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Context Predictive models of thyroid nodule cancer risk are presently based upon nodule composition, echogenicity, margins, and the presence of microcalcifications. Nodule shape has shown promise to be an additive factor helping determine the need for nodule biopsy. Objective We sought to determine if calculation of a nodule’s spherical shape independently associates with cancer risk. Methods This prospective cohort study, conducted at a single large academic healthcare system in the United States, included patients with 1 or 2 clinically relevant thyroid nodules (predominantly solid and over 1 cm) presenting for diagnostic evaluation. Thyroid ultrasound, cytological evaluation with fine-needle biopsy, and/or histopathological examination on occasion of thyroid surgery were performed. We calculated the nodule’s long to short ratio (spherical shape), and its association with tissue proven benign or malignant endpoints. Results The long to short nodule ratio was significantly lower in malignant compared to benign nodules indicating greater risk of malignancy in more spherical nodules (1.63 ± 0.38 for malignant nodules vs 1.74 ± 0.47 for benign, P 2.00, 14.6% cancer; ratio 1.51-2.00, 19.7%; ratio 1.00-1.50, 25.5%, P Conclusion The more a thyroid nodule is spherically shaped, as indicated by a long to short ratio approaching 1.0, the greater its risk of malignancy. This was independent of age, sex, and nodule size. Incorporating a nodule’s sphericity in the risk stratification systems may improve individualized clinical decision making.

Supplementary Table S2. Clinical response and outcomes to everolimus in patients with advanced differentiated thyroid cancers by histologic subgroup

Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer. We evaluated the efficacy of everolimus in aggressive, radioactive iodine–refractory (RAIR) thyroid cancer and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic thyroid cancer cohorts were included.Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009 to 2013 in patients with incurable RAIR thyroid cancer who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis.Results: Thirty-three patients with differentiated thyroid cancer (DTC), 10 with medullary thyroid cancer (MTC), and 7 with anaplastic thyroid cancer (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3–18.5) with a 2-year PFS of 23.6% (95% CI, 10.5–39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8–85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months after study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt–mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated.Conclusions: Everolimus has significant antitumor activity in thyroid cancer. While genomic profiling does not currently guide therapeutic selection in thyroid cancer patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine. Clin Cancer Res; 24(7); 1546–53. ©2018 AACR.

Comparison of minor allele frequencies between additional oncogenic mutations and BRAFV600E.

Purpose:The extent to which routine genomic sequencing can identify relevant secondary genomic alterations among BRAFV600E-mutant papillary thyroid carcinoma (PTC) is unknown. Such markers would prove highly valuable for prognostic purposes.Experimental Design:We reviewed clinicopathologic data of 225 patients with BRAFV600E-mutant PTC and integrated them with genomic data derived from targeted next-generation sequencing (NGS) on tumor specimens. We defined patient subgroups based on bona fide secondary oncogenic events (separate from BRAFV600E) and compared their clinical features and outcomes with those without additional oncogenic alterations.Results:Additional oncogenic alterations were identified in 16% of tumors. Patients in the “BRAF+additional mutations” group were more likely to be at high American Thyroid Association (ATA) risk of recurrence (48.6% vs. 17.6%; P = 0.0009), had larger baseline tumor (2.7 vs. 1.9 cm; P = 0.0005) and more advanced stage at presentation (14.3% vs. 1.1% stage 4; P < 0.0001). Importantly, over a 65-month follow-up, disease-specific mortality (DSM) was increased when additional mutations were identified (13.8% vs. 1.4% in the BRAF-only group; P = 0.005). Separately, we identified a subcluster of patients harboring oncogenic mutations in key effectors of the PI3K/AKT/mTOR pathway, which were independently associated with DSM (OR = 47.9; 95% confidence interval, 3.5–1,246.5; P = 0.0043).Conclusions:Identification of additional PIK3/AKT/mTOR alterations in patients with BRAFV600E-mutant PTC provides important and actionable prognostic risk stratification. These data support genomic profiling of PTC tumors to inform prognosis and clinical strategy.

Comparison of clinical and pathological features of thyroid cancer patients with BRAF mutations only versus BRAF plus additional mutations.

Purpose: The extent to which routine genomic sequencing can identify relevant secondary genomic alterations among BRAFV600E-mutant papillary thyroid carcinoma (PTC) is unknown. Such markers would prove highly valuable for prognostic purposes. Experimental Design: We reviewed clinicopathologic data of 225 patients with BRAFV600E-mutant PTC and integrated them with genomic data derived from targeted next-generation sequencing (NGS) on tumor specimens. We defined patient subgroups based on bona fide secondary oncogenic events (separate from BRAFV600E) and compared their clinical features and outcomes with those without additional oncogenic alterations. Results: Additional oncogenic alterations were identified in 16% of tumors. Patients in the “BRAF+additional mutations” group were more likely to be at high American Thyroid Association (ATA) risk of recurrence (48.6% vs. 17.6%; P = 0.0009), had larger baseline tumor (2.7 vs. 1.9 cm; P = 0.0005) and more advanced stage at presentation (14.3% vs. 1.1% stage 4; P < 0.0001). Importantly, over a 65-month follow-up, disease-specific mortality (DSM) was increased when additional mutations were identified (13.8% vs. 1.4% in the BRAF-only group; P = 0.005). Separately, we identified a subcluster of patients harboring oncogenic mutations in key effectors of the PI3K/AKT/mTOR pathway, which were independently associated with DSM (OR = 47.9; 95% confidence interval, 3.5–1,246.5; P = 0.0043). Conclusions: Identification of additional PIK3/AKT/mTOR alterations in patients with BRAFV600E-mutant PTC provides important and actionable prognostic risk stratification. These data support genomic profiling of PTC tumors to inform prognosis and clinical strategy.

The 2015 American Thyroid Association (ATA) guidelines recommended that low-risk, differentiated thyroid cancers (DTC) between 1 and 4 cm may be treated with thyroid lobectomy alone. We sought to determine the effect of these guideline changes on the rate of completion thyroidectomy (CT) for low-risk DTC and factors influencing surgical decision-making. All patients from 2014 to 2018 who received an initial thyroid lobectomy at our institution with final pathology demonstrating DTC were included. Patients were divided into “pre” and “post” guideline cohorts (2014–2015 and 2016–2018, respectively). The rate of CT was compared between the two cohorts. Patient demographics and tumor characteristics were examined for association with CT. A total of 163 patients met study criteria: 63 patients in the 2014–2015 (“pre”) and 100 in the 2016–2018 (“post”) group. In the “pre” period, 41 (65.1%) patients received CT compared with 43 (43.0%) in the “post” period (p

