The Bethesda System For Reporting Thyroid Cytopathology Categories Research Articles

Diagnostic interobserver agreement for thyroid fine-needle aspirates: Effects of reviewer experience and molecular diagnostics.

Few cytologically indeterminate thyroid fine-needle aspirations (FNAs) harbor BRAF V600E. Here, we assess interobserver agreement for The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) category III (atypia of undetermined significance [AUS]) FNAs harboring BRAF V600E and contrast their features with those harboring non-BRAF V600E alterations, with attention to cytopathology experience. Seven reviewers evaluated 5 AUS thyroid FNAs harboring BRAF V600E. To blind reviewers, cases were intermixed with 19 FNAs falling within other TBSRTC categories and in which genetic alterations other than BRAF V600E had been identified (24 FNAs total). Interobserver agreement against both "index" and most popular ("mode") diagnoses was calculated. Four additional BRAF V600E cases were independently reviewed. Reviewers included 3 trainees and 3 American Board of Pathology (board)-certified cytopathologists. Board-certified cytopathologists, whose experience ranged from 2 to more than 15 subspecialty practice years, had known AUS rates. BRAF V600E was identified in 5 of 260 (2%) AUS FNAs. Interobserver agreement was higher among cytopathologists with more experience. Mode diagnosis differed from index diagnosis in 6 of 11 cases harboring RAS-like alterations; mode diagnosis was AUS in 4 of 5 BRAF V600E FNAs. Atypia of undetermined significance of thyroid FNAs harboring BRAF V600E is uncommon yet relatively reproducible, particularly among pathologists with experience. It is advisable to sequence BRAF across V600 in such cases.

Atypia of undetermined significance and ThyroSeq v3-positive call rates as quality control metrics for cytology laboratory performance.

The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) recommends an upper limit of 10% for atypia of undetermined significance (AUS). Recent data suggest that this category might be overused when the rate of cases with molecular positive results is low. As a quality metric, the AUS and positive call rates for this facility's cytology laboratory and each cytopathologist (CP) were calculated. A retrospective analysis of all thyroid cytology cases in a 4.5-year period was performed. Cases were stratified by TBSRTC, and molecular testing results were collected for indeterminate categories. The AUS rate was calculated for each CP and the laboratory. The molecular positive call rate (PCR) was calculated with and without the addition of currently negative to the positive results obtained from the ThyroSeq report. A total of 7535 cases were classified as nondiagnostic, 7.6%; benign, 69%; AUS, 17.5%; follicular neoplasm/suspicious for follicular neoplasm, 1.4%; suspicious for malignancy, 0.7%; and malignant, 3.8%. The AUS rate for each CP ranged from 9.9% to 36.8%. The overall PCR was 24% (range, 13%-35.6% per CP). When including cases with currently negative results, the PCR increased to 35.5% for the cytology laboratory (range, 13%-42.6% per CP). Comparison analysis indicates a combination of overcalling benign cases and, less frequently, undercalling of higher TBSRTC category cases. The AUS rate in the context of PCR is a useful metric to assess cytology laboratory and cytopathologists' performance. Continuous feedback on this metric could help improve the overall quality of reporting thyroid cytology.

A Comprehensive Approach to the Thyroid Bethesda Category III (AUS) in the Transition Zone Between 2nd Edition and 3rd Edition of The Bethesda System for Reporting Thyroid Cytopathology: Subcategorization, Nuclear Scoring, and More

