patients with N1b PTC.Abbreviations: ATA = American Thyroid Association; DTC = well-differentiated thyroid carcinoma; FDG = F-18 fluorodeoxyglucose; IQR = interquartile range; LN = lymph node; N1b = metastatic lateral cervical lymph node; PET/CT = positron emission tomography/computed tomography; PTC = papillary thyroid carcinoma; RAI = radioactive iodine; ROC = receiver operating characteristic; SUVmax = maximum standardized uptake value; Tg = thyroglobulin; USG = ultrasonography     

Additional Surgery for Occult Risk Factors After Lobectomy in Solitary Thyroid Nodules is Predicted by Cytopathology Classification and Tumor Size

Objective: Clinical practice for differentiated thyroid cancer is moving towards lobectomy rather than total thyroidectomy in patients at low risk of recurrence. However, recurrence risk assessment depends on post-operative findings, while the surgical decision is based on preoperative factors. We determined the preoperative predictors of occult higher-risk pathology and rates of completion thyroidectomy among surgical candidates with nonbenign thyroid nodules 10 to 40 mm and no evidence of extrathyroidal extension or metastasis on preoperative evaluation.Methods: Thyroid surgery cases at a single institution from 2005–2015 were reviewed to identify those meeting American Thyroid Association (ATA) criteria for lobectomy. ATA-based risk stratification from postoperative surgical pathology was compared to preoperative cytopathology, ultrasound, and clinical findings.Results: Of 1,995 thyroid surgeries performed for nonbenign thyroid nodules 10 to 40 mm, 349 met ATA criteria for lobectomy. Occult high-risk features such as tall cell variant, gross extrathyroidal invasion, or vascular invasion were found in 36 cases (10.7%), while intraoperative lymphadenopathy led to surgical upstaging in 13 (3.7%). Intermediate risk features such as moderate lymphadenopathy or minimal extrathyroidal extension were present in an additional 44 cases. Occult risk features were present twice as often in Bethesda class 6 cases (35%) as in lower categories (12 to 17%). In multivariable analysis, Bethesda class and nodule size, but not age, race, sex, or ultrasound features, were significant predictors of occult higher-risk pathology.Conclusion: Most solitary thyroid nodules less than 4 cm and with cytology findings including atypia of undetermined significance through suspicious for papillary thyroid cancer would be sufficiently treated by lobectomy.Abbreviations: ATA = American Thyroid Association; CND = central neck dissection; DTC = differentiated thyroid cancer; ETE = extrathyroidal extension; FNA = fine needle aspiration; FTC/HCC = follicular thyroid carcinoma/Hurthle cell carcinoma; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; OR = odds ratio; PTC = papillary thyroid cancer; US = ultrasound     

Can the American Thyroid Association,K-Tirads,and Acr-Tirads Ultrasound Classification Systems Be Used to Predict Malignancy in Bethesda Category IV Nodules?

Objective: Management of thyroid nodules with Bethesda category III and IV cytology on fine needle aspiration (FNA) is challenging as they cannot be adequately classified as benign or malignant. Ultrasound (US) patterns have demonstrated the utility in evaluating the risk of malignancy (ROM) of Bethesda category III nodules. This study aims to evaluate the value of 3 well-established US grading systems (American Thyroid Association &lsqb;ATA], Korean Thyroid Imaging Reporting and Data System &lsqb;Korean-TIRADS], and The American College of Radiology Thyroid Imaging Reporting and Data System &lsqb;ACR-TIRADS]) in determining ROM in Bethesda category IV nodules.Methods: Ninety-two patients with 92 surgically resected thyroid nodules who had Bethesda category IV cytology on FNA were identified. Nodule images were retrospectively graded using the 3 systems in a blinded manner. Associations between US risk category and malignant pathology for each system were analyzed.Results: Of the 92 nodules, 56 (61%) were benign and 36 (39%) were malignant. Forty-seven per cent of ATA high risk nodules, 53% of K-TIRADS category 5 nodules, and 50% of ACR-TIRADS category 5 nodules were malignant. The ATA high-risk category had 25% sensitivity, 82% specificity, 47% positive predictive value (PPV) for malignancy. K-TIRADS category 5 had 25% sensitivity, 85% specificity, 53% PPV for malignancy. ACR-TIRADS category 5 had 25% sensitivity, 84% specificity, 50% PPV for malignancy. None of the 3 grading systems yielded a statistically significant correlation between US risk category and the ROM (P = .30, .72, .28).Conclusion: The ATA, Korean-TIRADS, and ACR-TIRADS classification systems are not helpful in stratifying ROM in patients with Bethesda category IV nodules. Clinicians should be cautious of using ultra-sound alone when deciding between therapeutic options for patients with Bethesda category IV thyroid nodules.     