Although prior studies have reported that patients with anaplastic thyroid carcinoma (ATC) with a focal anaplastic component may have a prolonged survival compared to other ATC patients, the outcome data are limited. We evaluated a cohort of ATC resected between 2003 and 2018. Tumor slides were reviewed to confirm the diagnosis and to identify cases with a minor ATC component (defined as comprising < 10% of the tumor). We evaluated the clinical outcome of these patients compared to that of all other cohort patients (characterized as having conventional ATC). Our cohort was composed of 24 cases of ATC that underwent resection, including 8 (33%) with a minor ATC component. Tumors with a minor ATC component were predominantly associated with papillary thyroid carcinoma. For patients with tumors with a minor ATC component, the 1-year and 2-year survival rates and median survival for patients who died of disease were 88%, 43%, and 17 months (range 6-73 months), respectively. In comparison, for patients with conventional ATC, the 1-year and 2-year survival rates and median survival for patients who died of disease were 56%, 44%, and 7 months (range 2-26 months), respectively. There was no difference in 1- and 2-year survival or overall survival by Kaplan-Meier analysis for patients with tumors with a minor ATC component and those with conventional ATC. In conclusion, the difference in overall survival between ATC groups in our cohort was not significant; however, this could be due to the small cohort size or due to characteristics of our group with a minor ATC component; that is, no tumors in this group were limited to the thyroid (stage IVA), resectability with negative margins was infrequent, and 38% of this group had distant metastases at diagnosis (stage IVC).

AIMS Hobnail variant of papillary thyroid carcinoma (PTC) is an aggressive PTC subtype characterised by a hobnail cytomorphology. However, some classic PTC have a 'hobnail-like' cytomorphology associated with thick, hyalinised, variably oedematous fibrovascular cores that appears to be a form of ischaemic/degenerative atypia. METHODS AND RESULTS We studied three cohorts to compare the histopathological characteristics and clinical outcome of 'hobnail-like' classic PTC and true hobnail variant of PTC: cohort 1, PTC consecutively resected between 2016 and 2017 (to assess frequency of 'hobnail-like' cytomorphology); cohort 2, 20 'hobnail-like' classic PTC resected between 2005 and 2007 (to assess clinical outcome); and cohort 3, seven true hobnail variant of PTC. A 'hobnail-like' cytomorphology was identified in 16% of consecutively resected PTC. Compared with true hobnail variant, 'hobnail-like' classic PTC occurred in younger patients (mean age 40 years versus 68 years, P

Objective To investigate the concordance of serologic and sonographic evidence of Hashimoto’s thyroiditis with its gold standard histopathologic identification. Design We performed a retrospective analysis on a cohort of 825 consecutive patients in whom TPOAb and thyroid ultrasound were performed, and in whom thyroid nodule evaluation led to surgical and histopathologic analysis. The presence or absence of Hashimoto’s thyroiditis on histopathology was correlated with serologic and sonographic markers. We further assessed the impact of low versus high titers of TPOAb upon this concordance. Results Of 825 patients, 277 (33.5%) had histologic confirmation of Hashimoto’s thyroiditis, 235 patients (28.4%) had elevated serum levels of TPOAb, and 197 (23.8%) had sonographic evidence of diffuse heterogeneity. Of those with histopathologic evidence, only 64% had elevated TPOAb (sensitivity: 63.9%; specificity: 89.4%), while only 49% were sonographically diffusely heterogeneous (sensitivity: 49.1%; specificity: 88.9%). A subset of only 102 of 277 (37%) with histologically proven Hashimoto’s thyroiditis was positive for both TPOAb and diffusely heterogeneous. Concordance analysis demonstrated that TPOAb and histopathology had higher agreement (κ = 0.55) than did ultrasound and histopathology (κ = 0.40) for the diagnosis of Hashimoto’s thyroiditis. Higher titers of TPOAb correlated with a higher likelihood of Hashimoto’s thyroiditis, with a best cutoff of 2.11-fold the upper normal level of TPOAb. Conclusion Only moderate concordance exists between serological evidence of Hashimoto’s thyroiditis and histopathologic findings, though it increases with higher TPOAb concentration. Diffuse heterogeneity on ultrasound is a less-sensitive diagnostic tool than elevated TPOAb.

Graves' disease (GD) is caused by the stimulation of thyrotropin receptors by autoantibodies. We compared the diagnostic accuracy of the thyroid-stimulating immunoglobulin (TSI) bioassay and thyrotropin-binding inhibitory immunoglobulin (TBII) assay in differentiating GD from other causes of thyrotoxicosis.We retrospectively evaluated 493 patients with thyrotoxicosis who were tested with the third-generation TSI and TBII assays simultaneously. Patients were classified according to the clinical, histopathologic, and imaging criteria into the following groups: positive reference group (PRG) (patients with GD), negative reference group (NRG) (patients without GD), and inconclusive group (patients without a definitive diagnosis).TSI and TBII assays were concordant in 88% of the cases and showed a strong positive correlation (rTSI and TBII assays showed similar performance in differentiating GD from other causes of thyrotoxicosis in a real-world sample of patients with active thyrotoxicosis. In combination, both tests showed little benefit compared with the TBII assay alone. Thyrotropin receptor antibody assay results should be carefully interpreted in patients with mild GD or longstanding disease.

Patient: Female, 62-year-old Final Diagnosis: Medullary thyroid microcarcinoma Symptoms: No pain or swelling in her neck • no dysphagia or odynophagia • no changes in voice Medication: — Clinical Procedure: Genetic analysis Specialty: Genetics Objective: Unusual clinical course Background: RET p.V804M is a known activating oncogenic variant that confers an increased risk for medullary thyroid carcinoma (MTC). Based on age-specific penetrance, the American Thyroid Association (ATA) categorizes this variant as posing moderate risk. Therefore, ATA guidelines endorse prophylactic thyroidectomy for carriers in childhood (by age 5–10 years) or adulthood, or when the serum calcitonin level becomes elevated. The recommendation for thyroidectomy is increasingly controversial due to the recently reported low penetrance of the RET p.V804M variant in a large unbiased ascertainment cohort. Case Report: We describe the unexpected identification of this variant in a 62-year-old woman undergoing broad, multigene cancer panel testing for her personal and family history of breast cancer. There was no known family history of MTC. Biochemical screening prompted by the RET p.V804M result revealed a mildly elevated serum calcitonin. Pathology examination of her thyroidectomy specimen revealed multifocal medullary thyroid microcarcinoma; her sibling’s prophylactic thyroidectomy after a RET p.V840M-positive result similarly revealed early-stage MTC. Conclusions: This report demonstrates the value of genetic counseling, shared decision-making, cascade testing, and timely thyroidectomy in the management of a patient with an unexpected RET p.V804M result.

Background: Similar to poorly differentiated thyroid carcinoma (PDTC), papillary thyroid carcinoma with high-grade features (PTC HGF) demonstrates increased mitotic activity and/or necrosis; howeve...