Significant interobserver variabilities exist for Bethesda category III: atypia of undetermined significance (AUS) of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Thus, subcategorization of AUS including AUS “nuclear” and AUS “other” is proposed in the recent 3rd edition of TBSRTC. This study investigated the impact of the nuclear features/architectural features/nuclear score (NS) (3-tiered)/subcategories and subgroups on risk of malignancy (ROM) in thyroid fine-needle aspirations (FNA). 6940 FNAs were evaluated. 1224 (17.6%) cases diagnosed as AUS were reviewed, and 240 patients (initial FNAs of 260 nodules and 240 thyroidectomies) were included. Subcategories and subgroups were defined according to TBSRTC 2nd and 3rd editions. Histological diagnostic groups included nonneoplastic disease, benign neoplasm, low-risk neoplasm, and malignant neoplasm. Overall, ROM was 30.7%. ROM was significantly higher in FNAs with nuclear overlapping (35.5%), nuclear molding (56.9%), irregular contours (42.1%), nuclear grooves (74.1%), chromatin clearing (49.4%), and chromatin margination (57.7%), and these features were independent significant predictors for malignancy. FNAs with NS3 had significantly higher ROM (64.2%). Three-dimensional groups were significantly more frequent in malignant neoplasms (35.7%). ROM was significantly higher in AUS-nuclear subcategory (48.2%) and in AUS-nuclear and architectural subcategory (38.3%). The highest ROM was detected in AUS-nuclear1 subgroup (65.2%). ROM was significantly higher in the group including AUS-nuclear and AUS-nuclear and architectural subcategories, namely “high-risk group” than the group including other subcategories, namely “low-risk group” (42.0%vs 13.9%). In conclusion, subcategorization may not be the end point, and nuclear scoring and evaluation of architectural patterns according to strict criteria may provide data for remodeling of TBSRTC categories.

Non-papillary thyroid carcinoma diagnoses in The Bethesda System for Reporting Thyroid Cytopathology categories V and VI: An institutional experience

BackgroundThe non-papillary thyroid carcinoma (PTC) subgroups of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) categories V (Suspicious for malignancy) and VI (Malignant) are rare, and specific tumor typing is difficult. We aimed to analyze histologic outcomes and to investigate the points of caution. MethodsWe reviewed the electronic database and identified 12,215 cases of thyroid fine-needle aspiration cytology between 2013 and 2022. In total, 2783 patients were diagnosed with TBSRTC V or VI. Of these, 51 patients with non-PTC diagnosis were identified. Histological outcomes were analyzed with the cytologic findings. ResultsThe subgroups of non-PTC diagnoses in TBSRTC category V or VI consisted of medullary thyroid carcinoma (MTC) (13/51, 25.5 %), anaplastic thyroid carcinoma (3/51, 5.9 %), lymphoma (2/51, 3.9 %), metastatic tumor (4/51, 7.8 %), and malignant, not otherwise specified (NOS) (29/51, 56.9 %). The concordance rate of the histological outcomes was 30 % (12/40), predominantly comprising MTC cases. The obscuring factors for specific tumor typing in the suspicious for malignancy/malignant NOS cytology diagnosis group was mixed pattern of well differentiated thyroid carcinoma and less differentiated carcinoma cells (9/24, 37.5 %), low cellularity (7/24, 29.2 %) and a history of non-thyroid organ malignancy (6/24, 25 %). The less differentiated carcinoma component in mixed pattern consisted of 2 poorly differentiated thyroid carcinomas, 2 anaplastic thyroid carcinomas, 4 high-grade PTCs and 1 high-grade MTC. ConclusionThe high-grade feature of PTC or MTC cytology is a noteworthy obscuring factor in specific tumor typing of non-PTC cytology diagnosis.

Rates of Malignancy by The Bethesda System for Reporting Thyroid Cytopathology Category 3 and Category 4 Thyroid Nodules

Aim: The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is employed to evaluate the cytopathology of thyroid nodules. The nodules reported as categories 3 and 4 constitute risk of malignancy at varying rates. This study aims to document the amount of actual malignancy rates in TBSRTC category 3 and 4 thyroid nodules.
 
 Materials and Methods: Patients having thyroid nodules with reported Bethesda category 3 and category 4 results on fine needle aspiration biopsy who subsequently underwent thyroidectomy between January 2013 and December 2018 were retrospectively analyzed.
 
 Results: Seventy-two patients and 72 nodules were included in our study. The Bethesda category 3 group consisted of 40 patients and 40 nodules. The histopathologic result was reported as benign in 23 (57,5%) patients and malignant in 17 (42,5%) patients. The Bethesda category 4 group covered the remaining 32 patients and 32 nodules. Histopathologic results were reported as benign in 12 patients (37,5%) and malignant in 20 patients (62,5%).
 
 Conclusion: Bethesda category 3 and 4 nodules bear varying rates of malignancy risk, and this rate increases with the presence of additional incidentally detected malignancies.

