Evolving approaches in paediatric thyroid cytopathology: A review.

The guidelines for the workup of thyroid nodules have been established in adult populations and secondarily applied to paediatric populations. In particular, The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is commonly applied to both adult and paediatric thyroid nodules. However, as paediatric nodules have distinct molecular drivers and behavioural trajectories, there is renewed interest in diagnostic and management strategies that are paediatric specific. Here, we review key differences between paediatric and adult thyroid cancer and recent literature evaluating the use of TBSRTC in paediatric populations.

Results of retrospective classification of thyroid FNAs according to the Bethesda system: would this have improved accuracy?

OBJECTIVES: To retrospectively reclassify the results of fine needle aspiration (FNA) cytology at our institution according to the Bethesda system for reporting thyroid cytopathology (TBSRTC), and to determine whether the introduction of the new classification system would have influenced the diagnostic accuracy compared with our existing system in which suspicious/indeterminate categories (categories III-IV) are managed according to clinical findings and cytopathologists' recommendations. METHODS: FNAs performed under ultrasound guidance between 2001 and 2012, and subsequently verified by histology or repeat FNA and follow-up, were reviewed and retrospectively reclassified according to TBSRTC. RESULTS: Among a total of 1310 histologically verified FNAs, the positive predictive values (%) for malignancy and neoplasia (carcinoma + follicular adenomas) for category I-VI according to the TBSRTC were 5.7/11.3, 2.6/5.5, 14.4/34.2, 23.6/55.0, 57.0/64.5 and 92.2/94.2, respectively. Although all the categories predict malignancy closely, the difference in malignancy rate between categories III and IV was not statistically significant; however, the difference in total neoplasia rate reached statistical significance. When patients with cytological and clinical follow-up were included, the malignancy rated dropped in category I to 2.4%, whereas, in category III, it remained at 13%. Repeat FNA instead of direct surgery spared half of the patients from surgery. The cytopathologists' recommendations for histological verification in category III were associated with an insignificant increase in malignancy rate, but the total neoplasia rate reached 57.5%. CONCLUSIONS: At our institution, the application of the TBSRTC did not improve the diagnostic accuracy for the detection of malignancy compared with current practice. In selected cases with cytological results falling into category III (according to clinical data and cytopathologists' opinions), direct lobectomy seems to be justified.

Diagnostic values of SurePath liquid-based cytology versus conventional smear in thyroid aspiration samples: A 13-year experience at a single institution.

BACKGROUND: Fine needle aspiration cytology (FNAC) is the most useful tool in the diagnosis of thyroid nodules. Liquid-based cytology (LBC) is replacing the conventional smear (CS) for evaluation of thyroid FNAC. In our institution, thyroid FNAC preparation was changed from CS to LBC SurePath in July 2016. This study aimed to compare the diagnostic value of SurePath with that of CS in thyroid lesions. METHODS: A total of 35,406 samples of thyroid FNAC (11,438 CS and 23,968 SurePath), collected from January 2010 to December 2022, were included in this study. We also examined the malignant rate using the surgical pathology diagnosis as the gold standard. RESULTS: The distribution of TBSRTC cytological categories was equivalent between CS and SurePath. The rate of nondiagnostic/unsatisfactory category was higher in CS compared to SurePath (43.4% vs. 22.3%; p < .05). After routine use of SurePath, the surgical resection rate was reduced from 12.0% to 8.6% (p < .05) and the malignant rate increased from 32.2% to 41.5% (p < .05). The sensitivities of CS and SurePath were 71.0% and 82.0%, respectively, and the specificities were 99.0% and 97.3%, respectively, whereas the positive predictive values were 97.8% and 96.8%, respectively, and the negative predictive values were 85.0% and 84.6%, respectively. Diagnostic accuracy of CS and SurePath were 88.5% and 89.7% respectively. CONCLUSION: SurePath can increase the sample adequacy, increase the sensitivity and reduce the workload and avoid unnecessary surgeries with similar accuracy to CS.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Use of the Afirma Xpression Atlas for cytologically indeterminate, Afirma Genomic Sequencing Classifier suspicious thyroid nodules: Clinicopathologic analysis with postoperative molecular testing.

