NONINVASIVE FOLLICULAR TUMOR WITH PAPILLARY-LIKE NUCLEAR FEATURES: NOT A TEMPEST IN A TEAPOT.

OBJECTIVE: Encapsulated non-invasive follicular variant papillary thyroid cancer (ENIFVPTC) has recently been retermed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This designation specifically omits the word "cancer" to encourage conservative treatment since patients with NIFTP tumors have been shown to derive no benefit from completion thyroidectomy or adjuvant radio-active iodine (RAI) therapy. METHODS: This was a retrospective study of consecutive cases of tumors from 2007 to 2015 that met pathologic criteria for NIFTP. The conservative management (CM) group included patients managed with lobectomy alone or appropriately indicated total thyroidectomy. Those included in the aggressive management (AM) group received either completion thyroidectomy or RAI or both. RESULTS: From 100 consecutive cases of ENIFVPTC reviewed, 40 NIFTP were included for the final analysis. Of these, 10 (27%) patients treated with initial lobectomy received completion thyroidectomy and 6 of 40 (16%) also received postsurgical adjuvant RAI. The mean per-patient cost of care in the AM group was $17,629 ± 2,865, nearly twice the $8,637 ± 309 costs in the CM group, and was largely driven by the cost of completion thyroidectomy and RAI. CONCLUSION: The term NIFTP has been recently promulgated to identify a type of thyroid neoplasm, formerly identified as a low-grade cancer, for which initial surgery represents adequate treatment. We believe that since the new NIFTP nomenclature intentionally omits the word "cancer," the clinical indolence of these tumors will be better appreciated, and cost savings will result from more conservative and appropriate clinical management. ABBREVIATIONS: AM = aggressive management CM = conservative management ENIFVPTC = encapsulated noninvasive form of FVPTC FVPTC = follicular variant of papillary thyroid carcinoma NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features PTC = papillary thyroid carcinoma PTMC = papillary thyroid microcarcinoma RAI = radio-active iodine US = ultrasound.

Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer.

Thyroid cancer is a common endocrine malignancy that encompasses well-differentiated as well as dedifferentiated cancer types. The latter tumors have high mortality and lack effective therapies. Using a paired-end RNA-sequencing approach, we report the discovery of rearrangements involving the anaplastic lymphoma kinase (ALK) gene in thyroid cancer. The most common of these involves a fusion between ALK and the striatin (STRN) gene, which is the result of a complex rearrangement involving the short arm of chromosome 2. STRN-ALK leads to constitutive activation of ALK kinase via dimerization mediated by the coiled-coil domain of STRN and to a kinase-dependent, thyroid-stimulating hormone-independent proliferation of thyroid cells. Moreover, expression of STRN-ALK transforms cells in vitro and induces tumor formation in nude mice. The kinase activity of STRN-ALK and the ALK-induced cell growth can be blocked by the ALK inhibitors crizotinib and TAE684. In addition to well-differentiated papillary cancer, STRN-ALK was found with a higher prevalence in poorly differentiated and anaplastic thyroid cancers, and it did not overlap with other known driver mutations in these tumors. Our data demonstrate that STRN-ALK fusion occurs in a subset of patients with highly aggressive types of thyroid cancer and provide initial evidence suggesting that it may represent a therapeutic target for these patients.

Tumor genotype determines phenotype and disease-related outcomes in thyroid cancer: a study of 1510 patients.