Risk of malignancy in thyroid nodules classified as Bethesda categories III, III - subcategories and IV: 2.5 years study

Introduction: Thyroid fine-needle aspiration cytology (FNAC) has gained significance as a quick, safe, and relatively simple method to differentiate malignant from benign thyroid nodules and is regarded as the gold-standard first-line diagnostic test in the evaluation of thyroid nodules. The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) established a standardized, category-based reporting system for thyroid FNAC with each category having an implied cancer risk. However, the optimal management of thyroid nodules in the Bethesda III and IV categories is controversial, given the variable malignancy rates. Aims/Objectives: (1) Analysis of the cytomorphological characteristics of patients with categories III and IV of “TBSRTC.” (2) Assessment of risk of malignancy of TBSRTC category III, IV, and substratification of TBSRTC category III. Materials and Methods: A retrospective and prospective study of cases categorized under TBSRTC as category III and IV at a tertiary-care center. Cytological along with their histological results were compared. Results: We identified an overall malignancy rate of 33% for nodules belonging to Bethesda category III and a malignancy rate between 19% and 33% for Bethesda category IV. Also, a significantly higher risk of malignancy in subcategories with nuclear and architectural atypia (66.6%) than only architectural atypia (28.7%). Conclusion: Although surgery is recommended in most of these cases, cytomorphology helps to predict the final histopathological findings with greater accuracy. Substratification of category III into subgroups may help reduce the heterogeneity of the atypia of undetermined significance/follicular lesion of undetermined significance category and more.

Real-life utility of five-gene panel test in preoperative thyroid fine-needle aspiration biopsy: a large cohort of 740 patients study.

Fine-needle aspiration (FNA) biopsy is an effective method to discriminate malignant thyroid nodules but reaches indeterminate results in approximately 30% of cases. Molecular testing can improve the diagnostic accuracy of FNA. This study aimed to investigate the real-life utility of the five-gene panel testing in thyroid FNAs. 759 thyroid nodules from 740 patients under FNAs were retrospectively enrolled. Gene mutation information and clinical parameters, including age, gender, tumor size, and lymph node metastasis, were respectively recorded. Cytological results were classified based on The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). We analyzed mutational hotspots in BRAF, KRAS, NRAS, HRAS, and TERT genes from FNA specimens. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated to assess diagnostic performance. We identified 549 five-gene mutations in 759 nodules (72.3%), and the mutation frequency increased from the lower TBSRTC category to the upper category. BRAF.p.V600E showed the highest mutation incidence (71.3%) in the five-gene panel, correlated with the small to medium diameter (p = 0.008, p = 0.012) and high cytological categories (p < 0.001). The sensitivity, specificity, PPV, NPV, and accuracy of the combination of FNA cytology and five-gene detection were 96.83%, 100%, 100%, 42.86%, and 96.90%, respectively. The mutation frequency of the five-gene panel is 72.3% in thyroid FNAs. BRAF.p.V600E has the highest alteration rate, which is closely associated with tumor size and cytological results. The five-gene panel can improve the sensitivity and accuracy of FNA cytology, which may represent a valid adjunct technique in distinguishing thyroid nodules.

Comparison of Diagnostic Rates and Concordance with Subsequent Surgical Resections between Conventional Smear and ThinPrep Preparations versus ThinPrep Only in Thyroid Fine Needle Aspiration (T-FNA) Specimens