Using the Ata and Acr Ti-Rads Sonographic Classifications as Adjunctive Predictors of Malignancy for Indeterminate Thyroid Nodules

Objective: Thyroid nodules with indeterminate cytology pose management challenges in clinical practice. The aim of this study was to determine the efficacy of ultrasound features in navigating clinical decision making in thyroid nodules with indeterminate cytology.Methods: We retrospectively reviewed ultrasound imaging from 186 adult patients with thyroid nodules and indeterminate cytology who underwent thyroidectomy at a quaternary hospital from 2010–2017. All nodules were classified based on the American Thyroid Association (ATA) and 2017 American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS). Nodules were included if good quality pre-operative ultrasound imaging and surgical pathology were available.Results: A total of 202 thyroid nodules were included. The median age was 57 years; 82.8% were female. Risk of malignancy (ROM) in resected nodules with Bethesda 3 and 4 cytology was 19.4% and 30.3%, respectively. ATA high-suspicious and TI-RADS 5 nodules had high ROM, 100% in both systems for Bethesda 3 nodules; 66.7% and 50.0%, respectively, for Bethesda 4 nodules. For ATA very-low suspicious/TI-RADS 1 and 2, ROM was 0%. ROM in ATA low-suspicious/TI-RADS 3 nodules with Bethesda 3 cytology was lower (15.2% and 16.0%, respectively) than Bethesda 4 cytology (33.8% and 34.3%, respectively). ATA intermediate-suspicious/TI-RADS 4 nodules with Bethesda 4 cytology had a lower ROM (11.1% and 18.2%, respectively) than Bethesda 3 cytology (28.6 % and 31.6%, respectively).Conclusion: Using either the ATA or the TI-RADS system to risk-stratify nodules with indeterminate cytology may help clinicians plan better for additional diagnostic testing and treatment.Abbreviations: ACR = American College of Radiology; ATA = American Thyroid Association; AUS = atypia of undetermined significance; FLUS = follicular lesion of undetermined significance; FN = follicular neoplasm; PPV = positive predictive value; ROM = risk of malignancy; SFN = suspicious for follicular neoplasm; TI-RADS = Thyroid Imaging Reporting and Data System     

Comparison of Diagnostic Performance between the American College of Radiology Thyroid Imaging Reporting and Data System and American Thyroid Association Guidelines: A Systematic Review

Objective: We aimed to compare the diagnostic accuracy of the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) with the American Thyroid Association (ATA) guidelines in risk stratification of thyroid nodules.Methods: We performed a computerized search of Medline, EMBASE, Web of Science, Cochrane Library, and Google Scholar to identify eligible articles published before July 31, 2019. We included studies providing head-to-head comparison between ACR TI-RADS and ATA guidelines, with fine-needle aspiration biopsy cytology results or pathology results as the reference standard. Quality assessment of included studies was conducted using the Quality Assessment of Diagnostic Accuracy Studies–2 tool. Summary estimates of sensitivity and specificity were calculated by bivariate modeling and hierarchical summary receiver operating characteristic modeling. We also performed multiple subgroup analyses and meta-regression.Results: Twelve original articles with 13,000 patients were included, involving a total of 14,867 thyroid nodules. The pooled sensitivity of ACR TI-RADS and ATA guidelines was 0.84 (95% confidence interval [CI], 0.76–0.89) and 0.89 (95% CI, 0.80–0.95), with specificity of 0.67 (95% CI, 0.56–0.76) and 0.46 (95% CI, 0.29–0.63), respectively. There were no significant differences between the two classification criteria in terms of both sensitivity (P = .26) and specificity (P = .05). For five studies providing direct comparison of ACR TI-RADS, ATA guidelines, and Korean TI-RADS, our analyses showed that the Korean TI-RADS yielded the highest sensitivity (0.89; 95% CI, 0.82–0.94), but at the cost of a significant decline in specificity (0.23; 95% CI, 0.17–0.30).Conclusion: Both classification criteria demonstrated favorable sensitivity and moderate specificity in the stratification of thyroid nodules. However, use of ACR TI-RADS could avoid a large number of biopsies at the cost of only a slight decrease in sensitivity.Abbreviations: ACR = American College of Radiology; ATA = American Thyroid Association; FNAB = fine-needle aspiration biopsy; HSROC = hierarchical summary receiver operating characteristic; SROC = summary receiver operating characteristic; TI-RADS = Thyroid Imaging Reporting and Data System; US = ultrasonography     

