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Objective: Molecular testing is a well-established tool that assists in the management of thyroid nodules. We describe our experience using molecular testing of thyroid nodules with Bethesda III to VI cytology., Methods: This is a retrospective multicenter, multinational study of thyroid nodules that underwent preoperative molecular profiling with ThyGenX/ThyGeNEXT or ThyroSeq V3 between 2015 and 2022. The clinical characteristics and mutational profiles of tumors were compared. Collected data included demographics, cytology results, surgical pathology, and molecular alterations. Molecular alterations were categorized into 3 main phenotypes: BRAF-like, RAS-like, and non-BRAF-non-RAS (NBNR)., Results: Overall, 784 patients who had surgery were included, of which 603 (76.2%) were females. The most common histologic type was papillary thyroid cancer (PTC) with 727 (91.9%) cases. In total, 205 (28.2%) cases showed an aggressive subtype of PTC (eg, tall cell and hobnail). BRAF-like alterations were most likely to be found in Bethesda V and VI nodules and show extrathyroidal extension (ETE), nodal disease, and/or aggressive subtypes of PTC (P < .001 for all). RAS-like alterations were more commonly found in Bethesda III and IV nodules and were less likely to show ETE, nodal disease, and/or aggressive histology (P < .001 for all). NBNR alterations were more commonly found in Bethesda III and IV nodules and were less likely to show ETE, nodal disease, and/or aggressive subtypes of PTC. However, they were rarely but significantly associated with poorly differentiated thyroid cancer (P < .005)., Conclusion: Molecular testing of thyroid nodules can help determine the likelihood of malignancy and classify nodules into several tumor phenotypes, predicting their behaviors and potentially allowing for a more tailored treatment. NBNR alterations should be managed with caution., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Background: Genomic testing has enhanced pre-surgical decision making for cytologically indeterminate thyroid nodules, but there remains uncertainty regarding RAS mutations. The addition of extra genetic alterations to previous driver mutation panels has been shown to improve predictive value. This study aims to evaluate the relationship between the mutant allele frequency (AF) and likelihood of malignancy in thyroid nodules with RAS mutations., Methods: A retrospective cohort review was performed evaluating patients with indeterminate cytology (Bethesda categories III, IV and V) and ThyroSeq® v3 testing demonstrating a RAS mutation, who underwent surgery. Univariate and multivariate regression analyses were used to evaluate relationships between AF, other genetic alterations, and malignancy., Results: Thirty-nine patients met criteria, 77% of the thyroid nodules (30/39) were found to be malignant. None demonstrated aggressive pathology. On univariate regression, there was no relationship between AF and likelihood of malignancy. There was, however, a significant correlation between AF and the rate of an additional genetic alteration. Multivariate analysis found a trend between RAS, a second genetic alteration and malignancy, but it did not reach statistical significance., Conclusions: There was no direct relationship between the level of allelic frequency in thyroid nodules expressing RAS mutations and the likelihood of malignancy. There was a statistically significant relationship between increasing AF and the presence of a second genetic abnormality, suggesting a possible progression from initial driver mutation and then a second genetic alteration prior to malignant transformation., (© 2023. The Author(s).)

Background: The EIF1AX mutation has been identified in various benign and malignant thyroid lesions, with a higher prevalence in poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma, especially when combined with RAS or TP53 mutation. However, data and clinical significance of EIF1AX mutations in thyroid nodules is still limited. We investigated the prevalence of EIF1AX mutations and co-mutations in cytologically indeterminate thyroid nodules at our institution., Methods: A 5-year retrospective analysis was performed on surgically resected thyroid nodules with identified EIF1AX mutations on molecular testing with ThyroseqV3 ® . Mutation type and presence of co-mutations were correlated with histopathologic diagnosis and clinical characteristics. Histopathology diagnoses were subsequently categorized as benign, borderline, malignant or aggressive malignant (≥ 10% PDTC component). Chi-square test was used to compare the malignancy associations of the: 1) A113&#95;splice mutation compared to non-A113&#95;splice mutations 2) singular A113&#95;splice mutations compared to singular non-A113&#95;splice mutations. Fisher's Exact Test was used to determine the association of A113&#95;splice mutation with aggressive malignancies compared to non-A113&#95;splice mutations. A p value of 0.05 or less was considered statistically significant., Results: Out of 1583 patients who underwent FNA, 621 had further molecular testing. 31 cases (5%) harbored EIF1AX mutations. Of these cases, 12 (38.7%) were malignant, 2 (6.5%) were borderline, and 17 (55%) were benign. 4/31 cases (13%) were aggressive malignant (≥ 10% PDTC component). The most prevalent mutation was the A113&#95;splice mutation at the junction of intron 5 and exon 6 (48%). All other mutations, except one, were located at the N-terminal in exon 2. 7/31 cases (22.6%) harbored ≥ 1 co-mutation(s), including 4 RAS, 3 TP53, 1 TERT and 1 PIK3CA, with 86% of them being malignant. All 4 nodules with RAS co-mutations were malignant including one PDTC., Conclusion: Our study reports the largest cohort of EIF1AX mutations in Bethesda III/IV FNA samples with surgical follow-up to our knowledge. The presence of the EIF1AX mutation confers a 45.2% risk of malignancy (ROM) or borderline after surgery. However, the coexistence of EIF1AX mutations with other driver mutations such as RAS, TERT or TP53 conferred an 86% ROM. While 55% of thyroid nodules were benign at the time of surgery, the possible malignant transformation of these nodules, had they not been resected, is unknown. Finally, 13% of the nodules with EIF1AX mutations were aggressive with a significant PDTC component. These findings can further aid in clinical decisions for patients with thyroid nodules., (© 2022. The Author(s).)