OBJECTIVES: Afirma has recently introduced its Xpression Atlas (XA) as an adjunct to its Genomic Sequencing Classifier (GSC) for risk stratification of cytologically indeterminate thyroid nodules. We evaluated the performance of Afirma XA and associated pathologic findings for Afirma GSC suspicious nodules. METHODS: Intradepartmental records of thyroid fine-needle aspirations (FNAs) from January 2021 to December 2022 were identified and reviewed for patient and nodule characteristics, FNA findings, molecular test results, and final surgical pathology, if available. RESULTS: Material for Afirma GSC testing was collected in 624 thyroid FNAs, and 148 (24%) were classified as cytologically indeterminate. Afirma GSC testing was successful in 132 (89%) of those cases, of which 35 (27%) were Afirma GSC suspicious. Afirma XA testing was positive in 11 cases (11/35 [31%]). Eight (73%) patients underwent surgery that revealed 7 patients with papillary thyroid carcinoma and 1 patient with noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) (risk of malignancy: 100% [8/8]). Among the 24 patients with negative Afirma XA results, 19 (79%) underwent surgery, revealing 5 patients with malignancy and 3 patients with NIFTP (risk of malignancy: 42% [8/19]). Overall, the risk of malignancy for Afirma GSC suspicious nodules was 59% (16/27). CONCLUSIONS: Afirma XA improved risk stratification of thyroid disease with a high risk of malignancy in Afirma GSC suspicious nodules. A negative Afirma XA result, however, should not be used as a rule-out test.

The Role of Cytomorphometric Image Analysis in the Diagnosis of Thyroid Nodules.

Introduction Fine needle aspiration cytology (FNAC) plays a vital role in the diagnosis of thyroid nodules. However, it is challenging due to the heterogeneity of thyroid nodules, overlapping cytomorphological features, and interobserver variability. Cytomorphometric analysis turns subjective observations into quantitative values. In this study, we performed cytomorphometric image analysis on cytological smears of thyroid nodules, classified according to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Materials and methods A retrospective analysis of Papanicolaou (PAP) and Hematoxylin & Eosin (H&E) stained fine needle aspirate smears from 50 patients with thyroid nodules with available follow-up histopathology was performed for a period of two years (March 2021 - March 2023), after obtaining approval from the institutional human ethical committee (IHEC-LOP/2020/IM0355). The nodules were categorized according to TBSRTC and were then subjected to cytomorphometric image analysis. Each nucleus was analyzed for 14 parameters, including aspect ratio, intensity, diameter, perimeter, roundness, area, fractal dimension, feret diameter, circularity, radii, fournier description, and chromatin texture parameters such as heterogeneity and clumpiness. The data obtained was analyzed through relevant statistical methods using SPSS version 23 (IBM Inc., Armonk, New York) and was compared by using the analysis of variance (ANOVA) test and post hoc test. Results Our results revealed that cytomorphometric image analysis not only distinguishes benign and malignant thyroid nodules but also can aid in categorizing thyroid nodules with predominant follicular patterns, such as follicular variant of papillary carcinoma, follicular adenoma and follicular carcinoma (p<0.001). Conclusions Morphometric analysis of cytological smears combined with cytomorphology has the potential to be an important tool in the diagnosis of thyroid nodules. It can improve diagnostic accuracy for better treatment and improved prognosis.

Impact of the 3rd Edition of the Bethesda System for Reporting Thyroid Cytopathology on Grey Zone Categories.