OBJECTIVES: To correlate thyroid cancer genotype with histology and outcomes. BACKGROUND: The prognostic significance of molecular signature in thyroid cancer (TC) is undefined but can potentially change surgical management. METHODS: We reviewed a consecutive series of 1510 patients who had initial thyroidectomy for TC with routine testing for BRAF, RAS, RET/PTC, and PAX8/PPARG alterations. Histologic metastatic or recurrent TC was tracked for 6 or more months after oncologic thyroidectomy. RESULTS: Papillary thyroid cancer (PTC) was diagnosed in 97% of patients and poorly differentiated/anaplastic TC in 1.1%. Genetic alterations were detected in 1039 (70%); the most common mutations were BRAFV600E (644/1039, 62%), and RAS isoforms (323/1039, 31%). BRAFV600E-positive PTC was often conventional or tall cell variant (58%), with frequent extrathyroidal extension (51%) and lymph node metastasis (46%). Conversely, RAS-positive PTC was commonly follicular variant (87%), with infrequent extrathyroidal extension (4.6%) and lymph node metastasis (5.6%). BRAFV600E and RET/PTC-positive PTCs were histologically similar. Analogously, RAS and PAX8/PPARG-positive PTCs were histologically similar. Compared with RAS or PAX8/PPARG-positive TCs, BRAFV600E or RET/PTC-positive TCs were more often associated with stage III/IV disease (40% vs 15%, P < 0.001) and recurrence (10% vs 0.7%, P < 0.001; mean follow-up 33 ± 21 mo). Distant metastasis was highest in patients with RET/PTC-positive TC (10.8%, P = 0.02). CONCLUSIONS: In this large study of prospective mutation testing in unselected patients with TC, molecular signature was associated with distinctive phenotypes including cancers, with higher risks of both distant metastasis and early recurrence. Preoperative genotype provides valuable prognostic data to appropriately inform surgery.

Discordance between growth hormone and insulin-like growth factor-1 after pituitary surgery for acromegaly: a stepwise approach and management.

INTRODUCTION: Follow-up management of patients with acromegaly after pituitary surgery is performed by conducting biochemical assays of growth hormone (GH) and insulin-like growth factor-1 (IGF1). Despite concordant results of these two tests in the majority of cases, there is increasing recognition of patients who show persistent or intermittent discordance between GH and IGF1 (normal GH and elevated IGF1 or vice versa). METHOD: In this narrative review, the last three decades materials on the issue of discrepancy between GH and IGF1 were thoroughly assessed. RESULTS: Various studies have obtained different discordance rates, ranging from 5.4 to 39.5%. At present, despite the use of current sensitive assays and more stringent criteria to define remission, the rate of discordance still remains high. A number of mechanisms have been proposed to explain the postoperative discordance of GH and IGF1 including; altered dynamics of the GH secretion after surgery, early postoperative hormone assay, inaccurate or less sensitive tests and laboratory errors, too high cut-off point for GH suppression in the GH assays, GH nadir values not adjusted to age, sex, and body mass index, the influence of concomitant medication, co-existing physiologic and pathologic conditions, and many other proposed reasons. Nevertheless, the underlying mechanisms are still far from clear, and the solution continues to evade complete elucidation. Similarly, the impacts of such a discrepancy over mortality and morbidity and the risk of biochemical and/or clinical recurrence are unclear. CONCLUSION: As a challenging clinical problem, a stepwise evaluation and management of these patients appears to be more rational.

Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay.

BACKGROUND: Fine-needle aspiration (FNA) cytology is a common approach to evaluating thyroid nodules, although 20% to 30% of FNAs have indeterminate cytology, which hampers the appropriate management of these patients. Follicular (or oncocytic) neoplasm/suspicious for a follicular (or oncocytic) neoplasm (FN/SFN) is a common indeterminate diagnosis with a cancer risk of approximately 15% to 30%. In this study, the authors tested whether the most complete next-generation sequencing (NGS) panel of genetic markers could significantly improve cancer diagnosis in these nodules. METHODS: The evaluation of 143 consecutive FNA samples with a cytologic diagnosis of FN/SFN from patients with known surgical outcomes included 91 retrospective samples and 52 prospective samples. Analyses were performed on a proprietary sequencer using the targeted ThyroSeq v2 NGS panel, which simultaneously tests for point mutations in 13 genes and for 42 types of gene fusions that occur in thyroid cancer. The expression of 8 genes was used to assess the cellular composition of FNA samples. RESULTS: In the entire cohort, histologic analysis revealed 104 benign nodules and 39 malignant nodules. The most common point mutations involved the neuroblastoma RAS viral oncogene homolog (NRAS), followed by the Kirsten rat sarcoma viral oncogene homolog (KRAS), the telomerase reverse transcriptase (TERT) gene, and the thyroid-stimulating hormone receptor (TSHR) gene. The identified fusions involved the thyroid adenoma associated (THADA) gene; the peroxisome proliferator-activated receptor γ (PPARG) gene; and the neurotrophic tyrosine kinase, receptor, type 3 (NTRK3) gene. Performance characteristics were similar in the retrospective and prospective groups. Among all FN/SFN nodules, preoperative ThyroSeq v2 performed with 90% sensitivity (95% confidence interval [CI], 80%-99%), 93% specificity (95% CI, 88%-98%), a positive predictive value of 83% (95% CI, 72%-95%), a negative predictive value of 96% (95% CI, 92%-100%), and 92% accuracy (95% CI, 88%-97%). CONCLUSIONS: The current results indicate that comprehensive genotyping of thyroid nodules using a broad NGS panel provides a highly accurate diagnosis for nodules with FN/SFN cytology and should facilitate the optimal management of these patients.