Objectives: The aim of this study was to ascertain the relationship between Bethesda category and molecular mutation of thyroid nodules in patients undergoing thyroidectomy., Design: A retrospective cohort of patients who underwent thyroidectomy following needle biopsy and molecular profile testing was performed., Setting: Two tertiary care academic hospitals., Participants: Consecutive patients with a dominant thyroid nodule who underwent both USFNA and molecular profile testing followed by thyroidectomy were included in the study., Main Outcome and Measures: The main outcome was postoperative diagnosis of thyroid cancer and aggressivity of disease based on histopathological variants, nodal metastasis or extra-thyroidal extension. Associations between Bethesda category, molecular mutation and postoperative pathology was assessed using descriptive analysis and chi-square testing., Results: Four hundred fifty-one patients were included. 95.9% (93/97) of patients with a BRAFV600E mutation had a Bethesda category V or VI (p < .001), and all had confirmed thyroid cancer on postoperative pathology. Those with H, K or N RAS or EIF1AX mutations, gene expression profiling (GEP) or copy number alterations showed an association with Bethesda categories III and IV (p ≤ .01). Those with no identified molecular mutation had a lower incidence of aggressive thyroid cancer compared to those with an identified mutation (12.6% vs. 44.3%, p < .01)., Conclusion: BRAFV600E mutations were associated with thyroid cancer subtypes known to be more aggressive whereas RAS and EIF1AX mutations, copy number alterations, and GEP were related to Bethesda categories III and IV. These findings may help thyroid specialists better identify aggressive thyroid nodules associated with indeterminate Bethesda categories., (© 2021 John Wiley & Sons Ltd.)

Background: Molecular testing has been used for cytologically indeterminate thyroid nodules (Bethesda III and IV), where the risk of malignancy is 10-40%. However, to date, the role of molecular testing in cytologically suspicious or positive for malignancy (Bethesda V and VI) thyroid nodules has been controversial. The aim of this study was to determine whether patients who had molecular testing in Bethesda V and VI thyroid nodules had the optimal extent of surgery performed more often than patients who did not have molecular testing performed., Methods: A retrospective chart review of 122 cases was performed: 101 patients from the McGill University teaching hospitals and 21 patients from the Hillel Yaffe Medical center, Technion University. Patients included in the study were those with Bethesda V or VI thyroid nodules who underwent molecular testing (ThyGenext® or ThyroseqV3®) (McGill n = 72, Hillel Yaffe n = 14). Patients with Bethesda V or VI thyroid nodules who did not undergo molecular testing were used as controls (McGill n = 29, Hillel Yaffe n = 7). Each case was reviewed in order to determine whether the patient had optimal surgery. This was defined as total thyroidectomy in the presence of either a positive lymph node, extrathyroidal extension, or an aggressive pathological variant of papillary thyroid carcinoma (tall cell, hobnail, columnar cell, diffuse sclerosing, and solid/trabecular) documented on the final pathology report. In all other cases, a lobectomy/hemi/subtotal thyroidectomy was considered as optimal surgery. Chi-squared testing was performed to compare groups., Results: When molecular testing was done, 91.86% (79/86) of surgeries in the molecular testing group were optimal, compared to 61.11% (22/36) in the control group. At McGill University teaching hospitals and at Hillel Yaffe, 91.67% (66/72) and 92.86% (13/14) of surgeries in the intervention group were considered as optimal, respectively. This compares to 58.62% (17/29) at McGill and 71.43% (5/7) at Hillel Yaffe when molecular testing was not performed (p = .001, p = .186)., Conclusions: In this study, molecular testing in Bethesda V and VI thyroid tumors significantly improved the likelihood of optimal surgery. Therefore, molecular testing may have an important role in optimizing surgical procedures performed in the setting of Bethesda V and VI thyroid nodules. Prospective studies with larger sample sizes are required to further investigate this finding.

Background: Although the current gold standard for diagnosing thyroid nodule malignancy is ultrasound-guided fine-needle aspiration (FNA) cytology, about 20-25% of cytological evaluations are considered indeterminate for malignancy. This limitation has led to the emergence of next-generation sequencing panels, for example, ThyroSeq v3 (TSv3), which recognize highly diagnostic genetic mutations of common thyroid carcinomas in FNA samples and classify them as test-negative or test-positive, helping optimize treatment for indeterminate thyroid nodules (ITNs). Our goals were to evaluate the benign call rate (BCR) of TSv3 and assess its diagnostic performance and clinical utility while highlighting the points of consideration for a public Canadian institution. Methods: This is a single-center study conducted at the Royal Victoria Hospital (McGill University Health Centre) in Montreal, Canada, between January and February 2019. Patients were offered TSv3 following the McGill algorithm for ITN workup, a novel protocol developed at our institution to select only diagnostic surgery candidates to minimize waste of public resources, considering the single-payer health care system. Patient demographics, cytopathology results, TSv3 data, treatment plan, and final histopathology result were reviewed. Results: A total of 50 ITNs underwent TSv3 testing; molecular analysis yielded 20 (40%) "positive" results and 24 (48%) "negative" results. Six (12%) results were classified as "currently negative" or "negative but limited." "Currently negative" results indicate a low-risk mutation that alone is insufficient for development of a malignant lesion. "Negative but limited" results indicate a sample that is nondiagnostic for malignancy due to low cell count. BCR was calculated as ("negative" and "currently negative")/total, resulting in a BCR of 58%. Twenty-three (46%) patients were scheduled for surgery and 27 (54%) patients continued with surveillance. Ninety-one percent (20 of 22) of the resected target nodules were malignant on final pathology. Conclusions: TSv3 proved beneficial in classifying ITNs as positive or negative, avoiding surgery in the latter cases. We found a lower reduction rate in surgery and BCR than the previously published studies, which is attributable to the criteria of the McGill algorithm. In the Canadian public health care system, preventing unnecessary surgery represents significant cost savings for the provincial government while also improving patient quality of life.