Background: Thyroid fine needle aspiration (T-FNA) is a mainstay in management of thyroid nodules. However, the preparation of T-FNA specimens varies across institutions. Prior studies have compared diagnostic rates between different specimen preparations of T-FNA specimens and their associated advantages and disadvantages. However, few have compared the rates of all diagnostic categories of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) between liquid-based preparations (LBPs) and a combination of LBP and conventional smear (CS) preparations. Our study compares TBSRTC diagnostic rates between these 2 cohorts and correlates cytologic diagnoses with subsequent thyroid resections to evaluate rates of neoplasia (RON) and malignancy (ROM). Methods: 584 consecutive thyroid FNA specimens were collected and stratified by preparation type (ThinPrep [TP] vs. CS & TP). Diagnostic rates for each TBSRTC diagnostic category were calculated. The institution’s electronic medical records database was searched for histologic diagnoses of previously sampled thyroid nodules to evaluate the RON and ROM. Results: Of 584 thyroid FNA specimens, 73 (12.5%) and 511 (87.5%) were evaluated by TP only and CS & TP, respectively, reflecting the predominance of rapid on-site evaluation (ROSE) with CS for T-FNAs at our institution. Of the TP only and CS & TP cohorts, 29 (39.7%) and 98 (19.2%) had subsequent resections, respectively. The frequency of non-diagnostic cases was lower in the CS & TP cohort (12.7% vs. 26%). While the diagnostic rate of follicular lesion of undetermined significance was similar for both cohorts, SFN categorization was only utilized in the CS & TP cohort (1.5% vs. 0%). Although RON and ROM were similar between cohorts in many of the TBSRTC categories, there was a higher RON associated with non-diagnostic specimens in the TP only cohort when the denominator included all non-diagnostic cases. Conclusion: The combination of CS and LBP may potentially decrease the non-diagnostic rate of T-FNA specimens as well as the number of passes required for diagnosis, particularly with ROSE. Evaluation of morphologic features highlighted in conventional smears may facilitate diagnostic categorization in the “suspicious for follicular neoplasm” category.

BRAF V600E mutation and the Bethesda System for Reporting Thyroid Cytopathology of fine-needle aspiration biopsy for distinguishing benign from malignant thyroid nodules.

Background:The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) predicts the risk of malignancy for the different categories of the ultrasound-guided fine-needle aspiration biopsy (FNAB). The objective of this study is to investigate the efficiencies of the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E mutation test and the TBSRTC categories in distinguishing between benign and malignant thyroid nodules.Methods:In this study, 362 ultrasound-guided fine-needle aspiration (FNA) samples from 344 patients aged from 17 to 76 years old were retrospectively reviewed. The patients were classified into six groups (I–VI) according to the TBSRTC system. The amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) was used to evaluate the BRAF V600E mutation level in total 362 samples. Among of the 344 patients, 128 patients (131 thyroid nodules) who underwent surgeries were followed by histopathological examination. The predictive values of the BRAF V600E mutation test and TBSRTC categories were evaluated in these 131 thyroid nodules.Results:The median ages of the patients in the TBSRTC IV–VI group were smaller than those in the TBSRTC I–III groups. The proportion of nodules over 1 cm was larger than it in the TBSRTC IV group compared to the other groups. Significant differences in BRAF V600E mutation were observed (P < .001) among these six groups. The sensitivity (89.57%) for the detection of malignant thyroid nodules, negative predictive value (NPV; 45.45%) for the detection of benign nodules, and accuracy (86.26%) for distinguishing between benign and malignant thyroid nodules increased by combining the BRAF V600E mutation test and TBSRTC system when compared with the BRAF V600E mutation test and TBSRTC system respectively. The BRAF V600E mutation test alone demonstrated the increased positive predictive value (PPV; 98.91%) and specificity (93.75%) for the detection of malignant thyroid nodules compared to the TBSRTC method (alone or in combination with the BRAF V600E method).Conclusion:In summary, significant differences in age, nodule diameter, and BRAF V600E mutation were noted among the six categories of the TBSRTC system. The combination of the BRAF V600E mutation test and TBSRTC system demonstrated increases in the NPV, sensitivity, and accuracy, while the BRAF V600E method proved superiority to the TBSRTC system with regard to the PPV and specificity.

The Bethesda System for Reporting Thyroid Cytopathology: A Retrospective Review of its Diagnostic Utility at Johns Hopkins Aramco Healthcare, Saudi Arabia

PurposeFine needle aspiration (FNA) is the gold standard for assessment of thyroid nodules, with the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) used to predict the malignancy risk of these nodules. Our aim was to evaluate the diagnostic utility of the TBSRTC for a Saudi population, by comparing the malignancy risk based on histopathology to FNA-based diagnosis of each of the TBSRTC categories and to previously published malignancy risk in other population. Materials and methodsThis was a retrospective study of the data of 241 patients who underwent FNA assessment of thyroid nodules and surgical resection with histopathology at John Hopkins Aramco Healthcare, Dhahran, Saudi Arabia, between January 2016 and December 2019. ResultsThe malignancy risk for each of the TBSRTC categories was as follows: non-diagnostic, 25%, benign; 5.74%; atypia of undetermined significance, 37%; suspicious for follicular neoplasm, 38%; suspicious for malignancy, 100%; and malignant, 95%. Our finding were comparable to previously published malignancy risks, except for a higher rate of malignancy in the benign category at 18% compared to 0–3%. ConclusionOur findings validate the diagnostic reproducibility of the TBSRTC for a Saudi population, with the risk of malignancy confirmed by histopathological assessment being consistent with those previously reported for other populations.