A clinical algorithm for fine-needle aspiration molecular testing effectively guides the appropriate extent of initial thyroidectomy.

OBJECTIVE: To test whether a clinical algorithm using routine cytological molecular testing (MT) promotes initial total thyroidectomy (TT) for clinically significant thyroid cancer (sTC) and/or correctly limits surgery to lobectomy when appropriate. BACKGROUND: Either TT or lobectomy is often needed to diagnose differentiated thyroid cancer. Determining the correct extent of initial thyroidectomy is challenging. METHODS: After implementing an algorithm for prospective MT of in-house fine-needle aspiration biopsy specimens, we conducted a single-institution cohort study of all patients (N = 671) with nonmalignant cytology who had thyroidectomy between October 2010 and March 2012, cytological diagnosis using 2008 Bethesda criteria, and 1 or more indications for thyroidectomy by 2009 American Thyroid Association guidelines. sTC was defined by histological differentiated thyroid cancer of 1 cm or more and/or lymph node metastasis. Cohort 2 patients did not have MT or had unevaluable results. In cohort 1, MT for a multigene mutation panel was performed for nonbenign cytology, and positive MT results indicated initial TT. RESULTS: MT guidance was associated with a higher incidence of sTC after TT (P = 0.006) and a lower rate of sTC after lobectomy (P = 0.03). Without MT results, patients with indeterminate (follicular lesion of undetermined significance/follicular or oncocytic neoplasm) cytology who received initial lobectomy were 2.5 times more likely to require 2-stage surgery for histological sTC (P < 0.001). In the 501 patients with non-sTC for whom lobectomy was the appropriate extent of surgery, lobectomy was correctly performed more often with routine preoperative MT (P = 0.001). CONCLUSIONS: Fine-needle aspiration biopsy MT for BRAF, RAS, PAX8-PPARγ, and RET-PTC expedites optimal initial surgery for differentiated thyroid cancer, facilitating succinct definitive management for patients with thyroid nodules.

Thyroid nodules (≥4 cm): can ultrasound and cytology reliably exclude cancer?

BACKGROUND: Whether a threshold nodule size should prompt diagnostic thyroidectomy remains controversial. We examined a consecutive series of patients who all had thyroidectomy for a ≥4 cm nodule to determine (1) the incidence of thyroid cancer (TC) and (2) if malignant nodules could accurately be diagnosed preoperatively by ultrasound (US), fine needle aspiration biopsy (FNAB) cytology and molecular testing. METHODS: As a prospective management strategy, 361 patients with 382 nodules ≥4 cm by preoperative US had thyroidectomy from 1/07 to 3/12. RESULTS: The incidence of a clinically significant TC within the ≥4 cm nodule was 22 % (83/382 nodules). The presence of suspicious US features did not discriminate malignant from benign nodules. Moreover, in 86 nodules ≥4 cm with no suspicious US features, the risk of TC within the nodule was 20 %. US-guided FNAB was performed for 290 nodules, and the risk of malignancy increased stepwise from 10.4 % for cytologically benign nodules, 29.6 % for cytologically indeterminate nodules and 100 % for malignant FNAB results. Molecular testing was positive in 9.3 % (10/107) of tested FNAB specimens, and all ten were histologic TC. CONCLUSIONS: In a large consecutive series in which all ≥4 cm nodules had histology and were systematically evaluated by preoperative US and US-guided FNAB, the incidence of TC within the nodule was 22 %. The false negative rate of benign cytology was 10.4 %, and the absence of suspicious US features did not reliably exclude malignancy. At minimum, thyroid lobectomy should be strongly considered for all nodules ≥4 cm.