Background: Molecular testing of thyroid nodules is a diagnostic tool used to better understand the nature of thyroid nodules. The aim of this study is to better comprehend the relationship between specific mutations and aggressive behavior of the tumour as demonstrated on postoperative pathological analysis., Methods: A retrospective chart review of 103 cases was performed. Included were patients who had undergone molecular testing using a panel that tests for 9 mutations (ThyGenX®) and were found to have malignant tumours. The following gene alterations were found pre-operatively in the nodules: BRAF V600E (n = 32), BRAF K601E (n = 4), NRAS (n = 11), HRAS (n = 4), KRAS (n = 3), RET/PTC1 rearrangement (n = 1), TERT promoter (n = 2), PAX8-PPARγ rearrangement (n = 1), and 45 cases where no mutation was detected. Aggressive behavior was defined by extra-thyroidal extension (ETE), lymph node metastasis (LN+), and the following variants of papillary thyroid carcinoma: tall cell, solid, diffuse sclerosing, columnar cell and hobnail. Chi-squared testing was performed to compare groups., Results: The group with BRAF V600E, RET/PTC1 rearrangement, and TERT promoter mutations was associated with ETE 37.1%, and LN+ 45.7% of the time compared to 4.3 and 13.0% in the group with other mutations, and 4.4 and 4.4% in the group with no mutations (p-value 0.02, p-value < 0.001, p-value 0.006). In addition, the BRAF V600E, RET/PTC1 rearrangement, and TERT mutations group demonstrated tall cell variants (17.1%), columnar cell variants (5.7%), and hobnail variants (3%). The other mutations group demonstrated columnar cell variants (4.3%), and the no mutations group demonstrated solid variants (2.2%)., Conclusions: In this study, BRAF V600E, RET/PTC1 rearrangement, and TERT mutations were associated with aggressive behaving thyroid malignancies as defined above. Molecular testing may be a useful method to anticipate aggressive tumour types and therefore assist in planning the extent and timing of surgery.

Objective The McGill Thyroid Nodule Score (MTNS) is a preoperative tool used to predict the risk for well-differentiated thyroid cancer given a specific nodule in adults. We evaluated the clinical utility of a modified pediatric MTNS with children and adolescents. Study Design Case series with chart review. Setting Tertiary care children's hospital. Subjects and Methods This is a retrospective chart review of 46 patients ≤18 years of age presenting with a solitary or dominant thyroid nodule treated with surgical resection between September 2008 and December 2015. The cumulative MTNS for each nodule was calculated and compared with the final pathology. Results Of 46 patients, 10 (21.7%) were diagnosed with well-differentiated thyroid cancer (80% papillary thyroid carcinoma, 10% follicular variant of papillary thyroid carcinoma, 10% follicular thyroid carcinoma). Malignant nodules were associated with a greater mean MTNS (benign, 5.72 ± 3.03; malignant, 16 ± 3.13; P < .05). The sensitivity, specificity, and positive predictive value of malignancy were 100%, 94.4%, and 83.3% for scores ≥10 and 80%, 100%, and 100% for scores ≥11, respectively. In nodules with indeterminate cytology (Bethesda III and IV), the pediatric MTNS showed good differentiation between benign and malignant disease, with mean scores of 7.95 and 12.5, respectively ( P = .006). Conclusion This pilot study suggests that a comprehensive scoring system may help assess the risk of malignancy in pediatric thyroid nodules and differentiate nodules with indeterminate cytology into higher- and lower-risk categories. Given these findings, larger, multi-institutional studies are warranted.

Background: The incidence of thyroid nodules is increasing among patients in North America. Few of these nodules harbour malignancy, thus further research is required to identify predictive markers of malignant thyroid disease. This study set out to understand the relationship between the levels of fT4 and fT3 and differentiated thyroid cancer., Methods: A case-control study was conducted with 142 cases and 86 controls from the McGill University Teaching Hospitals. All patients underwent thyroid surgery. Cases were defined as patients with malignant nodules confirmed on final pathology and controls were defined as patients with benign nodules. The serological levels of TSH, fT4 and fT3 were measured preoperatively. Odds ratios were determined for each parameter and logistic regressions were calculated between markers and probability of malignancy. Additionally, fT4 values were divided by fT3 values (fT4/fT3 quotient) for each patient and an odds ratio was calculated., Results: Amongst cases, the mean TSH was 2.25 ± 0.360U/mL, fT4 was 14.8 ± 0.689pmol/L, and fT3 was 4.65 ± 0.463pmol/L. Amongst controls, the mean TSH was 2.36 ± 1.68U/mL, fT4 was 14.3 ± 1.71pmol/L, and fT3 was 5.27 ± 0.957pmol/L. Patients in the control group were more likely to have low TSH, while patients in the case group would have high fT4 and patients in the control group were more likely to have a low fT4. The OR for patients with TSH >4.4U/mL was 2.13 (0.97, 4.65), and for patients with TSH <0.4U/mL was 0.46 (0.22, 0.95). The OR for patients with fT4 > 16pmol/L was 2.10 (1.09, 4.06), and for patients with fT4 < 10pmol/L was 0.45 (0.20, 0.98). The OR for patients with fT3 > 5.5pmol/L was 0.39 (0.14, 1.28). The OR for patients with fT3 < 3pmol/L was 1.83 (0.25, 13.69). The average fT4/fT3 was 3.39 ± 0.206 for cases and 2.93 ± 0.467 for controls. The fT4/fT3 quotient was considered high if it was >3.3 (OR =6.00 (2.94, 12.25))., Conclusion: In this study, a direct relationship between high levels of fT4 and malignancy was uncovered. Furthermore, low levels of TSH and fT4 increased the likelihood that a nodule was benign. In this study a fT4/fT3 ratio >3.3 increased the risk of malignancy by 3.6 times (p-value =0.0013).