Context Proteinuria can cause or exacerbate hypothyroidism, possibly due to urinary loss of protein-bound thyroid hormone. However, the precise relationship between proteinuria and hypothyroidism remains unclear. Objective This work aimed to determine the prevalence of hypothyroidism in patients with proteinuria and the relationship between hypothyroidism and degree of proteinuria. Design A retrospective cohort study was conducted from December 1979 to March 2015. Setting This study was conducted at a large academic hospital. Patients All paired samples of urine protein and serum thyrotropin (TSH), measured within 24 hours, were obtained from adults (age > 18 years) with at least one instance of urine protein greater than 0.2 g/day or mg/mg creatinine. Main Outcome Measures Samples were stratified by urine protein tertile. Mean TSH and risk of TSH elevation were compared among tertiles using analysis of covariance and generalized estimating equations controlled for age, sex, samples per patient, and levothyroxine treatment. Results A total of 2676 samples were identified from 2136 patients. Mean ± SE TSH (mIU/L) was increased in the highest tertile of urine protein (> 1.75g/day) compared to the lower 2 tertiles (2.09 ± 0.07 vs 1.59 ± 0.07, 1.59 ± 0.06, P 3.5g/day) to those with lesser proteinuria. Conclusion Hypothyroidism is common among adults with proteinuria, and the risk of hypothyroidism is directly related to the severity of proteinuria.

Context The impact of Hashimoto thyroiditis (HT) on the risk of thyroid cancer and its accurate detection remains unclear. The presence of a chronic lymphocytic infiltration imparts a logical mechanism potentially altering neoplastic transformation, while also influencing the accuracy of diagnostic evaluation. Methods We performed a prospective, cohort analysis of 9851 consecutive patients with 21,397 nodules ≥1 cm who underwent nodule evaluation between 1995 and 2017. The definition of HT included (i) elevated thyroid peroxidase antibody (TPOAb) level and/or (ii) findings of diffuse heterogeneity on ultrasound, and/or (iii) the finding of diffuse lymphocytic thyroiditis on histopathology. The impact of HT on the distribution of cytology and, ultimately, on malignancy risk was determined. Results A total of 2651 patients (27%) were diagnosed with HT, and 3895 HT nodules and 10,168 non-HT nodules were biopsied. The prevalence of indeterminate and malignant cytology was higher in the HT vs non-HT group (indeterminate: 26.3% vs 21.8%, respectively, P < 0.001; malignant: 10.0% vs 6.4%, respectively, P < 0.001). Ultimately, the risk of any nodule proving malignant was significantly elevated in the setting of HT (relative risk, 1.6; 95% CI, 1.44 to 1.79; P < 0.001), and was maintained when patients with solitary or multiple nodules were analyzed separately (HT vs non-HT: 24.5% vs 16.3% solitary; 22.1% vs 15.4% multinodular; P < 0.01). Conclusion HT increases the risk of thyroid malignancy in any patient presenting for nodule evaluation. Diffuse sonographic heterogeneity and/or TPOAb positivity should be used for risk assessment at time of evaluation.

The morphologic criteria for tall cell variant (TCV) of papillary thyroid carcinoma (PTC) were modified in the 2017 WHO Classification of Tumors of Endocrine Organs, with a decrease in the requirements for both the height of cells and in the percentage of tumor demonstrating a tall cell morphology. The aim of this study was to determine if the change in criteria would result in a significant increase in the percentage of tumors that meet criteria for TCV. In addition, we evaluated the correlation between morphology, molecular alterations, and clinical behavior of TCV. We studied three cohorts to evaluate the above stated questions. The first cohort was comprised of 97 PTC consecutively resected over a 12-month period that were originally diagnosed as classic PTC, PTC with tall cell features, or TCV. Tumor slides of each case were reviewed to determine the percentage of the tall cell component ( 30%, 30-49%, and 50%) and the height of the cells in this component. This cohort was evaluated to determine if the change in WHO criteria would result in a significant increase in the percentage of tumors that meet criteria for TCV. Our second cohort consisted of nine consecutively resected PTC with a tall cell component 30% (with tall cells defined as at least 2-3× as tall as wide) that had molecular characterization through a targeted, next-generation sequencing (NGS) assay. The molecular characteristics were correlated with the percentage of the tall cell component. Finally, a third cohort comprised of seven clinically aggressive TCV (defined as those with T4 disease, disease recurrence, or subsequent tumor dedifferentiation) was evaluated to determine histologic and molecular characteristics. In cohort 1, the number of cases classified as TCV increased significantly with the change in definition of TCV: 8 (8%) cases met the previous criteria for TCV (cells 3× as tall as wide in 50% of the tumor), whereas 24 (25%) cases met the new 2017 WHO criteria (cells 2-3× as tall as wide in 30% of the tumor) (p = 0.0020). Molecular analysis of cohort 2 revealed that all 9 cases harbored a BRAF V600E mutation. Pathogenic secondary mutations were absent in cases with 50% tall cells, but they were detected in 2 (33%) of 6 cases with 50% tall cells (2 cases with TERT promoter mutations, including 1 that also had an AKT2 mutation). Histologic and molecular analysis of the clinically aggressive cohort (cohort 3), revealed that all cases had 50% tall cells and 3 (43%) had secondary oncogenic mutations (all TERT promoter mutations). We found that the modified morphologic criteria put forth in the 2017 WHO tripled the number of cases that would be classified as TCV. Moreover, clinically aggressive tumors and those harboring secondary oncogenic mutations all had a tall cell component 50%. Additional large multi-institutional studies incorporating clinical outcome and molecular data would be valuable to determine the best histologic definition of TCV.

Thyrotropin (TSH) receptor antibody (TRAb) testing is considered accurate for the diagnosis of Graves disease (GD) and has been identified rarely in thyrotoxic patients without GD. We describe 4 patients with transient thyrotoxicosis and positive TRAb to highlight this clinical possibility.Patient demographics, symptoms, laboratory findings, and time to resolution of thyrotoxicosis are summarized. TRAb testing was performed by either a third-generation thyrotropin-binding inhibitory immunoglobulin (TBII) competitive-binding assay or a thyroid-stimulating immunoglobulin (TSI) bioassay from either Mayo Clinic Laboratory or Quest Diagnostics.Four patients with transient thyrotoxicosis and positive TRAb testing were identified. Of these, three were female, and the median age was 44 years (range, 25 to 49 years). Median symptom duration at evaluation was 6.5 weeks (range, 3 to 12 weeks). No patient had any clinical manifestations unique to GD or exposure to biotin, thyroid hormone, supplements, iodine, or relevant medications. The TSH was0.1 mIU/L in all patients. Three patients had a positive TSI, which was elevated less than twice the upper limit of the reference range in all cases, and 1 patient had a strongly positive TBII. None of the patients were treated with thionamides or radioactive iodine. Spontaneous resolution occurred in all patients at a median of 5.5 weeks (range, 2 to 14.4 weeks).These cases demonstrate that TSI or TBII may be present in thyrotoxic patients with transient thyrotoxicosis. For clinically stable patients presenting without pathognomonic evidence of GD, mildly elevated TRAb results may require cautious interpretation, and alterative diagnostic testing or close monitoring should be considered.cAMP = cyclic adenosine monophosphate; FT4 = free thyroxine; GD = Graves disease; TBII = thyrotropin-binding inhibitory immunoglobulin (also known as TBI); TRAb = thyrotropin receptor antibody; TSH = thyrotropin; TSHR = thyrotropin receptor; TSI = thyroid-stimulating immunoglobulin; TT3 = total triiodothyronine; TT4 = total thyroxine.

Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer. We evaluated the efficacy of everolimus in aggressive, radioactive iodine–refractory (RAIR) thyroid cancer and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic thyroid cancer cohorts were included. Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009 to 2013 in patients with incurable RAIR thyroid cancer who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis. Results: Thirty-three patients with differentiated thyroid cancer (DTC), 10 with medullary thyroid cancer (MTC), and 7 with anaplastic thyroid cancer (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3–18.5) with a 2-year PFS of 23.6% (95% CI, 10.5–39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8–85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months after study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt–mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated. Conclusions: Everolimus has significant antitumor activity in thyroid cancer. While genomic profiling does not currently guide therapeutic selection in thyroid cancer patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine. Clin Cancer Res; 24(7); 1546–53. ©2018 AACR.

In older patients, thyroid nodules are frequently detected and referred for evaluation, though usually prove to be benign disease or low-risk cancer. Therefore, management should be guided not solely by malignancy risk, but also by the relative risks of any intervention. Unfortunately, few such data are available for patients ≥70 years old.All consecutive patients ≥70 years old assessed by ultrasound (US) and fine-needle aspiration (FNA) between 1995 and 2015 were analyzed. Clinical, US, and histologic data, including patient comorbidities and outcomes, were obtained. Imaging and cytology results from initial evaluation were reviewed to detect significant-risk thyroid cancer (SRTC), which was defined as anaplastic, medullary, or poorly differentiated carcinoma, or the presence of distant metastases. Overall survival analyses were then performed to assist with risk-to-benefit assessment.A total of 1129 patients ≥70 years old with 2527 nodules ≥1 cm were evaluated. FNA was safe in all, and cytology proved benign in 67.3% of patients. However, FNA led to surgery in 208 patients, of whom 93 (44.7%) had benign histopathology. Among all patients who underwent FNA, only 17 (1.5%) SRTC were identified, all of which were preoperatively identifiable by imaging and/or cytology. These SRTC were responsible for all (n = 10; 0.9%) thyroid cancer deaths. Among all other patients (n = 1112), 160 deaths (14.4%) were confirmed during a median follow-up of four years. None of these were thyroid cancer related. Survival analysis for these 1112 patients demonstrated that a separate non-thyroidal malignancy or coronary artery disease at the time of nodule evaluation was associated with increased mortality compared to those without these diagnoses (hazard ratio = 2.32 [confidence interval 1.66-3.26]; p 0.01), confirming these are important variables to identify prior to thyroid nodule evaluation.For patients ≥70 years old, US and FNA are safe and prove helpful in identifying SRTC and benign cytology. However, the surgical management of patients ≥70 years old presenting without high-risk findings should be tempered, especially when comorbid illness is identified.

Diagnostic hemithyroidectomy (HT) is the most widely recommended surgical procedure for a nodule with indeterminate cytology; however, additional details may make initial total thyroidectomy (TT) preferable. We sought to identify patient-specific factors (PSFs) associated with initial TT in patients with indeterminate thyroid nodules. Retrospective analysis of all patients with a thyroid nodule ≥ 1 cm and initial cytology of atypia of undetermined significance or suspicious for follicular neoplasm between 2012 and 2015 who underwent thyroidectomy. Medical records were reviewed for patient demographics, neck symptoms, nodule size, cytology, molecular test results, final histopathology, and additional PSFs influencing surgical management. Variables were analyzed to determine associations with the use of initial TT. Logistic regression analyses were performed to identify independent associations. Of 325 included patients, 182/325 (56.0%) had HT and 143/325 (44.0%) had TT. While patient age and sex, nodule size, and cytology result were not associated with initial treatment, five PSFs were associated with initial TT (p

The 2015 American Thyroid Association (ATA) guidelines recommended that low-risk, differentiated thyroid cancers (DTC) between 1 and 4 cm may be treated with thyroid lobectomy alone. We sought to determine the effect of these guideline changes on the rate of completion thyroidectomy (CT) for low-risk DTC and factors influencing surgical decision-making.All patients from 2014 to 2018 who received an initial thyroid lobectomy at our institution with final pathology demonstrating DTC were included. Patients were divided into "pre" and "post" guideline cohorts (2014-2015 and 2016-2018, respectively). The rate of CT was compared between the two cohorts. Patient demographics and tumor characteristics were examined for association with CT.A total of 163 patients met study criteria: 63 patients in the 2014-2015 ("pre") and 100 in the 2016-2018 ("post") group. In the "pre" period, 41 (65.1%) patients received CT compared with 43 (43.0%) in the "post" period (p 0.01)-a 34% decrease in the rate of completion surgery (p 0.01). Of low-risk patients with DTC between 1 and 4 cm in size, 17 of 35 (48.6%) received CT in the "pre" period compared with 15 of 60 (25.0%) in the post period-a 48.6% decrease in the rate of completion surgery (p = 0.02). Greater tumor size, capsular invasion, and multifocality were associated with CT in low-risk "post" guideline patients (p 0.05 for all).The rate of CT decreased significantly by 48.6% for low-risk patients with DTC between 1 and 4 cm, demonstrating recognition of the 2015 ATA guidelines. However, 25% of these patients underwent CT, suggesting additional factors influencing the decision for further treatment.

Background: The 2017 World Health Organization (WHO) Classification of Tumors of Endocrine Organs defines poorly differentiated thyroid carcinoma (PDTC) as a tumor with conventional criteria of mal...