Thyroid nodule rupture after radiofrequency ablation: case report and literature review.

Purpose: Radiofrequency ablation (RFA) is an effective and safe modality for the treatment of thyroid nodules. Nodule rupture is a major complication of RFA. There is little known on the natural history of nodule rupture due to a lack of clinical experience and no consensus on its management. A comprehensive review of nodule rupture presentation, diagnosis, and management is needed. Methods: We report a case of nodule rupture and conduct a literature review. A total of 33 patients experiencing nodule rupture after RFA were included, and their clinical presentation, management, and outcomes were collected and analyzed. Results: Nodule rupture presents with acute swelling (90.3%) and pain (77.4%) within 7 months of RFA procedure, most commonly due to disruption of the anterior thyroid capsule (87%), and can be diagnosed with ultrasonography. Most ruptures can be managed conservatively, exemplified by our reported case. There are no reported cases of long-term sequalae. Conclusion: Nodule rupture is the second most common major complication of RFA. Based on the available evidence, we propose a treatment algorithm for nodule rupture and recommendations for future data collection to address gaps in our understanding of rupture etiology and effective management.

RAS mutations in thyroid cancer.

In recent years, our understanding of the genetic alterations underlying thyroid oncogenesis has greatly expanded. The use of molecular markers, including RAS, in the management of thyroid carcinoma is also increasing. This review summarizes the current literature surrounding RAS and discusses its potential as a diagnostic and prognostic indicator in the management of thyroid cancer.

BRAF V600E mutation independently predicts central compartment lymph node metastasis in patients with papillary thyroid cancer.

PURPOSE: This study was designed to examine whether available preoperative clinical parameters, including B-type Raf kinase (BRAF) V600E mutation status, can identify patients at risk for central compartment lymph node metastasis (CLNM). METHODS: Under an institutional review board-approved protocol, we conducted a single-center, retrospective review of all patients who had initial thyroidectomy for histologic papillary thyroid carcinoma (PTC) during 2010. The presence of CLNM was examined for correlation with available preoperative clinical parameters, including tumor size, gender, age, and BRAF mutation status. RESULTS: Cervical lymph node resection and molecular testing on FNAB or histopathologic specimen was performed on a consecutive series of 156 study patients with histologic PTC. Overall, CLNM was diagnosed in 37% and 46% were BRAF-mutation-positive. BRAF positivity was the only clinical parameter associated with CLNM (BRAF, p=0.002; tumor size≥2 cm, p=0.16; male gender, p=0.1; age≥45 years, p=0.3) and remained an independent predictor of CLNM on multiple logistic regression analysis (odds ratio (OR) 3.2, p=0.001). The PPV and NPV of BRAF positivity for CLNM was 50 and 74%, respectively. When restricting the analysis to the subset of 38 patients who had molecular testing performed preoperatively on FNAB, the PPV and NPV of BRAF positivity for CLNM was 47 and 91%, respectively, and BRAF positivity was still a significant predictor of CLNM on both univariate (OR 8.4, p=0.01) and multivariate (OR 9.7, p=0.02) analyses. CONCLUSIONS: Of the commonly used clinical parameters available preoperatively, the BRAF V600E mutation is the only independent predictor of CLNM in PTC and can be utilized to guide the extent of initial surgery.

Age-Associated Abnormalities of Water Homeostasis.

Deficits in renal function, thirst, and responses to osmotic and volume stimulation have been repeatedly demonstrated in older populations. The lessons learned over the past six decades serve to emphasize the fragile nature of water balance characteristic of aging. Older individuals are at increased risk for disturbances of water homeostasis due to both intrinsic disease and iatrogenic causes. These disturbances have real-life clinical implications in terms of neurocognitive effects, falls, hospital readmission and need for long-term care, incidence of bone fracture, osteoporosis, and mortality.