INTRODUCTION: Thyroid Bethesda Reporting System is a six-tiered system that aims to bring uniformity in reporting thyroid cytology and improve the communication with clinicians. The system has achieved its goal as a presurgical diagnostic method; however, it remains a screening method in the grey zone categories, namely atypia of undetermined significance (AUS) and follicular neoplasm (FN). The book recently released the 3rd edition, following the recent changes in thyroid pathology. One of the most important novelties is subgrouping AUS category and FN to be able to make a better risk stratification in these categories. Our group aims to retrospectively analyze a large dataset based on the new TBSRTC, with a focus on the grey zone categories. METHODS: Only patients who underwent lobectomy or total thyroidectomy were included, allowing for direct comparison between cytological and histopathological results. Cytological evaluations, based on the TBSRTC 3rd edition, were methodically compared with their respective histopathological results, enabling a comprehensive analysis. RESULTS: Of the 244 patients (female:male ratio = 8.8:1, mean age = 56), a total of 252 nodules were evaluated. A distinction was noted with 79 nodules (31%) diagnosed as AUS and 173 nodules (69%) as FN. Intriguingly, the risk of malignancy (ROM) for AUS-overall stood at 44.3%, with AUS-nuclear atypia at 50% and AUS-other at 43.2%. Although the AUS subdivisions did not demonstrate statistical significance, a significant disparity was observed in their distribution, with 15% as AUS-nuclear atypia compared to 85% as AUS-other. This disparity raises the question: Could AUS-other be considered the new waste-basket category in the TBSRTC 3rd edition? Using the TBSRTC 3rd edition as a base, we added a subclassification for FN nodules based on the presence or absence of papillary thyroid carcinoma (PTC) nuclear features. Our findings showed that differentiating FN with oncocytic characteristics correlated well with histological outcomes and ROMs. Though retrospective in design with inherent bias potential, our data suggest a possible improvement in PTC case segregation in the FN category when differentiating between FN nodules with and without PTC nuclear features. CONCLUSION: Our retrospective study sheds light on the potential advantages of the TBSRTC 3rd edition, particularly in refining the AUS and FN categories for thyroid nodules. The clear disparity in AUS subcategories raises important questions about their classification and potential future refinements. Moreover, the differentiation of FN nodules based on PTC nuclear features holds a promising approach for better risk stratification.

Indeterminate Thyroid Fine-Needle Aspirations in Pediatrics: Exploring Clinicopathologic Features and Utility of Molecular Profiling.

INTRODUCTION: The diagnostic utility of molecular profiling for the evaluation of indeterminate pediatric thyroid nodules is unclear. We aimed to assess pediatric cases with indeterminate thyroid fine-needle aspiration (FNA) alongside clinicopathologic features and mutational analysis. METHODS: A retrospective review of 126 patients with indeterminate cytology who underwent FNA between January 2010 and December 2021 at the Children's Hospital of Philadelphia was performed. Indeterminate cases defined by The Bethesda System for Reporting Thyroid Cytopathology (AUS/FLUS or TBSRTC III; FN/SFN or TBSRTC IV; SM or TBSRTC V) were correlated to clinicopathologic and genetic characteristics. RESULTS: Of the 114 surgical cases, 48% were malignant, with the majority of malignant cases diagnosed as follicular variant of papillary thyroid carcinoma (28/55). Risk of malignancy increased with TBSRTC category: 23% for AUS/FLUS, 51% for FN/SFN, and 100% for SM nodules. There were significant differences in surgical approach (p < 0.01), performance of lymph node dissection (p < 0.01), histological diagnosis (p < 0.01), primary tumor focality/laterality (p = 0.04), and lymphatic invasion (p = 0.02) based on TBSRTC classification, with resultant differences in post-surgical risk stratification per American Thyroid Association (ATA) Pediatric Guidelines (p = 0.01). Approximately 89% (49/55) of cases were classified as ATA low risk, and 5 of 6 patients with ATA intermediate- or high-risk disease had SM cytology. Somatic molecular testing was performed in 40% (51/126) of tumors; 77% (27/35) of malignant cases and 38% (6/16) of benign cases harbored driver alteration(s). Of the driver-positive malignant cases, 52% (14/27) were associated with low risk (DICER1, PTEN, RAS, and TSHR mutations), 33% (9/27) were associated with high risk (BRAF mutations and ALK, NTRK, and RET fusions), and 15% (4/27) had unreported risk for invasive disease (APC, BLM, and PPM1D mutations and TG-FGFR1 fusion). Incidence of high-risk drivers increased with TBSRTC category. Approximately 23% (8/35) of patients harboring thyroid malignancy did not have an identifiable driver alteration. CONCLUSIONS: Molecular analysis is useful to discriminate benign and malignant thyroid nodules with indeterminate cytology. Patients with driver genetic alteration(s) and indeterminate cytology should consider surgical management secondary to the high incidence (82%; 27/33) of thyroid malignancy in these patients.