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BACKGROUND Thyroid nodules with atypia of undetermined significance (AUS) on fine-needle aspiration (FNA) have a low risk of malignancy that appears to vary based on specific features described in the AUS diagnosis. The Afirma gene expression classifier (GEC) is a molecular test designed to improve preoperative risk stratification of thyroid nodules, but its performance for different patterns of AUS has not been defined. The objective of this study was to assess GEC results and clinical outcomes in AUS nodules with architectural atypia (AUS-A), cytologic atypia (AUS-C) or both (AUS-C/A). METHODS This was a retrospective review of all thyroid nodules with AUS cytopathology that underwent GEC testing at the authors' institution over a period of >4 years. RESULTS In 227 nodules that had AUS cytology results and Afirma GEC testing, the rate of benign GEC results was higher in AUS-A nodules (70 of 107; 65%) than in AUS-C/A nodules (25 of 65; 38%; P = .0008), and AUS-C nodules exhibited an intermediate rate of benign results (27 of 55 nodules; 59%). The risk of cancer among patients who had GEC-suspicious nodules, 86% of whom underwent resection, was 19% (6 of 25) for AUS-A nodules compared with 57% (21 of 37) for AUS-C/A nodules (P = .003) and 45% (10 of 22) for AUS-C nodules (P = .07). In nodules that had an indeterminate repeat cytology result, no difference was observed in the rate of benign GEC results or in the malignancy rate compared with nodules that had a single cytology result. CONCLUSIONS The performance characteristics of Afirma GEC testing vary, depending on qualifiers of cytologic atypia. Recognition of these differences may enable clinicians to provide improved counseling and treatment recommendations to patients. Cancer Cytopathol 2016. © 2017 The Authors. Cancer Cytopathology published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Thyroid nodule growth was once considered concerning for malignancy, but data showing that benign nodules grow questioned the use of this paradigm. To date, however, no studies have adequately evaluated whether growth rates differ in malignant vs. benign nodules.To sonographically evaluate growth rates in benign and malignant thyroid nodules ≥1 cm.Prospective, cohort study of patients with tissue diagnosis of benign or malignant disease, with repeated ultrasound evaluation six or more months apart.Growth rate in largest dimension of malignant compared with benign thyroid nodules. Regression models were used to evaluate predictors of growth.Malignant nodules (126) met inclusion criteria (≥6-month nonoperative followup) and were compared with 1363 benign nodules. Malignant nodules were not found to be uniquely selected or prospectively observed solely for low-risk phenotype. Median ultrasound intervals were similar (21.8 months for benign nodules; 20.9 months for malignant nodules). Malignant nodules were more likely to grow2 mm/y compared with benign nodules [relative risk (RR) = 2.5, 95% confidence interval (CI), 1.6 to 3.1; P0.001], which remained true after adjustment for clinical factors. The RR of a nodule being malignant increased with faster growth rates. Malignant nodules growing2 mm/y had greater odds of being more aggressive cancers [intermediate risk: odds ratio (OR) = 2.99; 95% CI, 1.20 to 7.47; P = 0.03; higher risk: OR = 8.69; 95% CI, 1.78 to 42.34; P = 0.02].Malignant nodules, especially higher-risk phenotypes, grow faster than benign nodules. As growth2 mm/y predicts malignant compared with benign disease, this clinical parameter can contribute to the assessment of thyroid cancer risk.

Mutations in the BRAF and RAS oncogenes are responsible for most well-differentiated thyroid cancer. Yet, our clinical understanding of how BRAF-positive and RAS-positive thyroid cancers differ is incomplete.We correlated clinical, radiographic, and pathological findings from patients with thyroid cancer harboring a BRAF or RAS mutation.Prospective cohort study.Academic, tertiary care hospital.A total of 101 consecutive patients with well-differentiated thyroid cancer.We compared the clinical, sonographic, and pathological characteristics of patients with BRAF-positive cancer to those with RAS-positive cancer.Of 101 patients harboring these mutations, 71 were BRAF-positive, whereas 30 were RAS-positive. Upon sonographic evaluation, RAS-positive nodules were significantly larger (P = .04), although BRAF-positive nodules were more likely to harbor concerning sonographic characteristics (hypoechogenicity [P.001]; irregular margins [P = .04]). Cytologically, 70% of BRAF-positive nodules were classified positive for PTC, whereas 87% of RAS-positive nodules were indeterminate (P.001). Histologically, 96% of RAS-positive PTC malignancies were follicular variants of PTC, whereas 70% of BRAF-positive malignancies were classical variants of PTC. BRAF-positive malignancies were more likely to demonstrate extrathyroidal extension (P = .003), lymphovascular invasion (P = .02), and lymph node metastasis (P.001).BRAF-positive malignant nodules most often demonstrate worrisome sonographic features and are frequently associated with positive or suspicious Bethesda cytology. In contrast, RAS-positive malignancy most often demonstrates indolent sonographic features and more commonly associates with lower risk, "indeterminate" cytology. Because BRAF and RAS mutations are the most common molecular perturbations associated with well-differentiated thyroid cancer, these findings may assist with improved preoperative risk assessment by suggesting the likely molecular profile of a thyroid cancer, even when postsurgical molecular analysis is unavailable.

Context Assessing thyroid nodules for malignancy is complex. The impact of patient and nodule factors on cancer evaluation is uncertain. Objectives To determine precise estimates of cancer risk associated with clinical and sonographic variables obtained during thyroid nodule assessment. Design Analysis of consecutive adult patients evaluated with ultrasound-guided fine-needle aspiration for a thyroid nodule ≥1 cm between 1995 and 2017. Demographics, nodule sonographic appearance, and pathologic findings were collected. Main Outcome Measures Estimated risk for thyroid nodule malignancy for patient and sonographic variables using mixed-effect logistic regression. Results In 9967 patients [84% women, median age 53 years (range 18 to 95)], thyroid cancer was confirmed in 1974 of 20,001 thyroid nodules (9.9%). Significant ORs for malignancy were demonstrated for patient age 75% compared with predominantly solid, P < 0.0001 for both], and the presence of additional nodules ≥1 cm [OR: 0.69 (0.60 to 0.79) for two nodules, OR: 0.41 (0.34 to 0.49) for three nodules, and OR: 0.19 (0.16 to 0.22) for greater than or equal to four nodules compared with one nodule, P < 0.0001 for all]. A free online calculator was constructed to provide malignancy-risk estimates based on these variables. Conclusions Patient and nodule characteristics enable more precise thyroid nodule risk assessment. These variables are obtained during routine initial thyroid nodule evaluation and provide new insights into individualized thyroid nodule care.

Background: For thyroid nodules with indeterminate cytology, the Afirma Gene Expression Classifier (GEC) identified benign nodules to reduce diagnostic surgery, though many nodules classified as su...