Utility of Afirma Gene Expression Classifier for Evaluation of Indeterminate Thyroid Nodules and Correlation with Ultrasound Risk Assessment: Single Institutional Experience

Objective: We assessed our experience with Afirma gene expression classifier (GEC) combined with sono-graphic risk assessment, using both the American Thyroid Association (ATA) and the Thyroid Imaging Reporting and Data System (TI-RADS) in evaluating indeterminate thyroid nodules.Methods: We identified 98 patients with 101 nodules who had a second fine needle aspiration biopsy (FNA) between January 1, 2014, and September 30, 2017, and sent to Veracyte for cytopathology and subsequent Afirma GEC testing. A second FNA biopsy was performed if the initial cytopathology was either Bethesda III or IV (n = 94) or nondiagnostic (n = 7). We correlated cytopathology, histopathology, and Afirma GEC results with sonographic risk assessment using both the ATA system and TI-RADS.Results: The mean age of the cohort was 57.4 ± 12.3 years; 84% women and 60% white. Repeat FNA was benign in 51 of 101 nodules, and of the remaining 50 nodules, 18 (36%) were GEC-benign and 32 (64%) GEC-suspicious. Eighteen of the 32 GEC-suspicious nodules underwent surgery with the following results: 7 benign (39%), 1 follicular thyroid carcinoma (6%), 6 follicular variant of papillary thyroid cancer (33%), and 4 noninvasive follicular tumor with papillary-like nuclear features (22%). The malignancy rate among the surgical cohort was 39% (without noninvasive follicular tumor with papillary-like nuclear features [NIFTP]) and 61% (with NIFTP) and about 50% and 20% of this group scored in the high suspicion category by ATA and TR5 by TI-RADS, respectively.Conclusion: Afirma GEC was useful in avoiding surgery in one-third of indeterminate nodules and performed similarly to ATA and TI-RADS. However, the use of echogenicity in scoring may underestimate the risk of malignancy in patients with indeterminate nodules.Abbreviations:ATA = American Thyroid Association; AUS = Atypia of Undetermined Significance; FLUS = Follicular Lesion of Undetermined Significance; FN = follicular neoplasm; FNA = fine needle aspiration; FTC = follicular thyroid cancer; FVPTC = follicular variant of papillary thyroid cancer; GEC = Gene Expression Classifier; ND = nondiagnostic; NIFTP = noninvasive follicular tumor with papillary-like nuclear features; TI-RADS = Thyroid Imaging Reporting and Data System; TR = TI-RADS     

Management of Patients With Low-Risk Papillary Thyroid Carcinoma

ObjectiveTo define a rational, cost-effective, simple approach to managing most patients with papillary thyroid cancer (PTC) who are at low-risk of either cause-specific mortality or tumor recurrence.MethodsTaking advantage of the collective experience of a cohort of 2512 patients with PTC who had initial definitive treatment at the Mayo Clinic in Rochester, Minnesota, between 1940 and 2000, a 5-step approach to the management of low-risk PTC has been devised. This program is based on appropriate preoperative ultrasound localization of neck disease and potentially curative surgery consisting of near-total or total thyroidectomy, with appropriate neck nodal exploration and resection.ResultsThe emphasis of the present program is on the extent of initial surgery, where optimal care is ascribed to a near-total thyroidectomy with curative intent and appropriate neck nodal resection as predicated by appropriate preoperative ultrasonography evaluation of regional lymph nodes. Radioiodine remnant ablation (RRA) is not applicable to patients with PTC who are defined on the day of definitive initial surgery to be at low risk as defined by a metastasis, age, completeness of resection, invasion, and size (MACIS) score of less than 6.ConclusionThe outlook for patients with low-risk PTC is very optimistic, with rates at 30 postoperative years of only 1% for cause-specific mortality and less than 15% for tumor recurrence at any site. The long-term results obtained by potentially curative bilateral resection, appropriate regional lymph nodal excision, and selective use of RRA are excellent. Realistically improving these acceptably low rates for cause-specific mortality and tumor recurrence may be difficult. (Endocr Pract. 2007;13:521-533)     