Usefulness of The Bethesda System of Reporting Thyroid Cytopathology in Surgical Planning.

The Bethesda system for reporting thyroid cytopathology (TBSRTC) has attempted to standardize thyroid fine needle aspiration cytology (FNAC) reporting internationally into six diagnostic categories and help in clinical decision making. But there exists a significant variation in the reporting percentage and rates of malignancies in each category across the centres which complicates clinical decision making. To study the usefulness of TBSRTC in surgical planning of thyroid nodules and to correlate TBSRTC with final histopathology. 85 patients with thyroid nodules who underwent surgery were evaluated prospectively. Preoperatively FNAC and TBSRTC reporting was done and following surgery histopathology was correlated with cytology. Distribution of 85 patients amongst the six categories of TBSRTC was as follows: 2.35% in Category I, 68.23% II, 7.05% III, 16.47% IV, 2.35% V and 3.52% VI. In 93% (79) of patients TBSRTC correlated with histopathology whereas in 7% (6) it did not. Risk of malignancy calculated was 0% in II, 33.33% in III, 7.14% in IV and 100% in V and VI categories. Sensitivity, specificity, Positive Predictive Value and Negative Predictive Value of TBSRTC was 100% for V, VI categories, whereas it was 100%, 78%, 15% and 100% respectively for III, IV. The diagnostic accuracy in our study is 100% for Category V and VI whereas it is 79% for Category III and IV. TBSRTC proved to be a very good screening platform for triaging patients with thyroid nodules into benign and malignant groups, as it is directly related to risk of malignancy in each category. It has helped in appropriate surgical planning in 96.4% of our patients.

Bethesda System Categories of Fine Needle Aspiration Cytology Are Not Associated with Thyroid Nodule Location: A Single Institution Experience

Introduction: Thyroid isthmus is defined as the thin band connecting thyroid tissue between both lateral thyroid lobes. Recently, a possible association between thyroid nodules located in the isthmus and malignancy was proposed. The aim of this study was to compare the frequency of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) categories between nodules from the isthmus and nodules from both thyroid lobes. Methods: All fine needle aspiration cytology procedures performed between January 2016 and December 2019 at the Pathology Institute of Araçatuba, São Paulo, Brazil, were analyzed. For each nodule, at least 2 conventional slides were produced (1 stained by Giemsa and the other by hematoxylin and eosin). All cases were reported according to the TBSRTC. Clinical information (gender, age, and localization) and ultrasound data (size of nodules) were collected from medical requisition forms. To assess the association between the frequency of TBSRTC categories and nodule location, univariate analysis was performed using the χ² test or Fisher’s exact test, as appropriate. A p value <0.05 was considered statistically significant. Nodules located in transition between the isthmus and a right or left lobe were included in the isthmus group. Results: Considering the p value between the TBSRTC categories and thyroid nodule location, statistic association was not observed: nondiagnostic or unsatisfactory (p = 0.1442), atypia of undetermined significance or follicular lesion of undetermined significance (p = 0.3296), follicular neoplasm or suspicious for a follicular neoplasm (p = 0.0817), suspicious for malignancy (p = 0.8464), and malignant (p = 0.1082). Conclusion: In the studied population, nodules located in the isthmus were not related to any Bethesda System category.

The importance of risk of neoplasm as an outcome in cytologic-histologic correlation studies on thyroid fine needle aspiration.