Correlation of fine needle aspiration cytology and cell block study of category III, IV, and V (TBSRTC-2017) thyroid lesions with special reference to cytokeratin-19 immunohistochemical staining.

Context: Ascertaining the role of cytokeratin-19 (CK19) and its staining pattern helps to differentiate papillary carcinoma from other thyroid lesions. Aims: To correlate fine needle aspiration cytology (FNAC) and cell block study of equivocal cases (Category III, IV, and V) with the role of CK19 staining in it. Settings and Design: A hospital-based cross-sectional observational study was designed and conducted at North Bengal Medical College and Hospital, Shusrutnagar, Darjeeling. Methods and Material: The FNAC performed and reported as per TBSRTC-2017.50 cases of Category III, IV, and V was selected for cell block study and CK19 staining followed by immunohistochemical scoring. Results: Out of 50 cases, 17 were follicular neoplasm, 21 papillary carcinoma, 6 lymphocytic thyroiditis, 1 Hürthle cell adenoma, 1 medullary carcinoma, 1 lymphoma, and 3 undifferentiated carcinomas. Among cases of papillary carcinoma, 10 showed 4+ positivity, 9 showed 3+ positivity, 2 showed focal 1+ and 2+ positivity. In the case of follicular neoplasm, 1 showed 3+ positivity, 3 cases had 1+ 2+ positivity, and 13 cases revealed negative staining. Conclusion: Role of CK19 in distinguishing papillary carcinoma of thyroid from other lesions in cytologically diagnosed Category III, IV, and V (TBSRTC-2017) cases can be demonstrated.

Comparative analysis of cytomorphology of thyroid lesion on conventional cytology versus liquid-based cytology and categorize the lesions according to The Bethesda System for Reporting Thyroid Cytopathology.

Introduction: Thyroid nodules are a common disorder of the thyroid. Most of these are benign and only 5%-30% are malignant. Fine-needle aspiration cytology (FNAC) plays a vital role in differentiating benign from malignant and hence directing toward timely intervention. Liquid-based cytology (LBC) has been recently started in sampling thyroid lesions and has shown good results. The aim of our study was to compare the cytomorphology of thyroid lesions by conventional smear (CS) and LBC method and categorize the lesions according to TBSRTC (The Bethesda System for Reporting Thyroid Cytopathology). Materials and Methods: A prospective study was conducted from January 2018 to June 2019 on 131 patients. Thyroid FNAC samples were taken to prepare 2-5 slides for conventional reporting and one sample for LBC preparation by SurePath method. Staining with hematoxylin and eosin, May-Grünwald-Giemsa, and Papanicolaou stain was done. Cases were reported by TBSRTC and compared. Results: The nonneoplastic lesions constituted the major proportion on both CS (83.2%) and LBC (73.2%). The neoplastic lesions constituted only 9.9% of all the diagnosis both on CS and LBC smear. The kappa agreement between CS and LBC cytology as per The Bethesda System for Reporting Thyroid Cytopathology came out to be 0.715, which was statistically significant. Discussion: Colloid appearance was statistically significant on comparison by both methods. The comparison of ill formed epithelioid granulomas was statistically significant in autoimmune thyroiditis cases. In malignancy cases, nuclear and cytoplasmic details were crisper on CS. Cytoplasm appeared fragile and fragmented on LBC smears.

Performance of the Bethesda System for Reporting Thyroid Cytology in Multi-Institutional Large Cohort of Pediatric Thyroid Nodules: A Detailed Analysis.