Prognosis of High-Risk Papillary Thyroid Cancer Patients with Pre-Ablation Stimulated TG <1 NG/ML

Objective: The prevalence of undetectable pre-ablation stimulated thyroglobulin (s-Tg) and its clinical implications in high-risk papillary thyroid cancer (PTC) patients remain poorly described. We investigated the rate of tumor recurrence in PTC patients initially classified as high risk but with pre-ablation s-Tg <1 ng/mL and negative anti-Tg antibody (TgAb).Methods: In order to have a follow-up period of at least 5 years for each patient, PTC patients consecutively seen at our department from May 2008 to June 2013 with the following characteristics were selected: (i) classified as American Thyroid Association high risk on the basis of tumor histopathologic features; (ii) submitted to adjuvant ¹³¹I therapy after total thyroidectomy; (iii) a postoperative pre-ablation s-Tg <1 ng/mL and negative TgAb.Results: Among 767 high-risk PTC patients submitted to adjuvant ¹³¹I therapy, 69 patients met the inclusion criteria. Sixty-seven patients (97.1%) were diagnosed as classical PTC, and the remaining 2 patients (2.9%) were diagnosed as follicular variant PTC. When evaluated 9 to 12 months after ¹³¹I therapy, 67 patients (97.1%) were classified as excellent response. Two (2.9%) patients had an s-Tg >1 ng/mL (<3 ng/mL) in the absence of apparent disease, as detected by imaging methods (indeterminate response). During a median follow-up duration of 5.6 years, recurrence was observed in only 2 (2.9%) patients. The 67 (97.1%) patients without tumor recurrence were not submitted to any additional therapy, and all had a suppressed Tg <1 ng/mL in the last assessment.Conclusion: High-risk PTC patients with pre-ablation s-Tg <1 ng/mL and negative TgAb had a favorable prognosis.Abbreviations: CT = computed tomography; L-T4 = levothyroxine; PTC = papillary thyroid cancer; SPECT/CT = single photon emission computed tomography/computed tomography; s-Tg = stimulated thyroglobulin; T4 = thyroxine; TgAb = anti-thyroglobulin antibody; US = ultrasound     

Sonographic Features Of Multifocal Papillary Thyroid Carcinomas

Objective: It is uncertain whether papillary thyroid carcinomas (PTCs) of the same subtype display similar sonographic features. This retrospective analysis of pre-operative sonographic and pathologic findings aimed to assess whether PTCs of the same subtype share sonographic features.Methods: Before undergoing thyroid surgery, 137 patients underwent ultrasound (US) examination. A single radiologist used a picture archiving and communication system and pathologic reports to investigate all sonographic features of the largest and second largest PTCs. Additionally, the radiologist evaluated the similarity of sonographic features between primary (largest), secondary (second largest), and daughter (secondary with same subtype as the primary) PTCs.Results: Of the 137 PTC patients, 48 (35.0%) had multiple PTCs; however, 5 had no US images of the secondary PTC. Of the 43 secondary PTCs with US images, 9 (20.9%) secondary PTCs were of a different subtype than the primary PTC and revealed sonographic features that differed from those of the primary PTC. Of the 48 patients with multiple PTCs, the subtype was the same in the primary and secondary PTCs in 34 (70.8%) patients. Of the 34 daughter PTCs, 32 (94.1%) had sonographic features similar to those of the primary PTC, whereas 2 (5.9%) showed different sonographic features than the primary PTC. There was no significant difference between primary and daughter PTCs in the size, location, sonographic features, or Korean Thyroid Imaging Reporting and Data System category (P>.05).Conclusion: Daughter PTCs show similar sonographic features as the primary PTC.Abbreviations: K-TIRADS = Korean Thyroid Imaging Reporting and Data System; PTC = papillary thyroid carcinoma; US = ultrasound     