Molecular Profiles of Noninvasive, Minimally Invasive, and Invasive Follicular Patterned Thyroid Neoplasms with Papillary Nuclear Features.

Background: An increasing amount of data is being published, which risk-stratify thyroid tumors according to genetic signatures and histological morphology. Typically, follicular patterned lesions have been shown to harbor RAS-like mutations with more indolent behaviors. Our study aims to examine the extent of similarity among three groups of follicular patterned lesions with papillary nuclear features-noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) with capsular invasion and/or angioinvasion, and infiltrative follicular variant of papillary thyroid carcinoma (iFVPTC)-to help clarify whether NIFTP and EFVPTC represent a histological continuum and the degree to which the genomic landscape further separates higher risk follicular patterned tumors such as iFVPTC from more indolent ones (EFVPTC and NIFTP). Methods: ThyroSeq test results were compared for cases with histological NIFTP, EFVPTC, and iFVPTC in this retrospective study. Genetic drivers were subcategorized by level of aggressiveness. Gene expression alterations (GEAs) and copy number alterations (CNAs) were compared among the three histological groups. Results: NIFTP and EFVPTC cases displayed predominantly RAS-like alterations (100% and 75%, respectively) and RAS-like GEAs (55.2% and 47.2%, respectively), and many showed CNAs with 22q-loss. Despite a predominance of RAS-like alterations, EFVPTC cases showed molecular heterogeneity with significantly more intermediate and aggressive drivers (22.3% of cases) than NIFTP (0%) (p = 0.0068). iFVPTC cases displayed molecular profiles in between that of traditional follicular patterned lesions and classical papillary thyroid carcinoma, predominantly displaying intermediate and aggressive drivers (61.6%), which was significantly higher than that of EFVPTC (22.3%, p = 0.0158) and NIFTP (0%, p < 0.0001), illustrating the higher MAP kinase activity of iFVPTC. There was no significant difference, however, in comparing GEAs among the three histological groups. Conclusions: While follicular patterned lesions with papillary nuclear features overall tend to display RAS-like alterations, EFVPTC cases, followed by iFVPTC in this series, showed increasing proportions of more aggressive drivers. EFVPTC and NIFTP show much molecular overlap, with predominance of RAS-like alterations, suggesting that these tumors are part of a genetic continuum, while still ranked differentially. Preoperative molecular testing can potentially distinguish EFVPTC and iFVTPC from NIFTP based on a particular molecular signature, optimizing patient management.

General Principles for the Safe Performance, Training, and Adoption of Ablation Techniques for Benign Thyroid Nodules: An American Thyroid Association Statement.

Background: The primary goal of this interdisciplinary consensus statement is to provide a framework for the safe adoption and implementation of ablation technologies for benign thyroid nodules. Summary: This consensus statement is organized around three key themes: (1) safety of ablation techniques and their implementation, (2) optimal skillset criteria for proceduralists performing ablative procedures, and (3) defining expectations of success for this treatment option given its unique risks and benefits. Ablation safety considerations in pre-procedural, peri-procedural, and post-procedural settings are discussed, including clinical factors related to patient selection and counseling, anesthetic and technical considerations to optimize patient safety, peri-procedural risk mitigation strategies, post-procedural complication management, and safe follow-up practices. Prior training, knowledge, and steps that should be considered by any physician who desires to incorporate thyroid nodule ablation into their practice are defined and discussed. Examples of successful clinical practice implementation models of this emerging technology are provided. Conclusions: Thyroid ablative procedures provide valid alternative treatment strategies to conventional surgical management for a subset of patients with symptomatic benign thyroid nodules. Careful patient and nodule selection are critical to the success of these procedures as is extensive pre-procedural patient counseling. Although these emerging technologies hold great promise, they are not without risk and require the development of a unique skillset and environment for optimal, safe performance and consistent outcomes.