BACKGROUND: To evaluate the performance of TBSRTC through multi-institutional experience in the paediatric population and questioning the management recommendation of ATA Guidelines Task Force on Paediatric Thyroid Cancer; Methods: A retrospective search was conducted in 4 institutions to identify consecutive thyroid FNAC cases in paediatric population between 2000 and 2018. Following the 2nd TBSRTC, the risk of malignancy ratios (ROMs) was given in ranges and calculated by 2 different ways. Sensitivity, specificity, PPV, NPV and DA ratios were calculated using histologic diagnosis as the gold standard; Results: Among a total of 405 specimens, the distribution of cases for each category was, 44 (11%) for ND, 204 (50%) for B category, 40 (10%) for AUS/FLUS, 36 (9%) for FN/SFN, 24 (6%) for SFM and 57 (14%) for M categories. 153 cases have a histological diagnosis. The ratio of surgery was 23% in ND, 16% in the B, 45% for AUS/FLUS, 75% for SFN/FN and 92% for SFM and 75% in M categories; Conclusions: The data underlines the high ROM values in paediatric population which might be clinically meaningful. The high rate of malignancy of the cohort of operated patients (50%) also underlines the need of better preoperative indicators for stratification. Considering that more than half of the nodules in AUS/FLUS category were benign, direct surgery recommendation could be questionable as proposed in ATA 2015 guidelines.

Diagnostic utility of fine needle aspiration cytology in pediatric thyroid nodules based on Bethesda Classification.

OBJECTIVES: The Bethesda system for reporting cytopathology (TBSRTC) has been widely adopted in the management of thyroid nodules. Based on the limited pediatric data available, the implied malignancy risk for each of the categories may be significantly different in pediatrics vs. adults, especially in the indeterminate categories (Bethesda Class III or IV). We report the diagnostic utility of fine needle aspiration (FNA) biopsy at our institution based on the Bethesda system and the risk of malignancy in each category. METHODS: We retrospectively reviewed all patients who underwent a thyroid FNA at our tertiary pediatric hospital from 12/1/2002 to 11/30/2018. FNA results were classified according to TBSRTC. Patient demographics, cytology, histopathology, radiological and clinical follow-ups were examined. RESULTS: A total of 171 patients were included with 203 cytological samples. Average age at initial FNA was 14.7 years (range 6.9-18.6 years). The numbers of nodules reported for Bethesda categories I-VI were 29, 106, 22, 14, 6 and 26, respectively, and the rate of malignancy was: 13.8, 4.7, 22.7, 35.7, 83.3 and 100%, respectively. Use of ultrasound guidance reduced the non-diagnostic rate from 38.1 to 11.5%. Introduction of on-site adequacy testing further reduced the non-diagnostic rate to 6.5% since 2014. CONCLUSIONS: The risk of malignancy for thyroid nodules in this pediatric cohort is higher than reported in adults. However, rates described here are much closer to adult ranges than previously published pediatric cohorts. The addition of adequacy testing improved the non-diagnostic rate of FNA procedures performed with ultrasound guidance.

A correlation study between thyroid imaging report and data systems and the Bethesda system for reporting thyroid cytology with surgical follow-up - an ultrasound-trained cytopathologist's experience.

INTRODUCTION: Thyroid Imaging Reporting and Data Systems (TI-RADS) including a modified system (M TI-RADS) and American College Radiology (ACR) TI-RADS are introduced. Correlation studies between both TI-RADSs and The Bethesda System for Reporting Thyroid Cytology (TBSRTC) for Ultrasound-guided fine-needle aspiration (US-FNA) cases with surgical follow-up (SFU) are presented. MATERIALS AND METHODS: Three hundred and forty six thyroid US-FNA cases performed at the US-FNA clinic of Stony Brook University Hospital by an Ultrasound-trained interventional Cytopathologist between December 1, 2014 to February 28, 2018 were reviewed. All ultrasound images from 346 cases were evaluated and assigned M TI-RADS scores based on ultrasound features present in Table 1. One hundred and fifty four cases from Dcember 1, 2014 to February 28, 2016 were assigned scores using ACR TI-RADS.TBSRTC category along with SFU data was collected and correlated with both TI-RADS scores by using Pearson's correlation coefficient (r). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy for M TI-RADS and TBSRTC were also calculated using SFU diagnosis as a gold standard. McNemar test was applied to evaluate the significance of the difference between M TI-RADS and TBSRTC. RESULTS: Based on 346 thyroid nodules studied, the overall r-value between M TI-RADS scores and TBSRTC categories is 0.465. The r-values between Composition, Echogenicity, Shape, Margin, Echogenic foci, the summary points, and the converted TR level of ACR TI-RADS and TBSRTC are 0.145, 0.042, 0.259, 0.310, 0.405, and 0.379, respectively. Fifty (14.5%) cases have SFUs. Considering TI-RADS 5&6 and TBSRTC 5&6 as positives, and TI-RADS 2 and TBSRTC 2 as negatives, the Sensitivity, Specificity, PPV, NPV, and accuracy are 96%, 53%, 76%, 89%, 79% for TI-RADS vs 100%, 93%, 96%, 100%, 97% for TBSRTC, respectively (P = .038). The data for indeterminate cases are summarized. CONCLUSION: Both TI-RADSs could be helpful to a moderate degree. M TI-RADS appeared to correlate to TBSRTC slightly better than that of ACR TI-RADS. TBSRTC is significantly more accurate than M TI-RADS for the majority of determined cases.