6513 Background: Treatment options for aggressive TC are limited. Pre-clinical data suggests efficacy of CTLA-4 plus PD-1 blockade in aggressive RAIR TC. Methods: This investigator initiated phase II study tested N (3mg/kg every 2 weeks) plus I (1mg/kg every 6 weeks) until disease progression or completion of 24 mo of treatment in RAIR differentiated TC including poorly differentiated TC (PDTC) with exploratory cohorts in anaplastic (ATC) and medullary TC (MTC). Radiographic response rate by RECIST v1.1 (CR+PR) was primary endpoint. At least 6 pts with disease response among n=32 DTC provided 84% power to distinguish between a 10% and a 25% RR (one-sided 9% binomial test). Results: Accrual is complete with n=32 patients with DTC, 10 with ATC and 7 with MTC enrolled between October 2017 and May 2019. Thirty-two DTC included: n=17 papillary, n=7 Hurthle, n=4 follicular TC, n=4 PDTC. Among n=49, median (range) age was 65 (30-88), 51% (25/49) were female. To date, in DTC, 3/32 achieved a PR (n=2 Hurthle and n=1 PDTC), 9.4% RR (.95CI:2%-25%). One near complete response has been observed. Among pts w ATC, 3/ 10 profound PR by RECIST occurred (30% RR, .95CI: 7%-65%). Among them, two remain without clear evidence of disease at 26 and 13 mo after treatment start. No PR's were observed in MTC. Most frequent grade 3-4 TRAEs were as expected and included increased lipase (n=8), increased serum amylase (n=4). There was an unexpected number of treatment related adrenal insufficiency (AI) (n=4) which was associated with long PFS (range 10.1—16.4+mo). Conclusions: N+I appears to have considerable activity in ATC. In unselected RAIR DTC, activity was low but responses were seen in PDTC and Hurthle cell TC. Exceptional responses with prolonged remissions were observed. Clinical trial information: NCT03246958 .

Since its inception, the Bethesda System for Reporting Thyroid Cytopathology (TBS) has been widely adopted. Each category conveys a risk of malignancy and recommended next steps, though it is unclear if each category also predicts the type and extent of malignancy. If so, this would greatly expand the utility of the TBS by providing prognostic information in addition to baseline cancer risk.All patients prospectively enrolled into the authors' thyroid nodule database from 1995 to 2013 with histologically proven malignancy were analyzed. The primary ultrasound-guided fine-needle aspiration cytology (AUS, atypia of unknown significance; FN, follicular neoplasm; SUSP, suspicious; M, malignant) was correlated with the type of thyroid cancer and histological features known to impact prognosis and recurrence, including lymph node metastasis (LNM), lymphovascular invasion, and extrathyroidal extension (ETE). Primary cytology was separately correlated with higher risk malignancy.A total of 1291 malignancies were identified, with primary cytology AUS in 130 cases, FN in 241 cases, SUSP in 411 cases, and M in 509 cases. AUS, SUSP, and M cytology were progressively associated with an increasing risk of high-risk disease (p 0.001), LNM (p 0.001), ETE (p 0.001), and margin positivity (p 0.001). Notably, 71% of malignancies with AUS cytology were follicular variants of papillary thyroid cancer compared with 63% with SUSP cytology and only 20% with M cytology. In contrast, high-risk malignancies were diagnosed in only 4% with AUS cytology, but 9% and 27% with SUSP and M cytology, respectively. FN conveyed a significantly increased risk of follicular thyroid carcinoma compared with all other types (28% vs. 2%; p 0.001). A composite endpoint of recurrence, distant metastases, and death similarly increased as cytology progressed from AUS to SUSP to M (p 0.001).In addition to predicting cancer prevalence, the TBS also imparts important prognostic information about cancer type, variant, and risk of recurrence. These data extend the utility of TBS classification by fostering an improved understanding of the risk posed by any confirmed malignancy.

Although advancing age is known to influence the formation of thyroid nodules, the precise relationship remains unclear. Furthermore, it is uncertain whether age influences the risk that any thyroid nodule may prove cancerous.The aim was to determine the impact of patient age on nodule formation, multinodularity, and risk of thyroid malignancy.We conducted a prospective cohort analysis of consecutive adults (ages 20-95 y) who presented for evaluation of nodular disease from 1995 to 2011. A total of 6391 patients underwent ultrasound and fine-needle aspiration of 12 115 nodules ≥ 1 cm. Patients were divided into six age groups and compared using sonographic, cytological, and histological endpoints.The prevalence of thyroid nodular disease increases with advancing age. The mean number of nodules at presentation increased from 1.5 in the youngest cohort (age, 20-30 y) to 2.2 in the oldest cohort (age,70 y; P.001), demonstrating a 1.6% annual increased risk for multinodularity (odds ratio, 1.02; P.001). In contrast, the risk of malignancy in a newly identified nodule declined with advancing age. Thyroid cancer incidence per patient was 22.9% in the youngest cohort, but 12.6% in the oldest cohort (odds ratio, 0.972; P.001), demonstrating a 2.2% decrease per year in the relative risk of malignancy between ages 20 and 60 years, which stabilized thereafter. Despite a lower likelihood of malignancy, identified cancers in older patients demonstrated higher risk histological phenotypes. Although nearly all malignancies in younger patients were well-differentiated, older patients were more likely to have higher risk papillary thyroid carcinoma variants, poorly differentiated cancer, or anaplastic carcinoma (P.001).With advancing age, the prevalence of clinically relevant thyroid nodules increases, whereas the risk that such nodules are malignant decreases. Nonetheless, when thyroid cancer is detected in older individuals, a higher-risk histological phenotype is more likely. These data provide insight into the clinical paradox that confronts physicians managing this common illness.

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.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.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.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%.

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is an indolent thyroid tumor characterized by frequent RAS mutations and an absence of the BRAF V600E mutation commonly seen in classical papillary thyroid carcinoma (cPTC). The ability to differentiate potential NIFTP/follicular variant of papillary thyroid carcinoma (FVPTC) from cPTC at the time of fine-needle aspiration (FNA) can facilitate conservative management of NIFTP. The aim of the current study was to investigate how molecular testing may add to cytologic assessment in the pre-operative differentiation of potential NIFTP/FVPTC and cPTC. We had previously evaluated cytologists' ability to prospectively distinguish potential NIFTP/FVPTC from cPTC in a cohort of 56 consecutive FNAs diagnosed as malignant or suspicious for malignancy. We utilized this cohort to perform molecular analysis. Detected molecular abnormalities were stratified into two groups: (1) those supporting malignancy and (2) those supporting a diagnosis of potential NIFTP/FVPTC. The cytologists' characterization of cases and the detected molecular alterations were correlated with the final histologic diagnoses. Molecular testing was performed in 52 (93%) of the 56 cases. For the 37 cases cytologists favored to be cPTC, 31 (84%) had a molecular result that supported malignancy (28 BRAF V600E mutations, 2 NTRK1 fusions, 1 AGK-BRAF fusion). For the 8 cases that were favored to be NIFTP/FVPTC by cytologists, 7 (88%) had a molecular result that supported conservative management (1 NRAS mutation, 6 wild-type result). Seven cases were designated as cytomorphologically indeterminate for NIFTP/FVPTC or cPTC, of which 6 (86%) had a molecular result that would have aided in the pre-operative assessment of potential NIFTP/FVPTC or cPTC/malignancy. These included 3 BRAF V600E mutations in nodules that were cPTC on resection, an HRAS mutation, and a wild-type result in the 2 nodules that were NIFTP, and a TERT promoter mutation along with an NRAS mutation in a poorly differentiated thyroid carcinoma. For nodules with an FNA diagnosis of suspicious for malignancy or malignant, cytologists can differentiate most cases of potential NIFTP/FVPTC from cPTC. However, molecular testing may be valuable for a subset of cases, especially those that are indeterminate for potential NIFTP/FVPTC versus cPTC based on cytologic features alone.