Background: Thyroid nodules are common and often benign, although prove to be malignant upon surgical pathology in 5-15% of cases. When assessed with ultrasound-guided fine-needle aspiration (USFNA), 15-30% of the nodules yield an indeterminate result. The Afirma® gene expression classifier (AGEC) was developed to improve management of indeterminate thyroid nodules (ITNs) by classifying them as "benign" or "suspicious." Objectives were (1) to assess the performance of the AGEC in two Canadian academic medical centres (2), to search for inter-institutional variation and (3) to compare AGEC performance in Canadian versus American institutions., Methods: We undertook a retrospective cohort study of patients with indeterminate cytopathology (Bethesda Class III or IV) as per USFNA who underwent AGEC testing. We reviewed patient demographics, cytopathological results, AGEC data and, if the patient underwent surgery, results from their final pathology., Results: In total, we included 172 patients with Bethesda Class III or IV thyroid nodules underwent AGEC testing, 109 in Montreal, Quebec and 63 in St. John's, Newfoundland, in this study. Among the nodules sent for testing, 55% (60/109) in Montreal and 46% (29/63) in St. John's returned as "benign." None of these patients underwent surgery. On the other hand, 45% (49/109) nodules in Montreal and 54% (34/63) in St. John's were found to be "suspicious," for a total of 83 specimens. Seventy seven of these patients underwent surgery. Both in Montreal and St. John's, the final pathology yielded malignant thyroid disease in approximately 50% of the specimens categorized as "suspicious." Since 2013, no patient diagnosed with a benign nodule as per AGEC testing was found to harbor a malignant thyroid nodule on follow-up., Conclusions: Molecular analysis is increasingly used in the management of indeterminate thyroid nodules. This study highlights the experience of two Canadian centres with AGEC testing. We found inter-institutional variability in the rate of nodules returning as "benign," however we found similar rates of confirmed malignancy in nodules returning as "suspicious." According the literature, results for AGEC testing in two Canadian institutions align with results reported in American centres.

Background: Management decisions are not straightforward when the Ultrasound Guided Fine Needle Aspiration (USFNA) demonstrates a Bethesda score of either category III or IV, and a diagnostic hemi-thyroidectomy or a repeat USFNA (r-USFNA) could be performed. The aim of this study is to assess the effectiveness of r-USFNA in the management of indeterminate thyroid nodules by evaluating the likelihood of obtaining a definite diagnosis., Methods: We reviewed the medical records of all patients with thyroid nodules between 2011 and 2015 at the Jewish General Hospital (Montreal, Canada). Three hundred fifty-one patients who had undergone a surgical procedure (hemi or total thyroidectomy) and a diagnosis of B3 or B4 on the primary USFNA (p-USFNA) were included in the study. Ninety-six of the included patients also had a repeat USFNA prior to the surgery. Demographic data, type of procedure, and McGill Thyroid Nodule Score (MTNS) were obtained from the medical records. Malignancy rates were calculated based on the final surgical histopathology report., Results: Upon r-USFNA, an average 76 % of patients did not change Bethesda categories, 7.4 % downgraded to a benign category. The results showed that, on an average 17.3 % of patients with p-USFNA of B3 and 20 % of patients with p-USFNA of B4, upgraded to a malignant or suspicious for malignancy category, thus changing the clinical management to total thyroidectomy. Our data demonstrates that r-USFNA facilitates choosing the correct surgery of total thyroidectomy in about 20 % of nodules that have upgraded from B3/B4 to a more definite malignant category., Conclusions: r-USFNA in patients with indeterminate diagnoses (B3 or B4) increases categorization into more definite categories. Approximately 20 % of patients are found to have malignant thyroid nodules and suspicious for malignancy thyroid nodules upon repeating the biopsy, hence a diagnostic hemi-thyroidectomy was avoided and a more definitive surgery could be performed. Furthermore, repeat USFNA results in a fewer number of hemi-thyroidectomy and completion thyroidectomy procedures.

Background: Ultrasound guided fine needle aspiration (USFNA) biopsies of thyroid nodules sometimes create a decision-making dilemma for surgeons as they may yield falsely benign results. The McGill Thyroid Nodule Score + (MTNS+) was developed to aid in clinical guidance regarding the management of patients with these USFNA results. The aim of this study was to assess the MTNS+ as a clinical tool in patients with benign preoperative thyroid nodule USFNAs and to analyze the relationship between nodule size and malignancy in these patients., Methods: We conducted a retrospective chart review of 1312 patients who underwent thyroidectomies between 2010 and 2015 at the McGill University Teaching Hospitals. Patients with Bethesda II (benign) USFNA results, calculated MTNS+, and nodule size evaluated on ultrasound were included in the study. The false-negative rate was calculated, and MTNS+ and nodule size were each compared to final pathology results. Binary logistic regression was used for statistical analysis., Results: Of the 1312 patients, 101 met the inclusion criteria and together had an average MTNS+ score of 6.83, which corresponds to a predicted malignancy rate between 25 and 33 %. Final pathology revealed malignancy in 16 (15.8 %) subjects. The average MTNS+ of patients with malignant nodules on surgical pathology was 8.25, while that of patients with benign nodules was 6.56. Patients with nodule size 1-1.9 cm (a) and 2-2.9 cm (b) each had an equal rate of malignancy of 2.97 % (n = 3), nodule size 3-3.9 cm (c) had a rate of 1.98 % (n = 2), and nodule size ≥4 cm (d) a rate of 7.92 % (n = 8)., Conclusion: The rate of malignancy (15.8 %) is higher than expected when reviewing the risk of malignancy in nodules considered as Bethesda class 2. On the other hand, the rate is lower than the 25-33 % predicted by the MTNS+. We also found a higher malignancy rate for nodules above 4 cm in size, but size was a poor predictor of malignancy when used alone. Therefore, while the MTNS+ may be helpful at helping to identify USFNAs that are incorrectly classified as benign, the percentage risk of malignancy is lower than expected.

