Predictors of radioiodine (RAI)-avidity restoration for NTRK fusion-positive RAI-resistant metastatic thyroid cancers.

Context: Two-thirds of metastatic differentiated thyroid cancer (DTC) patients have radioiodine (RAI)-resistant disease, resulting in poor prognosis and high mortality. For rare NTRK and RET fusion-positive metastatic, RAI-resistant thyroid cancers, variable success of re-induction of RAI avidity during treatment with NTRK or RET inhibitors has been reported. Case presentation and results: We report two cases with RAI-resistant lung metastases treated with larotrectinib: an 83-year-old male presenting with an ETV6::NTRK3 fusion-positive tumor with the TERT promoter mutation c.-124C>T, and a 31-year-old female presenting with a TPR::NTRK1 fusion-positive tumor (and negative for TERT promoter mutation). Post larotrectinib treatment, diagnostic I-123 whole body scan revealed unsuccessful RAI-uptake re-induction in the TERT-positive tumor, with a thyroid differentiation score (TDS) of -0.287. In contrast, the TERT-negative tumor exhibited successful I-131 reuptake with a TDS of -0.060. Conclusion: As observed for RAI-resistance associated with concurrent TERT and BRAF mutations, the co-occurrence of TERT mutations and NTRK fusions may also contribute to re-sensitization failure.

The Prospective Implementation of the 2015 ATA Guidelines and Modified ATA Recurrence Risk Stratification System for Treatment of Differentiated Thyroid Cancer in a Canadian Tertiary Care Referral Setting.

Objective: To present clinical outcomes of the prospective implementation of the 2015 American Thyroid Association (ATA) guidelines for the management of thyroid nodules and differentiated thyroid cancer (DTC) using the modified ATA recurrence risk (RR) stratification system. Methods: We prospectively analyzed 612 patients with DTC treated between April 2017 and December 2021 in Calgary, Alberta. Each patient was prospectively assigned a modified ATA RR and American Joint Committee Cancer 8th edition stage. Initial risk stratification and consideration of the 2015 ATA guidelines guided surgical management as well as the indication for and dose of radioiodine (RAI) and other adjuvant therapies. Patients were assessed for their response to treatment (RTT) at 2-years postoperatively. Results: There were 479 patients who had 2-year follow-up data and were included in the study. Of these patients, there were 253 (53%) low-, 129 (27%) intermediate-, and 97 (20%) high-RR patients. Of these, 227 patients (47%) underwent total thyroidectomy (TTX) plus RAI, 178 (37%) underwent TTX only, and 74 (16%) underwent lobectomy. The RTT at 2 years was excellent for 89% (66) of patients with lobectomy, 84% (149) for TTX only, and 53% (121) for TTX plus RAI. Among 253 patients who were deemed low RR, 85% (216) had excellent RTT, 13% (32) indeterminate RTT, 2% (4) biochemical incomplete RTT, and 1 patient had structural incomplete RTT. The intermediate RR group had the following RTT outcomes: 64% (83) excellent, 23% (30) indeterminate, 6% (7) biochemical incomplete, and 7% (9) structural incomplete. The high RR group had the worst RTT outcomes, with 38% (37) excellent, 19% (18) indeterminate, 10% (10) biochemical incomplete, and 33% (32) structural incomplete RTT. Conclusions: The 2015 ATA RR stratification system is useful for predicting disease status at 2-year post-treatment in patients with DTC. The 2015 ATA guidelines and modified ATA RR stratification treatment recommendations may reduce thyroid cancer overtreatment by including lobectomy as a definitive treatment option for low-risk thyroid cancers and selective use of RAI for intermediate and high-risk patients.

Accuracy of Thyroid Fine-Needle Aspiration Cytology: A Cyto-Histologic Correlation Study in an Integrated Canadian Health Care Region with Centralized Pathology Service.