The introduction of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) altered the practice of thyroid pathology and reduced the risk of malignancy (ROM) associated with the indeterminate categories in the Bethesda system for reporting thyroid cytopathology (TBSRTC). It has been proposed that the evaluation of the risk of neoplasm (RON) is important in cytologic-histologic correlation studies. A total of 5224 thyroid aspirates were performed at our institution during an 8-year period. Of the 1475 cases (28%) with surgical follow-up, the histologic diagnoses comprised benign non-neoplastic (BNN, n = 669), follicular adenoma (FA, n = 188), NIFTP (n = 42), papillary microcarcinoma (PMC) (n = 223), and malignant neoplasm excluding PMC (n = 353). The RON was calculated to include neoplasia with low risk biologic behavior (FA, NIFTP, PMC) and malignant neoplasms. In contrast, the ROM was reserved for malignant neoplasms excluding PMC. The RON for each TBSRTC category was: nondiagnostic (ND) 38.3%, benign 20.9%, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) 63.2%, follicular neoplasm or suspicious for follicular neoplasm (FN/SFN) 83.9%, suspicious for malignancy (SFM) 94%, and malignant 100%. The ROM excluding PMC was: ND 14%, benign 1.6%, AUS/FLUS 17.8%, FN/SFN 28.4%, SFM 84.4%, and malignant 99.5%. The RON and ROM support the recommended management guidelines from TBSRTC for all categories, except for FN/SFN. Histopathologic follow-up of FN/SFN aspirates in our study contain a very high rate of neoplasm (83.9%), which might support the management preference of conservative surgery.

Spectrum of thyroid lesions in FNAC - diagnostic implications and pitfalls

Thyroid nodule is one of the most common clinical presentations with annual incidence of 4% in general population. For clear communication between treating surgeon and cytopathologist the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) established a uniform, tiered reporting system for thyroid Fine needle aspiration (FNAC) specimens. Retrospective descriptive study was conducted for the duration of three years on all cases of thyroid FNAC.481 thyroid FNAC were performed, patients age ranged from 16 years to 78 years, with mean age of 39 years, majority of them in 4th decade 158 cases (32.8%).Male female ratio of 1: 8.6, with female predominance 443 cases (92%).Observation based on TBSRTC categories as follows category I - unsatisfactory – 36 cases (7.5%),Category II – Benign – 419 cases (87.1%),Category III - Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance 2 cases (0.4%), Category IV of Follicular Neoplasm or Suspicious for a Follicular Neoplasm 05 cases (1%), category V - suspicious of malignancy 5 cases (1%).The Bethesda system for reporting of thyroid cytology will give uniform categorization of thyroid smear globally among cytopathologist, and give clear communication to treating surgeon regarding decision on further treatment.

The Bethesda System for Reporting Thyroid Cytopathology: A Cytohistological Study.

Introduction The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is a significant step to standardize the reporting of thyroid fine needle aspiration (FNA). It has high predictive value, reproducibility, and improved clinical significance. Aim The study was aimed to evaluate the diagnostic utility and reproducibility of “TBSRTC” at our institute. Methods and Material. The study included 646 thyroid FNAs which were reviewed by three pathologists and classified according to TBSRTC. Cytohistological correlation was done for 100 cases with surgical follow-up and the sensitivity, specificity, positive predictive value, negative predictive value, diagnostic accuracy, and risk of malignancy (ROM) were calculated. The interobserver variation among three pathologists was also assessed. Results The distribution of cases in various TBSRTC categories is as follows: I—nondiagnostic 13.8%, II—benign 75.9%, III—atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS) 1.2%, IV—follicular neoplasm (FN)/suspicious for follicular neoplasm (SFN) 3.7%, V—suspicious for malignancy (SM) 2.6%, and VI—malignant 2.8%. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy are 72.4%, 94.3%, 84%, 89.2%, and 87.9%, respectively. The ROM of various TBSRTC categories were II—8.5%; III—66.7%; IV—63.6%; and V and VI—100%. Cohen's Weighted Kappa score was 0.99 which indicates almost perfect agreement among the three pathologists. Conclusions Our study substantiates greater reproducibility among pathologists using TBSRTC to arrive at a precise diagnosis with an added advantage of predicting the risk of malignancy which enables the clinician to plan for follow-up or surgery and also the extent of surgery.

Application of a machine learning algorithm to predict malignancy in thyroid cytopathology.