Introduction: It is not uncommon for patients with indeterminate thyroid nodules to undergo diagnostic hemithyroidectomy. When the final pathology determines that the nodule is in fact malignant, patients require counseling as to the whether a completion thyroidectomy is necessary., Objectives: 1. Determine the incidence of well differentiated thyroid cancer (WDTC) in the contralateral thyroid lobe in patients undergoing completion thyroidectomy. 2. Identify features of the malignant tumor in the initial resection that increase the likelihood of malignancy in the contralateral lobe., Methods: Retrospective chart review of 97 patients who underwent hemithyroidectomy and completion thyroidectomy in a university's teaching hospital network between 2006 and 2012. Pathology reports from both surgeries as well as patient and thyroid nodule characteristics were reviewed., Results: Of the 97 patients, 47 (48%) had a malignancy in the contralateral lobe. In the contralateral lobe, 42/47 (89%) of malignancies were papillary microcarcinomas (PMC) and 15/42 (36%) of the PMC were multifocal. Multifocal malignancies in the initial specimen had a 60% rate of contralateral malignancy and were found to be a predictor of bilateral disease (p = 0.04) with OR = 2.74 (95% CI: 1.11-6.79; p = 0.003) in WDTC and OR = 3.59 (95% CI:1.35 9.48; p = 0.01) in papillary cancer specifically. There was no statistical significant correlation established for the following variables: presence of positive cervical nodes, extrathyroidal extension, positive resection margins, size and angio-lymphatic invasion. Moreover, there was no statistical correlation between any of the variants of papillary thyroid cancer and bilateral disease, even though most aggressive subtypes were found to be bilateral., Conclusion: In this study, the rate of malignancy in the contralateral lobe was 48%. Multifocality and presence of an aggressive subtype of papillary thyroid cancer in the initial specimen were found to be more important variables to consider in decision-making regarding completion thyroidectomy than size of the initial tumor alone.

Background: Ultrasound guided fine-needle aspiration (USFNA) biopsy of thyroid nodules often gives a result of indeterminate pathology, placing thyroid specialists in difficult management situations. The aim of this study is to evaluate the incidence of malignancy in patients undergoing surgery and to correlate these results with the McGill Thyroid Nodule Score (MTNS)., Methods: We performed a retrospective study comparing USFNA results, MTNS and histopathology of patients undergoing thyroid surgery between 2010 and 2012. Pre-operative USFNA results were divided into three subgroups: benign, indeterminate and suspicious for/malignant. The indeterminate USFNA subgroup comprised of Bethesda type III (atypia of undetermined significance) and Bethesda type IV (follicular neoplasms, including Hurthle cell neoplasms) lesions. Post-operative histopathology was divided into benign or malignant groups., Results: Of the 437 patient charts reviewed, 57.0% had an indeterminate USFNA biopsy. Within the indeterminate group, the malignancy rate was 39.8%. For indeterminate USFNA, the median MTNS was 7 (32% risk of malignancy) for benign nodules and 9 (63% risk of malignancy) for malignant nodules on post-operative histopathology (p < 0.05)., Conclusion: The rate of malignancy in operated patients with an indeterminate USFNA result was 39.8%. The MTNS can be of value to thyroid specialists in pre-operative decision-making when dealing with an indeterminate result of a thyroid nodule on USFNA.

Purpose: Some authors have questioned the benefit of fine-needle aspiration (FNA) of thyroid nodules ≥ 4 cm. They report that the results of the FNA are not as reliable when compared to nodules <4 cm. The aims of this study are to evaluate the accuracy and predictive values of ultrasound-guided FNA (USFNA) of thyroid nodules ≥ 4 cm and compare these findings to nodules <4 cm., Methods: A retrospective study of 998 patients who underwent thyroid surgery between 2006 and 2012 at the McGill University Thyroid Cancer Center was performed. USFNA and post-operative pathology diagnoses of nodules ≥ 4 cm versus those <4 cm were compared. Pre-operative USFNA results were divided into three groups: benign, indeterminate, and malignant/suspicious for malignancy subgroups. Post-operative results were separated into benign and malignant groups., Results: There were 225 patients with nodules ≥ 4 cm and 773 patients with nodules <4 cm. The sensitivity, specificity, positive predictive value and negative predictive value for USFNA of nodules ≥ 4 cm were 84.62% (CI 71.91-93.10), 91.49% (CI 79.6-97.58), 91.67% (CI 80.0-97.63) and 84.31% (CI 71.4-92.95), respectively. The sensitivity, specificity, positive predictive value and negative predictive value for USFNA of nodules <4 cm were 90.48% (CI 86.1-93.8), 85.92% (CI 75.6-93.02), 95.8% (CI 92.41-97.96) and 71.76% (CI 60.95-81.0), respectively. The difference in diagnostic accuracy of USFNA between both groups was not statistically significant (p>0.05)., Conclusion: This study shows that the sensitivity, specificity, positive predictive value and negative predictive value for USFNA of nodules ≥ 4 cm are similar to that of smaller nodules. It is therefore suggested that these nodules undergo USFNA., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The McGill Thyroid Nodule Score (MTNS) is a scoring system devised to help physicians to assess the preoperative risk that a thyroid nodule is malignant. It uses 22 different known risk factors for thyroid cancer (radiation exposure, microcalcifications on ultrasound, positive HBME-1 stain on biopsy, etc.) and attributes a percentage risk that the nodule is malignant. Recently, preoperative thyroglobulin (Tg) levels have been shown to correlate with the risk of malignancy. The aim of this study was to incorporate Tg levels into the already established MTNS., Methods: This is a retrospective analysis of 184 thyroidectomy patients at the McGill University Thyroid Cancer Center. Patients with preoperative Tg levels were included in the study, and patients with incidental papillary microcarcinoma without extrathyroidal extent on final pathology were excluded. MTNS scores were calculated for all patients. Preoperative Tg levels of 75 ng/mL added one point to the MTNS, and levels of 187.5 ng/mL added two points. The new system is named MTNS+., Results: Malignancy rates were calculated for each MTNS+ score. Patients with a score of 0-1 were <5% at risk of malignancy. The malignancy rate for scores of 2-3 was 14.29%, followed by 28.95% for scores of 4-6, 32.65% for scores of 7-8, 64.86% for scores of 9-11, 71.43% for scores of 12-14, 78.57% for scores of 15-18, and 92.31% for scores of 19-22. All patients (five of five) with an MTNS+ score of 23 or more had a malignant final pathology result. Patients with scores greater than eight had a relative risk of 2.5 [CI 1.79-3.49] of malignancy compared to patients with lower scores. MTNS+ showed good specificity at higher scores, with 89%, 96%, and 100% at scores above 11, 14, and 20 respectively. Compared to MTNS, adding Tg levels did not improve positive predictive values (PPV) or specificity, but improved sensitivity by 7.89% for scores greater than eight, and by up to 10.48% for scores greater than seven., Conclusion: This study shows that adding Tg to the MTNS increases the sensitivity of this scoring system. Moreover, it suggests that a combined scoring system such as the MTNS+ can accurately stratify the risk of well-differentiated malignancy in patients with thyroid nodules.