INTRODUCTION: The reported ROM within TBSRTC categories varies widely and depends on several factors in the clinical care pathway for thyroid nodules, including sonographic risk stratification, cytology expertise, selection criteria for surgical resection, and definitions of malignancy used. METHODS: We present 5,867 consecutive thyroid FNAC and corresponding surgical pathology in the context of a comprehensive, single-payer health care system with centralized cytology and surgical pathology services for over 1.5 million inhabitants. RESULTS: We report higher usage of ND and AUS/FLUS categories than the literature (19% vs. <10% and 15% vs. <10%, respectively). Our surgical resection rate for malignant cytology is substantially higher than the literature (94% vs. 50%, respectively). The ROM by the TBSRTC category in our cohort was similar to the literature. The overall diagnostic accuracy of thyroid FNAC was 92%, which is similar to other studies. Inclusion of incidental PMC as histologically malignant raised the ROM in the ND, benign, and AUS/FLUS categories. DISCUSSION: The diagnostic performance of thyroid FNAC in our study is similar to the reported literature. Differences in TBSRTC category usage likely arise from cytologist variability and expertise. Our higher surgical resection rate in the malignant cytology category reflects the greater capture of surgical follow-up within our healthcare region with centralized pathology and a single EMR system. Keeping in mind the method of calculation of ROM, the malignancy rate by TBSRTC is similar to previous reports.

A Protocol for a Pan-Canadian Prospective Observational Study on Active Surveillance or Surgery for Very Low Risk Papillary Thyroid Cancer.

Background: The traditional management of papillary thyroid cancer (PTC) is thyroidectomy (total or partial removal of the thyroid). Active surveillance (AS) may be considered as an alternative option for small, low risk PTC. AS involves close follow-up (including regularly scheduled clinical and radiological assessments), with the intention of intervening with surgery for disease progression or patient preference. Methods: This is a protocol for a prospective, observational, long-term follow-up multi-centre Canadian cohort study. Consenting eligible adults with small, low risk PTC (< 2cm in maximal diameter, confined to the thyroid, and not immediately adjacent to critical structures in the neck) are offered the choice of AS or surgery for management of PTC. Patient participants are free to choose either option (AS or surgery) and the disease management course is thus not assigned by the investigators. Surgery is provided as usual care by a surgeon in an institution of the patient's choice. Our primary objective is to determine the rate of 'failure' of disease management in respective AS and surgical arms as defined by: i) AS arm - surgery for progression of PTC, and ii) surgical arm - surgery or other treatment for disease persistence or progression after completing initial treatment. Secondary outcomes include long-term thyroid oncologic and treatment outcomes, as well as patient-reported outcomes. Discussion: The results from this study will provide long-term clinical and patient reported outcome evidence regarding active surveillance or immediate surgery for management of small, low risk PTC. This will inform future clinical trials in disease management of small, low risk papillary thyroid cancer. Registration details: This prospective observational cohort study is registered on clinicaltrials.gov (NCT04624477), but it should not be considered a clinical trial as there is no assigned intervention and patients are free to choose either AS or surgery.

Malignancy risk of hyperfunctioning thyroid nodules compared with non-toxic nodules: systematic review and a meta-analysis.

BACKGROUND: Hyperfunctioning or hot nodules are thought to be rarely malignant. As such, current guidelines recommend that hot nodules be excluded from further malignancy risk stratification. The objective of this systematic review and meta-analysis is to compare the malignancy risk in hot nodules and non-toxic nodules in observational studies. METHODS: Ovid MEDLINE Daily and Ovid MEDLINE, EMBASE, Scopus, and Web of Science databases were searched. Observational studies which met all of the following were included: (1) use thyroid scintigraphy for nodule assessment, (2) inclusion of both hyperfunctioning and non-functioning nodules based on scintigraphy, (3) available postoperative histopathologic nodule results, (4) published up to November 12, 2020 in either English or French. The following data was extracted: malignancy outcomes include malignancy rate, mapping of the carcinoma within the hot nodule, inclusion of microcarcinomas, and presence of gene mutations. RESULTS: Among the seven included studies, overall incidence of malignancy in all hot thyroid nodules ranged from 5 to 100% in comparison with non-toxic nodules, 3.8-46%. Odds of malignancy were also compared between hot and non-toxic thyroid nodules, separated into solitary nodules, multiple nodules and combination of the two. Pooled odds ratio (OR) of solitary thyroid nodules revealed a single hot nodule OR of 0.38 (95% confidence interval (CI) 0.25, 0.59), toxic multinodular goiter OR of 0.51 (95% CI 0.34, 0.75), and a combined hot nodule OR of 0.45 (95% CI 0.31, 0.65). The odds of malignancy are reduced by 55% in hot nodules; however, the incidence was not zero. CONCLUSIONS: Odds of malignancy of hot nodules is reduced compared with non-toxic nodules; however, the incidence of malignancy reported in hot nodules was higher than expected. These findings highlight the need for further studies into the malignancy risk of hot nodules.