The Afirma gene expression classifier (GEC) is a molecular diagnostic test that has a high negative predictive value for ruling out malignancy in thyroid nodules with indeterminate cytology. Many patients with a cytologically indeterminate and GEC benign (Cyto-I/GEC-B) nodule undergo monitoring instead of diagnostic surgery, but few data describe their follow-up.The objective of the study was to determine the sonographic changes and clinical outcomes for patients with Cyto-I/GEC-B nodules compared with patients with cytologically benign (Cyto-B) nodules.This was a retrospective analysis of consecutive Cyto-I/GEC-B nodules evaluated at Brigham and Women's Hospital compared with Cyto-B nodules.Nodule growth of 20% or greater in two dimensions or of 50% or greater in volume, change in sonographic features, and rates of repeat fine-needle aspiration, thyroidectomy, and malignancy.Ninety-five Cyto-I/GEC-B nodules in 90 patients were identified. Five patients underwent primary surgical resection. Of the remaining 90 nodules, 58 (64.4%) had sonographic follow-up available at a median of 13 months (range 4-40 mo). Cyto-I/GEC-B nodules showed similar growth compared with 1224 Cyto-B nodules using either of the following criteria: 20% or greater in two dimensions (8.6% vs 8.3%, P = .80) or 50% or greater in volume (17.2% vs 13.8%, P = .44). Thyroidectomies were more frequent in the Cyto-I/GEC-B group (13.8% vs 0.9%, P.0001), but cancer was found in only one patient, with no evidence of persistent disease after initial treatment.Cyto-I/GEC-B nodules demonstrate similar growth to Cyto-B nodules during follow-up. Although Cyto-I/GEC-B nodules were more frequently resected, only one malignancy was found. These data suggest that reassessment of Cyto-I/GEC-B nodules may be performed similarly to those with benign cytology.

We report a case of primary secretory carcinoma of the thyroid with high-grade features to highlight cytologic and histologic clues to the diagnosis. The diagnosis of primary secretory carcinoma of the thyroid is challenging both due to the fact that it has only recently been described and because of its morphologic overlap with papillary thyroid carcinoma (PTC); however, differentiating secretory carcinoma from PTC is crucial both for prognostication and treatment purposes. This article is protected by copyright. All rights reserved.

Well-differentiated thyroid carcinoma (WDTC) generally has a favorable prognosis. However, patients with distant metastatic disease experience progression of disease with a higher mortality. A subset of patients not previously described may challenge the conventional dogma regarding the progressive nature of all metastatic WDTC. Through analysis of our database, we identified patients with distant metastatic WDTC and persistent, minimally progressive disease. In all patients, persistent metastatic disease was confirmed via tissue biopsy, abnormal PET scan, and/or biochemical elevations in thyroglobulin or antibody levels. Progression of disease was monitored clinically and with repeat imaging. We describe five patients with WDTC and pulmonary metastases, aged 8–43 years at diagnosis. All patients underwent initial surgery and radioactive iodine (RAI) ablation, with some receiving multiple treatments. Persistent pulmonary metastatic disease was confirmed over decades (mean 22 years, range 8–42 years) with minimal progression despite no further treatment beyond thyroid hormone suppression. Persistent disease was biopsy-proven in all patients at a mean of 9.6 years from last RAI treatment. All patients had elevated thyroglobulin or anti-thyroglobulin antibody levels, while three demonstrated metabolically active disease with positive FDG uptake on PET scan, and one patient with persistent radioactive iodine avid pulmonary metastasis 36 years after her last RAI treatment. This case series demonstrates that some patients with distant metastases, even if metabolically active and radioactive iodine resistant, remain stable for decades without further treatment. Clinical awareness of such patients and continual reassessment of disease risk following initial therapy are crucial as aggressive treatment may not be necessary.

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.The aim was to study the presenting features and cancer risk of sporadic childhood thyroid nodules using a standardized clinical assessment and management plan.Boston Children's Hospital and Brigham and Women's 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.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).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.

BACKGROUND Thyroid nodules with atypia of undetermined significance (AUS) on fine‐needle aspiration (FNA) have a low risk of malignancy that appears to vary based on specific features described in the AUS diagnosis. The Afirma gene expression classifier (GEC) is a molecular test designed to improve preoperative risk stratification of thyroid nodules, but its performance for different patterns of AUS has not been defined. The objective of this study was to assess GEC results and clinical outcomes in AUS nodules with architectural atypia (AUS‐A), cytologic atypia (AUS‐C) or both (AUS‐C/A). METHODS This was a retrospective review of all thyroid nodules with AUS cytopathology that underwent GEC testing at the authors' institution over a period of >4 years. RESULTS In 227 nodules that had AUS cytology results and Afirma GEC testing, the rate of benign GEC results was higher in AUS‐A nodules (70 of 107; 65%) than in AUS‐C/A nodules (25 of 65; 38%; P = .0008), and AUS‐C nodules exhibited an intermediate rate of benign results (27 of 55 nodules; 59%). The risk of cancer among patients who had GEC‐suspicious nodules, 86% of whom underwent resection, was 19% (6 of 25) for AUS‐A nodules compared with 57% (21 of 37) for AUS‐C/A nodules (P = .003) and 45% (10 of 22) for AUS‐C nodules (P = .07). In nodules that had an indeterminate repeat cytology result, no difference was observed in the rate of benign GEC results or in the malignancy rate compared with nodules that had a single cytology result. CONCLUSIONS The performance characteristics of Afirma GEC testing vary, depending on qualifiers of cytologic atypia. Recognition of these differences may enable clinicians to provide improved counseling and treatment recommendations to patients. Cancer Cytopathol 2017;125:313–322. © 2017 American Cancer Society., Thyroid nodules with atypia of undetermined significance cytology and Afirma gene expression classifier (GEC) testing are analyzed based on the presence of architectural, cytologic, or both cytologic and architectural atypia. Nodules with architectural atypia are the most likely to have a benign GEC result and least likely to be malignant, suggesting that clinicians should be aware of these cytologic qualifiers when advising patients regarding GEC testing and the risk of malignancy.

