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Context: The BRAFV600E mutation has been associated with more advanced clinical stage in papillary thyroid cancer (PTC) and decreased responsiveness to radioiodine (RAI). However, some BRAF mutant PTCs respond to RAI and have an indolent clinical behavior suggesting the presence of different subtypes of BRAF mutant tumors with distinct prognosis., Objective: To characterize the molecular and clinical features of 2 subtypes of BRAF-mutant PTCs defined by their degree of expression of iodine metabolism genes., Design: 227 BRAF-mutant PTCs from the Cancer Genome Atlas Thyroid Cancer study were divided into 2 subgroups based on their thyroid differentiation score (TDS): BRAF-TDShi and BRAF-TDSlo. Demographic, clinico-pathological, and molecular characteristics of the 2 subgroups were compared., Results: Compared to BRAF-TDShi tumors (17%), BRAF-TDSlo tumors (83%) were more frequent in blacks and Hispanics (6% vs 0%, P = 0.035 and 12% vs 0%, P = 0.05, respectively), they were larger (2.95 ± 1.7 vs 2.03 ± 1.5, P = 0.002), with more tumor-involved lymph nodes (3.9 ± 5.8 vs 2.0 ± 4.2, P = 0.042), and a higher frequency of distant metastases (3% vs 0%, P = 0.043). Gene set enrichment analysis showed positive enrichment for RAS signatures in the BRAF-TDShi cohort, with corresponding reciprocal changes in the BRAF-TDSlo group. Several microRNAs (miRs) targeting nodes in the transforming growth factor β (TGFβ)-SMAD pathway, miR-204, miR-205, and miR-144, were overexpressed in the BRAF-TDShi group. In the subset with follow-up data, BRAF-TDShi tumors had higher complete responses to therapy (94% vs 57%, P < 0.01) than BRAF-TDSlo tumors., Conclusion: Enrichment for RAS signatures, key genes involved in cell polarity and specific miRs targeting the TGFβ-SMAD pathway define 2 subtypes of BRAF-mutant PTCs with distinct clinical characteristics and prognosis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI)., Objectives: To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR)., Design: This was a pilot trial that enrolled from June 2014 to January 2016., Setting: Academic cancer center., Patients: Patients with RAIR, BRAF mutant thyroid cancer., Intervention: Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation., Main Outcome Measure: The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I., Results: Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048)., Conclusions: Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit., (Copyright © 2019 Endocrine Society.)

Context: This review provides historical context to recent developments in the classification of the follicular variant of papillary thyroid carcinoma (FVPTC). The evolution of the diagnostic criteria for papillary thyroid carcinoma is described, clarifying the role of molecular analysis and the impact on patient management., Methods: A PubMed search using the terms "follicular variant" and "papillary thyroid carcinoma" covering the years 1960 to 2016 was performed. Additional references were identified through review of the citations of the retrieved articles., Results: The encapsulated/well-demarcated, noninvasive form of FVPTC that occurs annually in 45,000 patients worldwide was thought for 30 years to be a carcinoma. Many studies have shown almost no recurrence in these noninvasive tumors, even in patients treated by surgery alone without radioactive iodine therapy. The categorization of the tumor as outright cancer has led to aggressive forms of treatment, with their side effects, financial costs, and the psychological and social impacts of a cancer diagnosis. Recently, the encapsulated/well-demarcated, noninvasive FVPTC was renamed as noninvasive follicular thyroid neoplasm with papillary-like nuclear features. The new terminology lacks the carcinoma label, enabling clinicians to avoid aggressive therapy., Conclusions: By understanding the history of FVPTC, future classification of tumors will be greatly improved., (Copyright © 2017 by the Endocrine Society)

Background: TERT encodes the reverse transcriptase component of telomerase, which adds telomere repeats to chromosome ends, thus enabling cell replication. Telomerase activity is required for cell immortalization. Somatic TERT promoter mutations modifying key transcriptional response elements were recently reported in several cancers, such as melanomas and gliomas., Objectives: The objectives of the study were: 1) to determine the prevalence of TERT promoter mutations C228T and C250T in different thyroid cancer histological types and cell lines; and 2) to establish the possible association of TERT mutations with mutations of BRAF, RAS, or RET/PTC., Methods: TERT promoter was PCR-amplified and sequenced in 42 thyroid cancer cell lines and 183 tumors: 80 papillary thyroid cancers (PTCs), 58 poorly differentiated thyroid cancers (PDTCs), 20 anaplastic thyroid cancers (ATCs), and 25 Hurthle cell cancers (HCCs)., Results: TERT promoter mutations were found in 98 of 225 (44%) specimens. TERT promoters C228T and C250T were mutually exclusive. Mutations were present in 18 of 80 PTCs (22.5%), in 40 of 78 (51%) advanced thyroid cancers (ATC + PDTC) (P = 3 × 10(-4) vs PTC), and in widely invasive HCCs (4 of 17), but not in minimally invasive HCCs (0 of 8). TERT promoter mutations were seen more frequently in advanced cancers with BRAF/RAS mutations compared to those that were BRAF/RAS wild-type (ATC + PDTC, 67.3 vs 24.1%; P < 10(-4)), whereas BRAF-mutant PTCs were less likely to have TERT promoter mutations than BRAF wild-type tumors (11.8 vs 50.0%; P = .04)., Conclusions: TERT promoter mutations are highly prevalent in advanced thyroid cancers, particularly those harboring BRAF or RAS mutations, whereas PTCs with BRAF or RAS mutations are most often TERT promoter wild type. Acquisition of a TERT promoter mutation could extend survival of BRAF- or RAS-driven clones and enable accumulation of additional genetic defects leading to disease progression.