Management of Low-Risk Differentiated Thyroid Cancer

ObjectiveTo summarize the definitions of and management recommendations for low-risk thyroid cancer made by the American and European Thyroid Associations and synthesize this information with the recent literature, including systematic evaluations of tumor staging systems guiding therapy.MethodsThe American Thyroid Association and European Thyroid Association guidelines were compared and pertinent literature since 2005 was reviewed.ResultsOf papillary thyroid microcarcinomas (PTMC), up to 50% breach the thyroid capsule, 64% have lymph node metastases, up to 43% are multifocal, and as many as 2.8% have distant metastases. Locoregional and distant recurrences are, respectively, as high as 5.9% and 1.5%. As many as 1 in 4 patients with a papillary thyroid carcinoma 1.5 cm or smaller develop persistent disease. Cancer-related mortality rates are usually less than 1%, but are as high as 2% in some reports. Tumor staging systems are too inaccurate to guide therapy.ConclusionIt is unlikely that many patients will forgo treatment after understanding their risk, especially when total thyroidectomy and radioiodine (¹³¹I) therapy can reduce the PTMC recurrence or persistence disease rate to zero. Preoperatively diagnosed PTMC should be treated with total or near-total thyroidectomy, regardless of tumor size. For very low-risk patients with unifocal PTMC smaller than 1 cm that is removed by chance during surgery to treat benign thyroid disease, lobectomy alone without ¹³¹I therapy may be sufficient therapy if there are no concerning histologic features and no tumor extension beyond the thyroid, metastases, history of head and neck irradiation, or positive family history—any of which requires total or near-total thyroidectomy and remnant ablation with 30 mCi. (Endocr Pract. 2007;13:498-512)     

A Direct Comparison of the Ata and Ti-Rads Ultrasound Scoring Systems

Objective: This study compares the American Thyroid Association (ATA) classification system with the 2017 American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) for predicting cancer risk in thyroid nodules.Methods: This is a retrospective review of ultrasound imaging of all adult patients with thyroid nodules >5 mm who underwent thyroidectomy at a tertiary care hospital in 2016. We assessed the ability of either system to predict malignancy based on surgical histopathology. Sensitivity, specificity, negative predictive values (NPV) and positive predictive values (PPV), and area-under-the-curve (AUC) were calculated and compared using McNemar's, Fisher exact, or DeLong's tests.Results: Three hundred and twenty-three nodules from 213 adults were included. Median patient age was 55 years; 75.6% were female. 27.2% nodules were malignant. Both ATA and ACR TI-RADS provide effective diagnostic performance, a sensitivity of 77.3% versus 78.4%, respectively, a specificity of 76.6% versus 73.2%, respectively, a PPV of 55.3% versus 52.3%, respectively, and a NPV of 90% for both. The level of agreement between the two classification systems was almost perfect (weighted Kappa statistic = 0.93, AUC 0.77 ATA versus 0.76 TI-RADS &lsqb;P = .18]). However, of the 40 (TI-RADS level 3) TR3 nodules (<2.5 cm), 10% were malignant, and of the 31 (TI-RADS level 4) TR4 nodules (<1.5 cm), 38% were malignant.Conclusion: The ATA and TI-RADS classification systems appear to have similar diagnostic value for predicting thyroid cancer. However, subanalysis of TR3 and TR4 nodules with consideration of size criteria showed that there is a higher risk of missing a malignancy if the ACR TI-RADS recommendation is followed. These results should be validated in a different patient cohort with a lower incidence of cancer.Abbreviations: ACR = American College of Radiology; ATA = American Thyroid Association; FNA = Fine Needle Aspiration; κ = weighted Kappa statistic; NPV = negative predictive values; PPV = positive predictive values; TI-RADS = Thyroid Imaging Reporting and Data System; TR1 = TI-RADS level 1; TR2 = TI-RADS level 2; TR3 = TI-RADS level 3; TR4 = TI-RADS level 4; TR5 = TI-RADS level 5     

An Italian Survey of Compliance With Major Guidelines for L-Thyroxine of Primary Hypothyroidism