SummaryObjective and design We explored the cross-sectional and longitudinal associations of thyroid function within the normal range with cardiovascular disease (CVD) risk factors and adiposity measures. Patients and measurements A total of 3483 (50·4% women) participants for the cross-sectional CVD study and 1630 (41·2% women) participants for the cross-sectional body composition substudy were drawn from the Framingham Third Generation Exam 1; 2912 participants (50·1% women) for the longitudinal CVD study and 713 participants (35·9% women) for the longitudinal body composition substudy were drawn from the Framingham Third Generation Exams 1–2. Thyroid function was assessed by thyrotropin [thyroid-stimulating hormone (TSH)] and free thyroxine (fT4) concentrations within the reference range at Exam 1. The associations between thyroid function and CVD risk factors were modelled via multivariable-adjusted regression models. Multivariable adjustment included age, sex, current smoking, postmenopausal status and BMI. Results Cross-sectionally, higher TSH concentration was associated with increased odds of hypertriglyceridaemia [odds ratio (OR)=1·10], and higher BMI (β = 0·19 kg/m2), total cholesterol (β = 0·05 mmol/l), triglycerides (β = 0·0006 mmol/l) and subcutaneous adipose tissue (SAT) volume (β = 38·8 cm3) (all P < 0·05). Cross-sectionally, fT4 was inversely associated with metabolic and adiposity-related CVD risk factors, including obesity (OR = 1·17), hypertriglyceridaemia (OR = 1·09), BMI (β = 0·42 kg/m2), total cholesterol (β = 0·05 mmol/l), triglycerides (β = 0·0002 mmol/l), visceral adipose tissue (VAT) volume (β = −20·7 cm3) and attenuation (0·17 HU) and VAT/SAT ratio (β = −0·01) (all P < 0·05). However, during 6·1 years of follow-up, baseline TSH and fT4 levels were not longitudinally associated with CVD risk factors and adiposity measures. Conclusions Thyroid function within the normal range is cross-sectionally, but not longitudinally, associated with CVD risk factors and adiposity measures.

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 institution’s 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.

A fine-needle aspiration sample composed exclusively of Hurthle cells is interpreted as “suspicious for a follicular neoplasm, Hurthle cell type” (SFNHCT). Because some nonneoplastic Hurthle cell proliferations in Hashimoto thyroiditis (HT) mimic this cytologic pattern, we examined the positive predictive value (PPV) for malignancy of SFNHCT in patients with HT. Between 1992 and 2007, 401 patients with cytologic findings of SFNHCT were identified at 3 institutions. Histologic follow-up was available for 287 (71.6%), and malignancy was diagnosed in 69 (24.0%). Malignancy was present in 2 (PPV = 9.5%) of 21 patients with HT compared with 67 (PPV = 25.2%) of 266 patients without HT ( P = .081). Although the difference in the rate of malignancy between the HT and non-HT cohorts did not reach statistical significance, the lower risk of malignancy in the HT cohort more closely approximates the risk of cases interpreted as “atypia of undetermined significance.” For this reason, it might be appropriate for Hurthle cell–only aspirates from patients with HT to be categorized as either atypia of undetermined significance or SFNHCT.

Context: Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a complex disorder caused by germline-inactivating mutations of the PTEN tumor suppressor gene. Carriers develop benign and malignant tumors of multiple tissues, including the breast, thyroid, intestine, and skin. Surveillance to facilitate the early detection and treatment of malignancies is recommended but, because thyroid cancers have been reported almost exclusively in adults, childhood risk is considered to be low, and consensus guidelines recommend that surveillance imaging begin at 18 yr of age. Objective/Patients: Seven children with PHTS referred to two thyroidologists form the basis of this report. Medical records, operative histology, and PTEN mutational analysis were reviewed to evaluate the pediatric presentation of PHTS-associated thyroid neoplasia. Results: Five of the seven children presented with thyroid nodules or thyroid cancer between the ages of 6 and 12 yr, often as the initially identified component of...

Struma ovarii is a rare tumor, characterized by the presence of thyroid tissue in an ovarian teratoma. In this article Yassa et al. describe a patient who presented to her gynecologist with a pelvic mass, which was found to be a malignant struma ovarii. The investigations and treatment options for this tumor are described. Background A 25-year-old woman presented to her gynecologist with pelvic pain. Pelvic ultrasonography showed a 9 cm left ovarian mass. The patient underwent left oophorectomy, omental biopsy, and lymph node sampling. The ovarian mass proved to be a struma ovarii with numerous microscopic foci of papillary thyroid carcinoma. The patient had no symptoms of hyperthyroidism, and her thyroid function and serum thyroglobulin levels were normal. Investigations Investigations included a pelvic ultrasound scan, histological examination of the ovarian mass and omental nodules, and lymph node sampling. Diagnosis Malignant struma ovarii. Management The patient was referred to an endocrinology clinic for further investigations. Serum levels of TSH, thyroglobulin and thyroglobulin antibodies were measured. In addition, the patient underwent thyroid ultrasonography, which showed a 1 cm nodule that proved benign on biopsy. She was treated with thyroxine to reduce TSH secretion. Follow-up pelvic ultrasonography 1 year later showed no evidence of recurrent disease, and her serum thyroglobulin levels remained normal.

Background Thyroid nodules are common, and most are benign. Given the risk of false-negative cytology (i.e. malignancy), follow-up is recommended after 1–2 years, though this recommendation is based solely on expert opinion. Sonographic appearance may assist with planning, but is limited by large inter-observer variability. We therefore compared the safety and efficacy of long- versus short-interval follow-up after a benign initial aspiration, regardless of sonographic appearance. Methods This study evaluated all patients referred to the Brigham and Women’s Hospital Thyroid Nodule Clinic, between 1999 and 2010, with a cytologically benign nodule >1 cm and who had returned for follow-up sonographic evaluation. Despite standard clinical recommendations, variation in patient compliance resulted in variable follow-up intervals from time of initial aspiration to the first repeat evaluation. Main outcome measures included nodule growth, repeat fine needle aspiration (FNA), thyroidectomy, malignancy, and disease-specific mortality. Results We evaluated 1,254 patients with 1,819 cytologically benign nodules, with a median time to first follow-up of 1.4 years (range, 0.5–14.1 years). The longer the follow-up interval, the more nodules grew and the more repeat FNAs were performed (P 3 years (4.9 % vs. 1.2 %, P = 0.0001), though no difference in malignancy risk was identified (0.2–0.8 %, P = 0.77). No (0 %) thyroid cancer-specific deaths were identified in either cohort. Conclusions While expert opinion currently recommends repeat evaluation of a cytologically benign nodule at 1–2 years, these are the first data to demonstrate that this interval can be safely extended to 3 years without increased mortality or patient harm. Nodule growth can be expected, though detection of malignancies is unchanged. While replication of these data in large prospective multicenter studies is needed, this extension in follow-up interval would reduce unnecessary visits and medical interventions for millions of affected patients worldwide, leading to healthcare savings. Please see related commentary article: http://dx.doi.org/10.1186/s12916-016-0559-9 and research article: http://dx.doi.org/10.1186/s12916-015-0419-z.