The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) comprises 6 categories used for the diagnosis of thyroid fine-needle aspiration biopsy (FNAB). Each category has an associated risk of malignancy, which is important in the management of a thyroid nodule. More accurate predictions of malignancy may help to reduce unnecessary surgery. A machine learning algorithm (MLA) was developed to evaluate thyroid FNAB via whole slide images (WSIs) to predict malignancy. Files were searched for all thyroidectomy specimens with preceding FNAB over 8years. All cytologic and surgical pathology diagnoses were recorded and correlated for each nodule. One representative slide from each case was scanned to create a WSI. An MLA was designed to identify follicular cells and predict the malignancy of the final pathology. The test set comprised cases blindly reviewed by a cytopathologist who assigned a TBSRTC category. The area under the receiver operating characteristic curve was used to assess the MLA performance. Nine hundred eight FNABs met the criteria. The MLA predicted malignancy with a sensitivity and specificity of 92.0% and 90.5%, respectively. The areas under the curve for the prediction of malignancy by the cytopathologist and the MLA were 0.931 and 0.932, respectively. The performance of the MLA in predicting thyroid malignancy from FNAB WSIs is comparable to the performance of an expert cytopathologist. When the MLA and electronic medical record diagnoses are combined, the performance is superior to the performance of either alone. An MLA may be used as an adjunct to FNAB to assist in refining the indeterminate categories.

Molecular Testing for BRAFV600E and RAS Mutations from Cytoscrapes of Thyroid Fine Needle Aspirates: A Single-Center Pilot Study.

Context and Aim:Molecular testing of thyroid FNA has been advocated in the indeterminate categories of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) 2018. The utility of cytoscrapes of thyroid FNA samples for BRAF V600E and RAS mutations was evaluated in this pilot study.Methods and Materials:Thyroid FNA samples between 2015 and 2018 from TBSRTC categories 3–6 were included. DNA was extracted from one to two representative smears (cytoscrape). Real-time PCR for BRAF V600E and RAS (KRAS, NRAS, and HRAS) gene mutations was performed. Histopathology correlation was available in 44 cases.Statistical Methods:Chi-square test and calculation of sensitivity, specificity, and positive/negative predictive values were performed.Results:A total of 73 thyroid FNA cases and 11 nodal metastases of papillary thyroid carcinoma (PTC) were evaluated. The DNA yield ranged from 1.9 to 666 ng/μl (mean 128 ng/μl) in 80 cases and was insufficient in four cases. Overall, mutations were seen in 45 (56.25%) cases with BRAF V600E, NRAS, HRAS, and KRAS in 21 (46.7%), 19 (42.2%), 4, and 1 cases, respectively. BRAF V600E mutation was seen in PTC (11/18, 61%), nodal PTC metastases (5/10, 50%), and occasionally in TBSRTC category 3 (1/18, 5.5%). NRAS mutations were seen across all categories and were maximum in the AUS/FLUS group (6/18, 33%). BRAF V600E /RAS testing had an overall sensitivity, specificity, and positive and negative predictive values of 61.7%, 80%, 91.3%, and 38%, respectively, for the detection of malignancy. In indeterminate thyroid nodules, the sensitivity, specificity, PPV, and NPV were 56.2%, 80%, 81.8%, and 53.3%, respectively.Conclusion:BRAF V600E/RAS mutation testing from cytoscrapes are useful as a rule-in test for indeterminate thyroid nodules and provide molecular confirmation in nodal metastases of PTC.

Differences in surgical resection rate and risk of malignancy in thyroid cytopathology practice between Western and Asian countries: A systematic review and meta‐analysis