The Use of the Bethesda System for Reporting Thyroid Cytopathology in Pediatric Thyroid Nodules: A Meta-Analysis.

Background: Little is known about the application of the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) in pediatric thyroid nodules. This meta-analysis was aimed to investigate the use of TBSRTC in the pediatric population. Methods: Relevant articles were searched in PubMed and Web of Science. Meta-analysis of proportion and its 95% confidence interval (CI) were computed utilizing the random-effect model. We used subgroup analyses and meta-regression to explore the sources of heterogeneities. Egger's regression test and funnel plot visualization were used to examine publication bias. Results: We included 17 articles comprising of 3687 pediatric thyroid nodules for meta-analyses. TBSRTC outputs including frequency and risk of malignancy (ROM) for the majority of categories were not statistically different from recently published meta-analysis of 145,066 thyroid nodules in adult patients. The resection rate (RR) in the pediatric group was significantly higher in most of the categories compared with published adult data: benign, 23.2% [CI = 18.6-27.9] vs. 13.0% [CI = 9.5-16.5]; atypia of undetermined significance/follicular lesion of undetermined significance, 62.6% [CI = 50.3-74.9] vs. 36.2% [CI = 29.9-42.5]; follicular neoplasm/suspicious for follicular neoplasm, 84.3% [CI = 75.2-93.4] vs. 60.5% [CI = 54.5-66.5]; and suspicious for malignancy, 93.8% [CI = 90.1-97.6] vs. 69.7% [CI = 64.0-75.5]. Conclusion: TBSRTC is a valuable tool to make clinical decisions for pediatric patients with thyroid nodules. Pediatric patients with benign and indeterminate thyroid nodules had a higher RR than adult counterpart, but ROM of these categories in adults and children was not statistically different suggesting a potential risk of overtreatment in pediatric patients. Determining the best treatment guidelines and additional tools for risk stratification must be a top priority to precisely identify the target patient groups for surgical intervention.

Impact of Molecular Testing on the Management of Indeterminate Thyroid Nodules Among Western and Asian Countries: a Systematic Review and Meta-analysis.

Molecular testing has a potential to improve the management of patients with indeterminate thyroid nodules considered for surgery. This study examined the influence of molecular tests on the treatment of indeterminate nodules, particularly the differences between Western and Asian countries. Electronic databases including PubMed and Web of Science were searched for relevant articles from 2010 to March 2019. We computed meta-analysis of proportion and their 95% confidence intervals (CIs) utilizing the random-effect model. We used independent samples t test to compare the resection rate (RR), rate of malignancy (ROM), rate of preoperative molecular testing (RMT), and rate of positive test (RP) between subgroups. We included a total of 34 studies with 7976 indeterminate nodules. The multigene panel testing methods were exclusively used in the USA. Compared with the non-molecular era, molecular testing was associated with a significantly increased ROM (47.9% versus 32.1%; p = 0.001). The ROM of indeterminate nodules in Asian institutes was significantly higher than that in Western countries (75.3% versus 36.6%; p < 0.001, respectively). Institutes employing single-gene tests achieved a higher ROM (59.8% versus 37.9%; p = 0.013). Molecular testing is a promising method to tailor the clinical management for indeterminate thyroid FNA. Certain differences in routine thyroid cytopathology practice among the West and the East are still present. The combination of molecular testing and active surveillance enhances the accuracy of case selection for surgery in Asian countries.