Objective: The adherence by endocrinologists to guideline regarding levothyroxine (LT4) therapy and the compliance of patients may impact the management of hypothyroidism. The aim of this study was to compare the adherence of Italian endocrinologists to the ATA/AACE and ETA guidelines on the management of newly diagnosed primary hypothyroidism and to validate the Italian version of the Morisky-Green Medical Adherence Scale-8 (MMAS-8) questionnaire as applied to the evaluation of the adherence of patients with hypothyroidism to LT4 treatment.Methods: This was an observational, longitudinal, multicenter, cohort study, involving 12 Italian Units of Endocrinology.Results: The study enrolled 1,039 consecutive outpatients (mean age 48 years; 855 women, 184 men). The concordance of Italian endocrinologists with American Association of Clinical Endocrinologists/American Thyroid Association (AACE/ATA) and European Thyroid Association (ETA) recommendations was comparable (77.1% and 71.7%) and increased (86.7 and 88.6%) after the recommendations on LT4 dose were excluded, considering only the remaining recommendations on diagnosis, therapy, and follow-up. The MMAS-8 was filled out by 293 patients. The mean score was 6.71 with 23.9% low (score <6), 38.6% medium (6 to <8), 37.5% highly (= 8) adherers; the internal validation coefficient was 0.613. Highly adherent patients were not more likely to have good control of hypothyroidism compared with either medium (69% versus 72%, P = .878) or low (69% versus 43%, P = .861) adherers.Conclusion: Clinical management of hypothyroidism in Italy demonstrated an observance of international guidelines by Italian endocrinologists. Validation of the Italian version of the MMAS-8 questionnaire provides clinicians with a reliable and simple tool for assessing the adherence of patients to LT4 treatment.Abbreviations: AACE = American Association of Clinical Endocrinologists; ATA = American Thyroid Association; EDIPO = Endotrial SIE: DIagnosis and clinical management of Primitive hypothyrOidism in Italy; eCRF = electronic case report form; ETA = European Thyroid Association; fT3 = free triiodothyronine; fT4 = free thyroxine; LT4 = levothyroxine; MMAS-8 = Morisky-Green Medical Adherence Scale-8; PH = primary hypothyroidism; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; US = ultrasonography     

Guideline Implementation on Fine-Needle Aspiration for Thyroid Nodules: Focusing on Micronodules

Objective: We investigated patients who were referred to our institution after fine-needle aspiration (FNA) was performed at outside clinics to evaluate how many nodules satisfied the FNA indications of the Korean Thyroid Imaging Reporting and Data System (K-TIRADS) and compare that to the number of thyroid nodules that satisfy the FNA indications of the American College of Radiology (ACR)-TIRADS and American Thyroid Association (ATA) guidelines.Methods: Between January 2018 and December 2018, 2,628 patients were included in our study. The included patients were those referred for thyroid surgery after having a suspicious thyroid nodule. We retrospectively applied the three guidelines to each thyroid nodule and determined whether each nodule satisfied the FNA indications. We compared the proportion of nodules satisfying the FNA indications of each guideline using a generalized linear model and generalized estimating equation.Results: The median size of the 2,628 thyroid nodules was 0.9 cm (range, 0.2 to 9.5 cm). We found that FNA was not indicated for 54.1%, 47.7%, and 19.1% of nodules and 87.3%, 99.0%, and 97.8% among them were micronodules (<1 cm) according to the ACR-TIRADS, ATA guideline, and K-TIRADS, respectively. The proportion of micronodules which satisfied the FNA indications was significantly higher for the K-TIRADS (65.1%) compared to the ACR TIRADS (12.1%) and ATA guideline (12.1%) (P<.001).Conclusion: Among patients referred for thyroid surgery to our institutions, about 35% of the micronodules underwent FNA despite not being appropriate for indications by the K-TIRADS. Systematic training for physicians as well as modifications to increase the sensitivity of the guideline may be needed to reduce the overdiagnosis of thyroid cancers, especially for micronodules.     