Molecular Profiling of 50 734 Bethesda III-VI Thyroid Nodules by ThyroSeq v3: Implications for Personalized Management.

CONTEXT: Comprehensive genomic analysis of thyroid nodules for multiple classes of molecular alterations detected in a large series of fine needle aspiration (FNA) samples has not been reported. OBJECTIVE: To determine the prevalence of clinically relevant molecular alterations in Bethesda categories III-VI (BCIII-VI) thyroid nodules. METHODS: This retrospective analysis of FNA samples, tested by ThyroSeq v3 using Genomic Classifier and Cancer Risk Classifier at UPMC Molecular and Genomic Pathology laboratory, analyzed the prevalence of diagnostic, prognostic, and targetable genetic alterations in a total of 50 734 BCIII-VI nodules from 48 225 patients. RESULTS: Among 50 734 informative FNA samples, 65.3% were test-negative, 33.9% positive, 0.2% positive for medullary carcinoma, and 0.6% positive for parathyroid. The benign call rate in BCIII-IV nodules was 68%. Among test-positive samples, 73.3% had mutations, 11.3% gene fusions, and 10.8% isolated copy number alterations. Comparing BCIII-IV nodules with BCV-VI nodules revealed a shift from predominantly RAS-like alterations to BRAF V600E-like alterations and fusions involving receptor tyrosine kinases (RTK). Using ThyroSeq Cancer Risk Classifier, a high-risk profile, which typically included TERT or TP53 mutations, was found in 6% of samples, more frequently BCV-VI. RNA-Seq confirmed ThyroSeq detection of novel RTK fusions in 98.9% of cases. CONCLUSION: In this series, 68% of BCIII-IV nodules were classified as negative by ThyroSeq, potentially preventing diagnostic surgery in this subset of patients. Specific genetic alterations were detected in most BCV-VI nodules, with a higher prevalence of BRAF and TERT mutations and targetable gene fusions compared to BCIII-IV nodules, offering prognostic and therapeutic information for patient management.

A combined molecular-pathologic score improves risk stratification of thyroid papillary microcarcinoma.

BACKGROUND: Thyroid papillary microcarcinoma (TPMC) is an incidentally discovered papillary carcinoma that measures ≤1.0 cm in size. Most TPMCs are indolent, whereas some behave aggressively. The objective of the study was to evaluate whether the combination of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation and specific histopathologic features allows risk stratification of TPMC. METHODS: A group aggressive TPMCs was selected based on the presence of lymph node metastasis or tumor recurrence. Another group of nonaggressive tumors included TPMCs matched with the first group for age, sex, and tumor size, but with no extrathyroid spread. A molecular analysis was performed, and histologic slides were scored for multiple histopathologic criteria. A separate validation cohort of 40 TPMCs was evaluated. RESULTS: BRAF mutations were detected in 77% of aggressive TPMCs and in 32% of nonaggressive tumors (P = .001). Several histopathologic features differed significantly between the groups. By using multivariate regression analysis, a molecular-pathologic (MP) score was developed that included BRAF status and 3 histopathologic features: superficial tumor location, intraglandular tumor spread/multifocality, and tumor fibrosis. By adding the histologic criteria to BRAF status, sensitivity was increased from 77% to 96%, and specificity was increased from 68% to 80%. In the independent validation cohort, the MP score stratified tumors into low-risk, moderate-risk, and high-risk groups with the probability of lymph node metastases or tumor recurrence in 0%, 20%, and 60% of patients, respectively. CONCLUSIONS: BRAF status together with several histopathologic features allowed clinical risk stratification of TPMCs. The combined MP risk stratification model was a better predictor of extrathyroid tumor spread than either mutation or histopathologic findings alone.

Minimally Invasive Techniques for the Management of Thyroid Nodules.

Image-guided interventional techniques have emerged as promising treatments for thyroid disease. Percutaneous ethanol ablation, radiofrequency ablation, laser ablation, high intensity focused ultrasound, and microwave ablation have shown efficacy in treating benign thyroid disease. There is increasing evidence that these techniques may effectively treat papillary thyroid microcarcinomas, recurrent and metastatic disease, follicular neoplasms, and parathyroid lesions. They are performed in an outpatient setting, well-tolerated, with negligible risk for thyroid hormone supplementation, making them a popular alternative to surgical resection. In this comprehensive review, we discuss the devices, techniques, advantages, and disadvantages of each intervention, and summarize the published outcomes.