Thyroseq v3, Afirma GSC, and microRNA Panels Versus Previous Molecular Tests in the Preoperative Diagnosis of Indeterminate Thyroid Nodules: A Systematic Review and Meta-Analysis.

Background: Molecular tests are being used increasingly as an auxiliary diagnostic tool so as to avoid a diagnostic surgery approach for cytologically indeterminate thyroid nodules (ITNs). Previous test versions, Thyroseq v2 and Afirma Gene Expression Classifier (GEC), have proven shortcomings in malignancy detection performance. Objective: This study aimed to evaluate the diagnostic performance of the established Thyroseq v3, Afirma Gene Sequencing Classifier (GSC), and microRNA-based assays versus prior iterations in ITNs, in light of "rule-in" and "rule-out" concepts. It further analyzed the impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) reclassification and Bethesda cytological subtypes on the performance of molecular tests. Methods: Pubmed, Scopus, and Web of Science were the databases used for the present research, a process that lasted until September 2020. A random-effects bivariate model was used to estimate the summary sensitivity, specificity, positive (PLR) and negative likelihood ratios (NLR), and area under the curve (AUC) for each panel. The conducted sensitivity analyses addressed different Bethesda categories and NIFTP thresholds. Results: A total of 40 eligible studies were included with 7,831 ITNs from 7,565 patients. Thyroseq v3 showed the best overall performance (AUC 0.95; 95% confidence interval: 0.93-0.97), followed by Afirma GSC (AUC 0.90; 0.87-0.92) and Thyroseq v2 (AUC 0.88; 0.85-0.90). In terms of "rule-out" abilities Thyroseq v3 (NLR 0.02; 95%CI: 0.0-2.69) surpassed Afirma GEC (NLR 0.18; 95%CI: 0.10-0.33). Thyroseq v2 (PLR 3.5; 95%CI: 2.2-5.5) and Thyroseq v3 (PLR 2.8; 95%CI: 1.2-6.3) achieved superior "rule-in" properties compared to Afirma GSC (PLR 1.9; 95%CI: 1.3-2.8). Evidence for Thyroseq v3 seems to have higher quality, notwithstanding the paucity of studies. Both Afirma GEC and Thyroseq v2 performance have been affected by NIFTP reclassification. ThyGenNEXT/ThyraMIR and RosettaGX show prominent preliminary results. Conclusion: The newly emerged tests, Thyroseq v3 and Afirma GSC, designed for a "rule-in" purpose, have been proved to outperform in abilities to rule out malignancy, thus surpassing previous tests no longer available, Thyroseq 2 and Afirma GEC. However, Thyroseq v2 still ranks as the best rule-in molecular test. Systematic Review Registration: http://www.crd.york.ac.uk/PROSPERO, identifier CRD42020212531.

Diagnostic performances of the Afirma Gene Sequencing Classifier in comparison with the Gene Expression Classifier: A meta-analysis.

The Afirma microarray-based Gene Expression Classifier (GEC) with its high negative predictive value (NPV) and sensitivity has been used to rule out cancer from thyroid nodules with an indeterminate cytology but not to rule in cancer because of its low positive predictive value (PPV) and specificity. The Gene Sequencing Classifier (GSC) has been reported to improve on the weakness of GEC. In this study, a meta-analysis was performed to compare the clinical impact and diagnostic performance of GEC and GSC. Relevant data were searched in PubMed and Web of Science. Meta-analyses for proportion and dichotomous outcomes were performed to compare the benign call rates (BCRs), resection rates (RRs), risks of malignancy (ROMs), sensitivities, specificities, PPVs, and NPVs of GSC and GEC. Seven studies were included for the meta-analyses. Compared with GEC, GSC had a higher BCR (65.3% vs 43.8%; P < .001), a lower RR (26.8% vs 50.1%; P < .001), and a higher ROM (60.1% vs 37.6%; P < .001). The BCR of Hürthle cell-predominant nodules was significantly elevated (73.7% vs 21.4%; P < .001). In addition, the specificity (43.0% vs 25.1%; P = .003) and PPV (63.1% vs 41.6%; P = .004) of Afirma GSC were significantly improved while it still maintained a high sensitivity (94.3%) and a high NPV (90.0%). In conclusion, this study confirms and highlighted the clinical and diagnostic significance of GSC. With an increased BCR and improved diagnostic performance, GSC could reduce the rate of unnecessary surgical interventions and better tailor the clinical decisions of patients with indeterminate thyroid fine-needle aspiration results.