Practical Barriers to Implementation of Thyroid Cancer Guidelines in the Asia-Pacific Region

Objective: Numerous published guidelines have described the optimal management of thyroid cancer. However, these rely on the clinical availability of diagnostic and therapeutic modalities. We hypothesized that the availability of medical resources and economic circumstances vary in Asia-Pacific countries, making it difficult to implement guideline recommendations into clinical practice.Methods: We surveyed participants at the 2009 and 2013 Congresses of the Association of Southeast Asian Nations Federation of Endocrine Societies by distributing questionnaires to attendees at registration.Results: Responses were obtained from 268 respondents in 2009 and 163 respondents in 2013. Similar to the high prevalence of low-risk thyroid cancer observed in the Surveillance, Epidemiology, and End Results database, across the Asia-Pacific countries surveyed in 2009 and 2013, 50 to 100% of the respondents from the Philippines, Malaysia, Singapore, China, Taiwan, Thailand, Hong Kong, Korea, and Sri Lanka reported that more than 50% of the patients had low-risk thyroid cancer on follow-up. Importantly, there was much variation with regards to the perceived availability of investigation and treatment modalities.Conclusion: We found a wide variation in clinicians' perception of availability of diagnostic and therapeutic modalities in the face of a rise in thyroid cancer incidence and thyroid cancer management guidelines that emphasized their importance. The lack of availability of management tools and treatments will prove to be a major barrier to the implementation of thyroid cancer management guidelines in Southeast Asia, and likely in other parts of the world as well.Abbreviations: AFES = ASEAN Federation of Endocrine Societies ASEAN = Association of Southeast Asian Nations ATA = American Thyroid Association FNA = fine-needle aspiration PET = positron emission tomography RAI = radioactive iodine Tg = thyroglobulin TSH = thyroid-stimulating hormone     

Drivers of the Decision to Biopsy and Follow-Up of Small Suspicious Thyroid Nodules

Objective: In 2015, the updated American Thyroid Association (ATA) guidelines recommended observation for suspicious subcentimeter thyroid nodules, based on their indolent course. We aimed to evaluate the frequency of biopsy in suspicious thyroid nodules since the introduction of these guidelines, including factors contributing to clinical decision-making in a tertiary care center.Methods: We conducted a retrospective study of patients in the Mayo Clinic, Rochester, Minnesota, with new, subcentimeter suspicious thyroid nodules (by report or by sonographic features) between March, 2015, and November, 2017, not previously biopsied.Results: We identified 141 nodules in 129 patients: mean age 58.1 ± 14.1 years, 74% female, 87% Caucasian. The frequency of biopsy in suspicious thyroid nodules was 39%. Ultrasound features that were the strongest predictors for biopsy on multivariate analysis included: nodule volume (odds ratio [OR] 37.3 [7.5–188.7]), radiology recommendation for biopsy (OR 2.6 [1.8–3.9]) and radiology report of the nodule as “suspicious” (OR 2.1 [1.4–3.2]). Patient’s age and degree of comorbidities did not change the likelihood for biopsy, nor did it vary by clinician type or how the nodule was initially found (incidentally or not incidentally). Among 86 nodules that were not biopsied, 41% had no specific follow-up recommendations.Conclusion: One third of suspicious thyroid nodules underwent biopsy since the release of updated ATA guidelines. Factors driving thyroid biopsy seem to be associated with nodule characteristics but not with patient factors including age and comorbidities. Further studies and development of decision aides may be helpful in providing individualized approaches for suspicious thyroid nodules.Abbreviations: ATA = American Thyroid Association; OR = odds ratio     

Unfavorable Responses to Radioiodine Therapy in N1b Papillary Thyroid Cancer: A Propensity Score Matching Study