Both BRAF V600E mutation and older age (≥ 65 years) are associated with recurrent papillary thyroid cancer.

PURPOSE: This study was designed to examine the aggressive features of BRAF-positive papillary thyroid cancer (PTC) and association with age. METHODS: We compared the clinicopathologic parameters and BRAF V600E mutation status of 121 elderly (age ≥65 years) PTC patients who underwent thyroidectomy from January 2007 to December 2009 to a consecutive cohort of 98 younger (age <65 years) PTC patients. RESULTS: Younger and elderly PTC patients had similar incidences of BRAF-positive tumors (41% vs. 38%; p = 0.67). The elderly cohort was more likely to have smaller tumors (mean 1.6 vs. 2.1 cm; p = 0.001), present with advanced TNM stage (36% vs. 19%; p = 0.008), and have persistent/recurrent disease (10% vs. 1%; p = 0.006). BRAF-positive status was associated with PTC that were tall cell variant (p < 0.001), had extrathyroidal extension (p < 0.001), lymph node involvement (p = 0.008), advanced (III/IV) TNM stage (p < 0.001), and disease recurrence (p < 0.001). Except for lymph node involvement, the association between aggressive histology characteristics at presentation and BRAF-positive PTC also was observed within the age-defined cohorts. In short-term follow-up (mean, 18 months), persistent/recurrent PTC was much more likely to occur in patients who were both BRAF-positive and elderly (22%). CONCLUSIONS: BRAF mutations are equally present in younger and older patients. Aggressive histology characteristics at presentation are associated with BRAF-positive PTC, irrespective of age. However, the well-established association of BRAF with recurrence is limited to older (age ≥65 years) patients.

Cancer risk and clinicopathological characteristics of thyroid nodules harboring thyroid-stimulating hormone receptor gene mutations.

BACKGROUND: Thyroid-stimulating hormone receptor (TSHR) gene mutations play a critical role in thyroid cell proliferation and function. They are found in 20%-82% of hyperfunctioning nodules, hyperfunctioning follicular thyroid cancers (FTC), and papillary thyroid cancers (PTC). The diagnostic importance of TSHR mutation testing in fine needle aspiration (FNA) specimens remains unstudied. METHODS: To examine the association of TSHR mutations with the functional status and surgical outcomes of thyroid nodules, we evaluated 703 consecutive thyroid FNA samples with indeterminate cytology for TSHR mutations using next-generation sequencing. Testing for EZH1 mutations was performed in selected cases. The molecular diagnostic testing was done as part of standard of care treatment, and did not require informed consent. RESULTS: TSHR mutations were detected in 31 (4.4%) nodules and were located in exons 281-640, with codon 486 being the most common. Allelic frequency ranged from 3% to 45%. Of 16 cases (12 benign, 3 FTC, 1 PTC) with surgical correlation, 15 had solitary TSHR mutations and 1 PTC had comutation with BRAF V600E. Hyperthyroidism was confirmed in all 3 FTC (2 overt, 1 subclinical). Of 5 nodules with solitary TSHR mutations detected at high allelic frequency, 3 (60%) were FTC. Those at low allelic frequency (3%-22%) were benign. EZH1 mutations were detected in 2 of 4 TSHR-mutant malignant nodules and neither of 2 benign nodules. CONCLUSION: We report that TSHR mutations occur in ∼5% thyroid nodules in a large consecutive series with indeterminate cytology. TSHR mutations may be associated with an increased cancer risk when present at high allelic frequency, even when the nodule is hyperfunctioning. Benign nodules were however most strongly correlated with TSHR mutations at low allelic frequency.

Hyperthyroidism.

Thyrotoxicosis is a condition resulting from elevated levels of thyroid hormone. In this article, the authors review the presentation, diagnosis, and management of various causes of thyrotoxicosis.