There is increasing evidence showing that clinicians employ different management strategies in their use of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). In this meta-analysis, we investigated the differences in diagnosis frequency, resection rate (RR), and risk of malignancy (ROM) between Western (ie, American and European) and Asian cytopathology practices. We searched PubMed and Web of Science from January 2010 to January 2019. Proportion and 95% CIs were calculated using a random-effect model. We used independent sample t tests to compare frequencies, RR, and ROM between Western and Asian practices. We analyzed a total of 38 studies with 145,066 fine-needle aspirations. Compared with Asian practice, Western series had a significantly lower ROM in most of TBSRTC categories, whereas the RR was not statistically different. Focusing on indeterminate nodules, the RR in Western series was significantly higher (51.3% vs 37.6%; P=.048), whereas the ROM was significantly lower (25.4% vs 41.9%; P=.002) compared with those in Asian series. The addition of Asian cohorts increased ROM for most of diagnostic categories compared with the original TBSRTC. In conclusion, this study demonstrates a difference in Western and Asian thyroid cytology practice, especially regarding the indeterminate categories. Lower RR and higher ROM suggest that Asian clinicians adopt a more conservative approach, whereas immediate diagnostic surgery is favored in Western practice for indeterminate nodules. The addition of Asian series into a meta-analysis of TBSRTC altered ROM for several categories, which should be considered in future revisions of TBSRTC.

The influence of the reclassification of NIFTP as an uncertain tumour on risk of malignancy for the diagnostic categories according to the Bethesda system for reporting thyroid cytopathology.

The noninvasive encapsulated, follicular variant of papillary thyroid carcinoma was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The exclusion of NIFTP from the group of malignant tumours decreases the risk of malignancy (RoM) as defined by the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). The aim of the present study was to evaluate the RoM for each category in TBSRTC with and without exclusion of NIFTP from the tally of malignancies. The present study included 998 thyroid nodules cases. All patients underwent diagnostic tests, including fine-needle aspiration cytology, and received surgical treatment. Slides for all resection specimens with a diagnosis of cancer were reviewed to identify NIFTP. The RoM for each of the categories in TBSRTC with and without exclusion of NIFTP from the malignant tumours was evaluated. The RoM decreased with the exclusion of NIFTP from malignant categorisation with the following values for the different TBSRTC categories: non-diagnostic (ND): 0%; benign: 0%; atypia/follicular lesion of undetermined significance (AUS/FLUS): 1.6%; follicular neoplasm/suspicious for follicular neoplasm (FN/SFN): 0.7%; suspicious for malignancy (SUS): 6.9%; and malignant: 2.5%. The difference of 2.5% in the malignant category was statistically significant (p = 0.0253). The RoM for specific TBSRTC categories needs to be defined for each treatment centre because it is important for the selection of the appropriate surgical treatment for thyroid tumours.

Clinical Impact of Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features on the Risk of Malignancy in the Bethesda System for Reporting Thyroid Cytopathology: A Meta-Analysis of 14,153 Resected Thyroid Nodules

Objective: It is still controversial as to how the reclassification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) affects the risk of malignancy (ROM) in The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). This meta-analysis was aimed to investigate the impact of NIFTP on the ROM in each TBSRTC category. Methods: We accessed three electronic databases including PubMed, Web of Science, and Scopus to search for relevant data from January, 2016 to July, 2018. Relative risk and meta-analysis of proportions using the DerSimonian-Laird method, and each corresponding 95% confidence interval (CI) was pooled using a random-effect model. Results: A total of 14 studies consisting of 14,153 resected nodules were included for meta-analyses. Overall, there was a significant reduction in ROM in all TBSRTC categories following the NIFTP reclassification, except TBSRTC category I. The largest absolute and relative decrease in ROM was observed in TBSRTC category V (16%; 95% CI = 8 to 24) and category III (32%; 95% CI = 24 to 39), respectively. There was a positive correlation between the rate of NIFTP and resection rate (r = 0.83; P = .02). The decreases in ROM were more prominent in Western than in Asian cohorts. Conclusion: We confirmed the decrease in ROM due to the NIFTP reclassification for most of TBSRTC categories, which was more significant in Western than in Asian practice. The incidence of NIFTP was higher in institutions where surgical resection rates were high in patients with indeterminate cytology nodules. Abbreviations: AUS/FLUS = atypia of undetermined significance/follicular lesion of undetermined significance; CI = confidence interval; FNA = fine-needle aspiration; FN/SFN = follicular neoplasm/suspicious for follicular neoplasm; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; NI-FVPTC = noninvasive follicular variant of papillary thyroid carcinoma; ROM = risk of malignancy; RR = relative risk; SM = suspicious for malignancy; TBSRTC = The Bethesda System for Reporting Thyroid Cytopathology.