Sensitive Sequencing Analysis Suggests Thyrotropin Receptor and Guanine Nucleotide-Binding Protein G Subunit Alpha as Sole Driver Mutations in Hot Thyroid Nodules.

Background: Constitutively activating mutations in the thyrotropin receptor (TSHR) and the guanine nucleotide-binding protein G subunit alpha (GNAS) are the primary cause of hot thyroid nodules (HTNs). The reported prevalence of TSHR and GNAS mutations in HTNs varies. Previous studies show TSHR mutations in 8-82% of HTNs and GNAS mutations in 8-75% of HTNs. With sensitive and comprehensive targeted next-generation sequencing (tNGS), we re-evaluated the prevalence of TSHR and GNAS mutations in HTNs. Methods: Samples from three previous studies found to be TSHR and GNAS mutation negative were selected and re-evaluated using high-resolution melting (HRM) PCR. Remaining mutation negative samples were further reanalyzed by tNGS with a sequencing depth between 3000 × and 10,000 × . Our tNGS panel covered the entire TSHR coding sequence along with mutation hot spots in GNAS. Sequencing reads were aligned to reference and variants were called using Torrent Suite software v5.8. Results: In total, 154 of 182 previously mutation negative HTNs were positive for TSHR or GNAS mutations, resulting in an 85% prevalence of TSHR and GNAS mutations in HTNs, 79% and 6%, respectively. In a subset of 25 HTNs with multiple samples per nodule, and analyzed by tNGS at high sequencing depth, TSHR mutations were detected in 23 (92%) HTNs and 1 GNAS mutation was detected in 1 (4%) HTN, 96% mutation positive HTNs in this subset. Conclusions: Owing to the higher sensitivity of tNGS as compared with denaturing gradient gel electrophoresis and HRM-PCR, TSHR or GNAS mutations could be detected in 85% of HTNs. The detection of TSHR and GNAS mutations occurred in 96% of HTNs in a sample set with multiple samples per nodule analyzed by tNGS. Taken together with the fact that no other driver mutations could be identified by whole exome sequencing, our study strongly supports the hypothesis that TSHR and GNAS mutations are the main somatic mutations leading to HTNs.

Using the American Thyroid Association Risk-Stratification System to Refine and Individualize the American Joint Committee on Cancer Eighth Edition Disease-Specific Survival Estimates in Differentiated Thyroid Cancer.