Background: Traditional teaching demonstrated that solitary thyroid nodules were more likely to be malignant. Newer studies show that there is no clear answer regarding the influence of the number or the distribution of nodules on the risk of malignancy., Objectives: The purpose of this study was to establish whether patients undergoing thyroid surgery and presenting with a solitary thyroid nodule show a greater rate of malignancy when compared to those presenting with multiple nodules. The secondary goal was to evaluate the impact of the distribution of the nodules (multiple unilateral nodules versus bilateral nodules) on the rate of malignancy in this population., Method: Retrospective review of the medical records of the 656 patients who underwent thyroidectomy at one of the hospitals of the McGill University Thyroid Cancer Centre between July 2006 and April 2011 was conducted., Results: There was no significant difference in the malignancy rate between patients with a solitary nodule and patients with two to six thyroid nodules at ultrasonography, between patients with unilateral nodule(s) and patients with bilateral nodules, or between patients with at least one nodule > 1.0 cm and patients without any nodules > 1.0 cm (p  =  .870, .578, and .361, respectively)., Conclusion: This study demonstrates that the likelihood of thyroid cancer is independent of the number of thyroid nodules. Moreover, our data show that the malignancy rate is not influenced by the distribution of the nodules or their size.

Objective: There are presently a great number of publications pertaining to the clinical risk factors associated with thyroid cancer. These studies deal mostly with a single feature from either patient demographics, physical examination, laboratory values, imaging, or cytology. We sought to create a novel scoring system that integrates the diagnostic indices of each of these clinical features for carcinoma., Methods: A retrospective analysis of 1047 consecutive thyroidectomy patients was performed. Each patient was assigned a cancer risk score according to a newly devised 22-variable scoring scheme termed the McGill Thyroid Nodule Score (MTNS). The MTNS was developed by a multidisciplinary team of endocrinologists, thyroid surgeons, and pathologists using already established evidence-based risk factors for thyroid cancer., Results: The exact incidence of malignancy was calculated for each MTNS score based on final pathology. The incidence for scores of 1 to 3 was 27%, of 4 to 7 was 32%, of 8 was 39%, of 9 to 11 was 63%, of 12 to 13 was 88%, and of 14 to 18 was 93%. All (130 of 130) patients with a score ≥ 19 had carcinoma. A score ≤ 8 correlated with a 32% (115 of 357) risk of thyroid cancer, whereas a score > 8 implied an 86% (417 of 487) risk., Conclusion: Our data suggest that a combined scoring system, the MTNS, can serve as an accurate predictor of the risk for thyroid cancer in a specific thyroid nodule. This will help physicians better formulate management decisions accordingly.

Objective: To determine whether preoperative variables can be used to predict malignancy for thyroid nodules with follicular, Hürthle, or nondiagnostic cytology on fine-needle aspiration biopsy (FNAB)., Materials and Methods: Retrospective analysis of 77 consecutive patients selected for total or subtotal thyroidectomy for follicular, Hürthle, or nondiagnostic lesions of the thyroid in two university hospitals. Eleven clinical variables, as well as nodule size, multiplicity, and ultrasound calcifications, were correlated with final histopathologic diagnosis of benign or malignant disease. Analysis was preformed using the Pearson chi-square test., Results: The overall rate of malignancy in our series was 61% (n = 47). FNABs classified as follicular or Hürthle lesions without cellular atypia had a significantly lower risk of malignancy (49% vs 71%; p = .05). Patients who presented with a solitary nodule and FNAB cellular atypia displayed an increased risk of malignancy (92% vs 55%; p = .011). The rate of malignancy was higher for patients with a positive family history (100% vs 59%), a solitary nodule (73% vs 53%), cellular atypia (76% vs 54%), or intrathyroidal calcifications on ultrasonography (71% vs 57%), although none were found to be statistically significant (p > .05). Male gender, age > 45 years, nodule size > 3 cm, mass effect symptoms, and radiation exposure to the neck were not associated with malignancy in our series., Conclusion: When presented with follicular, Hürthle, or nondiagnostic biopsies for thyroid nodules, thyroid surgeons should rely systematically on sonographic findings and cytopathologic features to guide their management approach.