Background: The mutated BRAF V600E protein has been specifically detected in papillary thyroid carcinomas (PTCs) using immunohistochemical (IHC) analysis. The clonal origin of PTCs harboring BRAF mutations has recently been called into question., Objectives: The purpose of this study was 2-fold: (1) to compare BRAF V600E IHC expression in PTCs, poorly differentiated thyroid carcinomas (PDTCs), and anaplastic thyroid carcinomas (ATCs) with DNA mutation analysis; and (2) to study the distribution of BRAF V600E IHC staining within thyroid cancer tissues., Methods: Whole sections and tissue microarrays from 31 PTCs, 38 PDTCs, and 22 ATCs were subjected to both mass spectrometry genotyping for the BRAF(T1799A) mutation as well as IHC staining for BRAF V600E protein., Results: Of the 31 PTCs, 16 (52%) showed strong (3+) IHC staining and harbored BRAF(T1799A), whereas the remaining 15 (48%) showed absent/faint (0/1+) staining, and were wild type for BRAF (BRAF-wt). Only 5 of 38 (13%) PDTCs harbored mutant BRAF, and these were the only ones with moderate (2+) or 3+ IHC staining. All 14 ATCs with a staining intensity of 3+ harbored BRAF(T1799A), whereas the 2 ATCs with 0/1+ staining were BRAF-wt. Six ATCs showed staining of 2+, 5 of which had high background staining. Of those 6 cases, BRAF(T1799A) was present only in the tumor without background. Homogeneous staining was found in 13 of 14 (93%) PTCs, 3 of 3 (100%) PDTCs, and 12 of 14 ATCs (86%)., Conclusions: First, absent/faint staining for BRAF V600E correlates perfectly with the lack of the BRAF(T1799A) mutation, whereas strong staining is highly specific for the BRAF(T1799A) mutation in PTCs, PDTCs, and ATCs. Moderate staining intensity cannot be relied on and should lead to genotypic analysis. Second, homogeneous staining occurs in the vast majority of cases, demonstrating that the BRAF(T1799A) mutation is a clonal event in thyroid cancer.

Background: Radioiodine (RAI) remains the mainstay of therapy for RAI-avid (RAIA) distant metastatic thyroid carcinoma. We previously demonstrated that RAI-refractory distant metastatic thyroid cancers commonly harbor BRAF mutations. However, the molecular profile of RAIA metastatic thyroid cancer is unknown. Here we describe the mutational profile of thyroid tumors from follicular cell-derived cancer (FCDTC) patients presenting with RAIA distant metastases. In addition, we aimed to correlate clinical outcomes of RAI therapy with clinicopathological factors and tumor mutational status., Methods: We retrospectively identified 43 patients with FCDTC who had RAI uptake in the lungs and/or bones on their initial ¹³¹I postablation scan. Primary tumors were genotyped for known mutations in thyroid cancer genes. Structural response to RAI was assessed 6-18 months after each administered RAI activity and at the end of follow-up., Results: RAS, BRAF, RET/PTC, and PIK3CA mutations were found in 42, 23, 10, and 2% of tumors, respectively, and the remaining 23% were wild type. None of these patients achieved cure after repeat RAI therapies, and most patients (54%) experienced disease progression despite repeated RAI administration. There was an increased prevalence of RAS mutations in these RAIA tumors. RAS-mutant cancers were more likely to concentrate iodine on diagnostic whole body scans. Despite this, structural response to RAI was not influenced by tumor genotype., Conclusions: RAIA metastatic FCDTC are overrepresented with RAS mutations, whereas RAI refractory metastatic thyroid cancers are enriched with BRAF mutations. Despite a seemingly preserved ability to concentrate iodine, RAI therapy is ineffective in achieving cure in most patients with RAIA metastatic FCDTC, even in RAS-mutant disease. These poor outcomes may be improved based on recent evidence that pretreatment with MAPK kinase 1/2 inhibitors enhances responses to RAI, particularly in patients with RAS-mutant tumors.

Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome., Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs., Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC., Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons., Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.

Clinical recurrences of differentiated thyroid carcinoma occur in 20% of patients after thyroid surgery. We performed a retrospective analysis of a cohort of patients undergoing routine follow-up testing to detect recurrent thyroid carcinoma over a 2-yr period. One group was prepared for testing by thyroid hormone withdrawal (THW), and the other group remained on thyroid hormone and received injections of recombinant human TSH (rhTSH) before diagnostic whole-body radioiodine scanning (DxWBS). We hypothesized that no differences in the ability to detect residual disease would exist between these 2 groups. Two hundred and eighty-nine patients were examined by both DxWBS and by measurement of the serum thyroglobulin (Tg) response to elevated TSH levels. THW was used for 161 patients, and rhTSH preparation was used for 128 patients. Based on all available testing results, we categorized patients as having metastatic disease, thyroid bed uptake only, or no evidence of disease. We examined the sensitivity, specificity, positive and negative predictive values of the DxWBS, and the stimulated Tg after preparation by THW or rhTSH. Patients with thyroid bed were not considered in accuracy testing. The sensitivity and specificity of the 2 tests were comparable between groups. No significant differences were present in the positive or negative predictive values between groups. The highest negative predictive value (97%) was in patients who had both a negative DxWBS and low stimulated Tg levels after rhTSH. In summary, we were unable to demonstrate a difference in the diagnostic accuracy of DxWBS and/or Tg between patients prepared by either THW or rhTSH. We conclude that preparing patients by rhTSH is diagnostically equivalent to preparing them by THW.