BACKGROUND: The eighth edition of the American Joint Committee on Cancer (AJCC) staging system has reclassified up to one third of differentiated thyroid cancer patients into one of the younger prognostic stage groups (<55 years of age at diagnosis, stage I or stage II). This reclassification widens the spectrum of disease in these lower stages without significantly impacting overall disease-specific survival (DSS) for the entire stage group. However, the optimistic DSS estimates in the <55-year-old stage groups may not accurately reflect the prognosis of individual patients with American Thyroid Association (ATA) high-risk features. Therefore, the aim of this study was to integrate the ATA risk classification system into the eighth edition AJCC staging system to refine and individualize DSS estimates for differentiated thyroid cancer patients aged <55 years at diagnosis. METHODS: Using the Memorial Sloan Kettering Cancer Center tumor registry, 4881 adult DTC patients aged <55 years at diagnosis receiving initial therapy between 1980 and 2016 were retrospectively analyzed. Using Memorial Sloan Kettering Cancer Center registry coded data, all patients were assigned an eighth edition AJCC stage (I or II), ATA risk of recurrence (low, intermediate, or high), and age group at diagnosis (younger patients defined as ≤45 years old, older patients defined as 45-55 years old). The primary outcome was 10-year DSS. RESULTS: A total of 122 (2.5%) disease-related deaths were observed in the cohort of 4881 patients during a median follow-up of 6.6 years. Integration of the AJCC stage, ATA risk, and age groups identified six subgroups with differing outcomes: (i) stage I/ATA low risk, younger and older, 100% DSS; (ii) stage I/ATA intermediate risk, younger and older, 98% DSS; (iii) stage I/ATA high risk, younger, 95% DSS; (iv) stage I/ATA high risk, older, 89% DSS; (v) stage II/ATA high risk, younger, 78% DSS; and (vi) stage II/ATA high risk, older, 61% DSS. CONCLUSIONS: Integration of AJCC stage, ATA risk, and age group (i) identifies six subgroups of patients with progressively worse DSS as AJCC stage, ATA risk, and age increases, and (ii) provides a more individualized estimate of DSS, especially in ATA high-risk patients.

Thyroid nodule ultrasound reports in routine clinical practice provide insufficient information to estimate risk of malignancy.

PURPOSE: Ultrasonographic characteristics of thyroid nodules play an important role in estimating the risk of malignancy (ROM). Guidelines mandate all thyroid nodules be characterized by six key ultrasonographic features to estimate the ROM. Our objective was to evaluate how frequently these characteristics were identified by radiologists and the ensuing utility to estimate ROM. METHODS: We retrospectively reviewed 1930 consecutive diagnostic thyroid ultrasound reports from a large community radiology practice. A total of 1339 individual patients were found to have one or more thyroid nodules. Each report was analyzed for six key ultrasonographic features. A utility score (UtS) was calculated (range 0-6) with a single point given for a comment on each feature. RESULTS: Of the 1339 patients, 75% of the studies reported more than one nodule (mean number of nodules = 3.4). Mean maximal diameter of the largest nodule per patient = 1.8 cm. The mean UtS was 2.57. Nodule size did not influence the UtS.: Nodule <1 cm (UtS: 2.53), 1-2 cm (UtS: 2.68) and >2 cm (UtS: 2.49). We believe a UtS of four or greater is needed to confidently estimate ROM: we found this in 13.7% of reports. CONCLUSIONS: Our retrospective analysis of a large number of consecutive thyroid ultrasound reports in routine clinical practice suggests that the vast majority provide insufficient information to allow the clinician to risk stratify the nodules by estimating the ROM. This could lead to both over-diagnosis and over-treatment of benign/indolent thyroid lesions or under-diagnosis of clinically important thyroid cancers.

Molecular profiling of thyroid nodule fine-needle aspiration cytology.

The differential diagnosis and malignancy risk stratification of thyroid nodules requires multidisciplinary expertise and knowledge of both local ultrasonography practices and the local malignancy rates for a given fine-needle aspiration (FNA) result. Even in such a multidisciplinary setting, FNA cytology has the inherent limitation that indeterminate cytology results cannot distinguish between follicular adenomas, follicular thyroid carcinomas or follicular variant papillary thyroid carcinomas. Accumulating evidence suggests that this limitation can be overcome by using molecular diagnostic approaches. In this Review, we present the advantages and disadvantages of the different molecular diagnostic methodologies, which can be divided into two approaches: those that 'rule out' malignancy (to reduce the overtreatment of benign nodules) and those that 'rule in' malignancy (to optimize surgical planning). We identify microRNA classifiers as potential additional markers for use in a two-step diagnostic approach, consider the potential implications of the reclassification of noninvasive encapsulated follicular variant papillary thyroid carcinomas to noninvasive follicular thyroid neoplasms with papillary-like nuclear features and discuss the cost-effectiveness of molecular testing. Molecular FNA diagnostics is an important complementary addition to FNA cytology that could substantially reduce unnecessary surgery and better define the need for appropriate surgery in patients who have thyroid nodules with indeterminate FNA cytology.