Objective: Regional nodal metastases carry prognostic significance in papillary thyroid cancer (PTC). However, whether different locational nodal metastases correlate with different therapeutic responses remains controversial. We innovatively applied the response to therapy restratification system to evaluate the dynamic disease status after surgery and radioactive iodine (RAI) therapy in PTC patients with different locational nodal metastases.Methods: A total of 585 nondistant-metastatic PTC patients who underwent total thyroidectomy and RAI therapy were retrospectively enrolled. Patients with nodal metastases were categorized into N1a and N1b groups. Propensity score matching was used to balance the bias between the 2 groups. Therapeutic responses were dynamically evaluated, and responses to RAI therapy were classified into excellent (ER), indeterminate (IDR), biochemical incomplete (BIR) and structural incomplete response (SIR).Results: N1b group patients showed a significantly higher pre-ablation stimulated thyroglobulin (Ps-Tg) level than N1a group patients (7.4 ng/mL versus 3.2ng/mL, P<.001). After RAI therapy, N1b group patients took a longer time to achieve ER (9.86 months versus 3.29 months, P<.001) and exhibited a higher proportion of non-ER (IDR, BIR, and SIR) (39.15% versus 17.46%, P<.001) compared to N1a group patients. In logistic regression, N1b and Ps-Tg ≥10 ng/mL were confirmed to be independent factors predicting non-ER (odds ratio: 2.591, and 9.196, respectively). In Cox regression, patients with N1b disease and Ps-Tg ≥10 ng/mL showed significantly lower hazards for achieving ER (hazard ratio: 0.564, and 0.223, respectively).Conclusion: N1b PTC patients showed inferior responses to surgery and RAI therapy compared to N1a patients. N1b was confirmed to be an independent factor predicting unfavorable responses to RAI therapy.Abbreviations: AJCC = American Joint Committee on Cancer; ATA = American Thyroid Association; BIR = biochemical incomplete response; BRAF^V600E = proto-oncogene B-Raf V600E mutation; CI = confidence interval; CT = computed tomography; DNA = deoxyribonucleic acid; DTC = differentiated thyroid cancer; ER = excellent response; ETE = extrathyroidal extension; HR = hazard ratio; IDR = indeterminate response; LNM = lymph node metastasis; N1a = central cervical LNM; N1b = lateral cervical LNM; OR = odds ratio; PSM = propensity score matching; Ps-Tg = pre-ablation stimulated thyroglobulin; PTC = papillary thyroid cancer; RAI = radioactive iodine; SIR = structural incomplete response; Tg = thyroglobulin; TgAb = thyroglobulin antibody; TSH = thyroid-stimulating hormone     

Size of the Largest Metastatic Focus to the Lymph Node is Associated with Incomplete Response of Pn1 Papillary Thyroid Carcinoma

Objective: To evaluate the influence of the size of the metastatic focus in lymph nodes (LNs) on therapeutic response among papillary thyroid cancer (PTC) and cervical pathologically proven LN metastases (pN1).Methods: Patients with pN1 PTC who underwent total or near-total thyroidectomy, LN dissection, and postoperative radioactive iodine therapy in a university hospital between 2014 and 2016 were retrospectively reviewed. Furthermore, 554 patients were assigned to three groups according to the size of the metastatic focus in the LNs (≤0.2 cm, 0.2 to 1.0 cm, ≥1.0 cm). Structural incomplete response (SIR) was defined as structural or functional evidence of disease with any thyroglobulin level and/or anti-thyroglobulin antibodies.Results: Among the 554 patients, the proportion of patients with SIR was 2.5% (4/161) in group 1, 13.9% (37/267) in group 2, and 46.8% (59/126) in group 3 (χ² = 100.073; P<.001). The optimal cutoff value of the size of the largest metastatic focus to the LNs was 0.536 cm to predict SIR with a corresponding sensitivity of 0.82, a specificity of 0.716, and an area under the curve of 0.821 (95% confidence interval &lsqb;CI], 0.777 to 0.864; P<.001). Size of the largest metastatic focus to the LNs was confirmed to be an independent predictive factor for SIR (odds ratio, 9.650; 95% CI, 4.925 to 18.909; P<.001).Conclusion: In patients with pN1 PTC, there is an association between the size of the largest metastatic focus to the LNs and incomplete response.Abbreviations: AJCC = American Joint Committee on Cancer; ATA = American Thyroid Association; BIR = biochemical incomplete response; CI = confidence interval; ER = excellent response; ETE = extranodal extension; 18F-FDG = 18F-fluorodeoxyglucose; IDR = indeterminate response; LN = lymph node; OR = odds ratio; PET/CT = positron emission tomography/computed tomography; pN1 = pathologically proven LN metastases; PTC = papillary thyroid carcinoma; RAI = radioactive iodine; ROC = receiver operating characteristic; SIR = structural incomplete response; sTg = stimulated thyroglobulin; TgAb = anti-thyroglobulin antibody; TSH = thyroid-stimulating hormone