Background: Obesity has been linked to numerous diseases including thyroid cancer, but the exact nature of the relationship, especially with respect to patients with thyroid nodules, remains unclear. The objective of this study was to evaluate the impact of body mass index (BMI) on thyroid cancer risk in a population of patients with indeterminate cytology on fine-needle aspiration biopsy (FNAB)., Methods: A total of 253 consecutive patients with indeterminate thyroid nodule FNABs who underwent total thyroidectomy in a tertiary care teaching hospital between 2002 and 2007 were reviewed. Height and weight reported on the anesthesia summary were recorded for each patient. Malignancy rates were calculated for the underweight, normal, overweight, and obese groups stratified according to their BMI. Subanalyses according to age and sex were also performed., Results: The risk of malignancy tended to be lower in obese patients compared to patients with BMIs in the underweight, normal, and overweight ranges (52% vs. 61%, p = 0.195). In men, a BMI classified as obese was associated with a significantly lower rate of malignancy (36% vs. 72%, p = 0.003). Women older than 45 years were a subgroup in which higher malignancy rates were associated with obesity (65% vs. 54%, p = 0.293). Conversely, in men over the age of 45 years and women under 45 years, a BMI in the obesity range was linked to a lower incidence of malignancy (20% vs. 68% p = 0.009 and 36% vs. 68% p = 0.043, respectively). When older women were excluded from the population studied, the rate of malignancy in obese patients was 36% versus 70% in nonobese patients (p = 0.002) with an associated reduction of 5% in the risk of malignancy per increased unit of BMI., Conclusions: For patients with FNAB results of indeterminate significance, a higher BMI correlates with lower rates of thyroid malignancy for all patients except women over the age of 45 years.

Objectives: To evaluate the positive predictive value of a thyroid nodule being malignant when categorized as atypical, and to determine the prognostic implications of specific cytopathological features., Design: Retrospective review of consecutive patients undergoing thyroid surgery following fine-needle aspiration biopsy (FNAB) of thyroid nodules., Setting: Academic teaching hospital in Toronto, Ontario., Patients: A total of 111 consecutive patients with atypical findings from an FNAB who underwent thyroid surgery from January 2000 to November 2005., Results: Of 111 patients included in this study, 62 (56%) were diagnosed with a thyroid malignancy on final histopathological examination. The remaining 49 patients (44%) had benign disease. When comparing patients with a postoperative diagnosis of malignancy vs those with benign disease, micronucleoli (71% vs 49%; P = .01), nuclear grooves (50% vs 31%; P = .03), and powdery chromatin (37% vs 16%; P = .01) were more frequently observed in the group with cancer. The probability of malignancy was 83% if all 3 of these features were present; 32% if none of these features was present (P = .001)., Conclusions: At our institution, when findings from a thyroid nodule FNAB sample were categorized as atypical, the positive predictive value of the nodule being malignant was 56%. In this series of patients, the presence of micronucleoli, nuclear grooves, and powdery chromatin increased the likelihood that an atypical specimen was representative of malignant disease. These features may help guide treatment of patients with atypical findings from a thyroid nodule FNAB sample.

Background: Although more common in females, thyroid cancer is deemed to be more aggressive in males. The reasons for sex disparities in thyroid cancer are not well understood. We hypothesised that differences in molecular mutations between females and males contribute to this phenomenon. Methods: Retrospective multicentre multinational study of thyroid nodules that underwent preoperative molecular profiling between 2015 and 2022. The clinical characteristics and mutational profiles of tumours in female and male patients were compared. Collected data included demographics, cytology results, surgical pathology, and molecular alterations. Results: A total of 738 patients were included of which 571 (77.4%) were females. The extrathyroidal extension was more common in malignancies in males (chi‐squared, p = 0.028). The rate of point mutations and gene fusions were similar in both sex groups (p > 0.05 for all mutations). Patients with nodules with BRAFV600E mutations were significantly younger than BRAF wild‐type nodule patients (t‐test, p = 0.0001). Conversely, patients with TERT promoter mutations were significantly older than patients with wild‐type TERT (t‐test, p < 0.0001). For patients harbouring both BRAFV600E and TERT mutations, the difference in age at presentation was significantly different in females (t‐test, p = 0.009) but not in males (t‐test, p = 0.433). Among females, patients with BRAFV600E and TERT mutations were significantly older than their wild‐type or single‐mutation counterpart (t‐test, p = 0.003). Conclusion: The absolute rate of molecular mutations was similar in females and males. We found that extrathyroidal extension was more common in males. Moreover, BRAFV600E and TERT mutations occur at a younger age in males than in females. These two findings are factors that may explain the tendency of more aggressive disease in males. [ABSTRACT FROM AUTHOR]

Simple Summary: This original research article aims to clarify the clinical and pathological features of thyroid nodules that express a specific category of genetic alterations found on molecular testing, known as gene expression alterations (GEAs). Using a sample of patients with thyroid nodules at two McGill University teaching hospitals in Montreal, Canada, this study shows that GEA is a potentially effective tool for diagnosing thyroid cancer and deciding between surgical versus non-surgical management of thyroid nodules. ThyroSeq V3 (TsV3) tests for various genetic alterations, including gene expression alterations (GEAs), to improve diagnostic accuracy and clinical decision-making for indeterminate thyroid nodules. This study aimed to clarify the clinico-pathological features and outcomes of GEA-positive thyroid nodules, which have not yet been well-described in the literature. A retrospective chart review was performed whereby patients were included if they underwent thyroid surgery between January 2018 and May 2022 at two McGill University teaching hospitals and their surgery was preceded by pre-operative molecular TsV3 testing. In total, 75 of the 328 patients with thyroid nodules (22.9%) who underwent molecular testing and surgery were GEA-positive. On surgical pathology, GEA-positive nodules showed a significantly higher malignancy rate compared to their GEA-negative counterparts (90.7% vs. 77.7%, respectively, p = 0.011). Among those that were malignant, 48.5% had at least one aggressive pathological feature, including histological subtype, extra-thyroidal extension, or lymph node metastasis. BRAF V600E mutation had a significantly greater association with aggressive malignant GEA-positive nodules compared to non-aggressive ones (p < 0.001). This study demonstrates that GEA may be an effective diagnostic and prognostic tool for thyroid nodule management. However, further investigation is needed to characterize the clinico-pathological features of GEA in isolation and in association with other gene alterations. [ABSTRACT FROM AUTHOR]

Simple Summary: Copy number alterations are known to be present in some thyroid tumors; however, their idiosyncratic clinicopathological implications are not yet well elucidated. In this study we reviewed 67 thyroid nodules with positive copy number alterations who underwent surgery. We discovered that most of the thyroid nodules with positive copy number alterations were malignant or non-invasive follicular thyroid neoplasm with papillary-like nuclear features and the presence of coexisting molecular alterations increased the risk of malignancy in these nodules. These findings may affect the decision-making in individuals with copy number alterations positive thyroid nodules. Molecular mutations and alterations play a role in thyroid tumorigenesis. Different alterations are associated with different clinical and pathological characteristics. Copy number alterations (CNAs) are known to be present in some thyroid tumors; however, their idiosyncratic clinicopathological implications are not yet well elucidated. A retrospective chart review was performed to identify patients with CNAs on pre-operative molecular testing results who subsequently underwent surgical treatment between January 2016 and April 2022 at McGill University teaching hospitals. Of the 316 patients with thyroid nodules who opted for molecular testing with ThyroSeqV3 followed by surgery, 67 (21.2%) nodules were positive for CNAs, including 23 Bethesda III, 31 Bethesda IV, 12 Bethesda V and 1 Bethesda VI nodules. On surgical pathology, 29.9% were benign and 70.1% were malignant or non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Among those that were malignant/NIFTP, 17.02% were considered to be aggressive cancers. The presence of other molecular alterations was found to be an independent predictor of malignancy in multivariate analysis (OR = 5.087, 95% C.I. = 1.12–23.04, p = 0.035). No unique factor was correlated with aggressiveness; however, CNA-positive thyroid nodules that were associated with high-risk mutations such as BRAF V600E, TP53, NTRK1/3 fusion, or PTEN mutation with high allele frequency (AF) ended up being aggressive cancers. Most of the CNA-positive thyroid nodules resulted in follicular patterned tumors in 41 (65.2%) cases and oncocytic tumors in 20 (29.9%) cases. This study demonstrates that 70.1% of surgically resected thyroid nodules with CNAs were malignant/NIFTP. Most CNA-positive thyroid nodules were either oncocytic patterned tumors or follicular patterned tumors. Furthermore, CNA-positive thyroid nodules were more likely to be malignant if they were associated with other molecular alterations or mutations. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of this review is to provide a general overview about the molecular markers (mutations and alterations) of thyroid cancers, present several molecular tests, and discuss the clinical applications of identifying these markers supported by the clinical experience of several high-volume thyroid cancer specialists at the McGill university teaching hospitals in Montreal, Canada. In the past few decades, molecular characterization of thyroid cancer has made significant progress and is able to identify thyroid-cancer-related molecular markers that can then be applied clinically for improved decision making. The aim of this review is to provide a general overview about the molecular markers (mutations and alterations) of thyroid cancers, present several molecular tests, and discuss the clinical applications of identifying these markers supported by the clinical experience of several high-volume thyroid cancer specialists at the McGill university hospitals in Montreal, Canada. Our group experience showed that molecular testing can reclassify more than half of the patients with indeterminate thyroid nodules (Bethesda III and IV) into benign and spare these patients from unnecessary diagnostic surgery. Furthermore, it can help optimize the initial management in thyroid cancers with no evidence of high risk of recurrence of disease preoperatively. While routine molecular testing is not firmly established for thyroid FNA specimens that are suspicious or positive for malignancy (Bethesda V and VI), knowledge of a thyroid nodule's molecular risk group profile in such cases, together with its clinical and radiologic features, can help select the optimal surgical options (lobectomy versus upfront total thyroidectomy and central neck dissection), as demonstrated by our studies. [ABSTRACT FROM AUTHOR]

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Simple Summary: The Bethesda classification system is a widespread tool used in the initial screening test for thyroid nodules. The system classifies the biopsy of the nodule into 6 categories, each with its associated malignancy risk and recommendations for management. Nodules classified as Bethesda III and IV are considered intermediate risk, and although Bethesda III nodules are more likely to be benign than Bethesda IV, our hypothesis is that out of those that are malignant, a subset may be more aggressive given their diverse cellular features. In this study we looked at 628 individuals who underwent surgery with a Bethesda III or IV nodule and compared the number of aggressive features found in those with confirmed malignancy. We discovered that Bethesda III nodules that were found to be malignant were more likely to have aggressive features, such as aggressive sub-types of thyroid cancer, spread of cancer beyond the thyroid capsule, and spread of cancer to the lymph nodes. Our results suggest that Bethesda III thyroid nodules may not as indolent as they seem, and these findings may affect management decisions in individuals with indeterminate thyroid nodules. The Bethesda classification system for thyroid fine needle aspirate (FNA) is used to predict the risk of malignancy and to guide the management of thyroid nodules. We postulated that thyroid malignancies characterized as Bethesda III on FNA have more aggressive features than those classified as Bethesda IV. A retrospective chart review was performed to identify those who underwent thyroid surgery at a single tertiary hospital setting between 2015 and 2020. Associations between Bethesda category, molecular genetic test results, and histopathologic findings were examined. Out of 628 surgeries that were performed, 199 (54.2%) Bethesda III nodules and 216 (82.8%) Bethesda IV nodules were malignant. Of those that were malignant, 37 (18.6%) and 22 (10.2%) Bethesda III and Bethesda IV nodules showed aggressive features, respectively (p value = 0.014). There was a proportionally increased number of aggressive features in extra-thyroidal extension, lymph nodes metastasis, and all aggressive subtypes of papillary thyroid cancer in the Bethesda III category. Although Bethesda IV nodules are much more likely to be malignant (p value = 0.002), our study suggests that Bethesda III nodules that are resected are more likely to have aggressive features than Bethesda IV nodules, with a statistically significant increase in the solid variant of papillary thyroid cancer and lymph node metastasis. [ABSTRACT FROM AUTHOR]