Characterization of "suspicious for malignancy" for non-papillary carcinoma diagnoses on thyroid fine-needle aspiration.

INTRODUCTION: To evaluate the incidence, risk of malignancy, and management of "suspicious for malignancy" (SFM) for non-papillary carcinoma diagnoses according to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). MATERIALS AND METHODS: A retrospective search was performed for all thyroid fine-needle aspirations (FNAs) with an SFM diagnosis in the electronic Pathology database at The Johns Hopkins Hospital from 2000 to 2019. During this period, a total of 644 cases were diagnosed as SFM. Of these, 55 cases of "suspicious for non-papillary thyroid carcinoma" (SNPTC) were identified. These 55 cases were then compared with 65 random cases of "suspicious for papillary thyroid carcinomas" (SPTC) diagnoses as a control group. RESULTS: The SNPTC subgroup consisted of 28 cases of "suspicious for medullary thyroid carcinoma" (SMTC) (50.91%), 4 cases of "suspicious for metastasis" (SMET) (7.27%), 3 cases of "suspicious for malignant lymphoma" (SML) (5.45%), 2 cases of "suspicious for poorly-differentiated thyroid carcinoma" (SPDC) (3.64%), and 18 cases of "suspicious for malignancy, not otherwise specified" (SNOS) (32.73%). When compared to SPTC, SNPTC patients' average age was older (P = 0.004). Ancillary studies assisted in diagnosing SNPTC more so than SPTC (P < 0.001). Immunohistochemical studies were performed for 11 cases, molecular studies for 6 cases, and needle rinse calcitonin level for 1 case. When correlated with surgical follow-ups, the risk of malignancy (ROM) was 91.18% for SNPTC compared to 93.75 for SPTC%. CONCLUSIONS: SNPTC was rarely diagnosed when compared with SPTC. SMTC was the most commonly diagnosed SNPTC subgroup, followed by SNOS. The ROM of SNPTC was slightly lower than that of SPTC. Ancillary studies and previous clinical history, in addition to cytomorphology, was helpful when rendering the diagnosis of SNPTC.

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 diversities in thyroid cytopathology practices among Asian countries using the Bethesda system for reporting thyroid cytopathology.

BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) has been adopted and widely used among Asian countries. This study aims to investigate the application of TBSRTC in thyroid cytology practice among Asian countries. METHODS: We searched electronic databases including PubMed and Web of Science from 2010 to 2019. Meta-analysis of proportion and their 95% confidence intervals (CIs) were calculated using the random-effect model. Meta-regression and subgroup analysis were used to search for heterogeneity origins. RESULTS: We included 42 Asian studies with 84.953 fine-needle aspirations. Among six categories, benign was the most commonly diagnosed category. The resection rate (RR) and risk of malignancy (ROM) were highest in malignant and SM categories, and lowest among benign nodules. Thyroid cytology practice in Asia was characterized by a low RR and high ROM in patients with indeterminate thyroid nodules. There was a significant amount of heterogeneities of TBSRTC outputs (frequency, resection rate, and malignancy risk) among Asian countries. Meta-regression showed that the sources of heterogeneity might stem from the differences in study origin and the application of molecular testing. We highlighted the usefulness of preoperative molecular testing to select patients for surgery. CONCLUSIONS: Our study provided insight regarding thyroid cytology practice among Asian countries. Active surveillance is commonly used in Asian practice resulting in a low RR and high ROM for indeterminate nodules. There are still variations in general thyroid cytology practice in Asia. Future guidelines and consensus regarding the application of TBSRTC in thyroid cytology practice among Asian countries are required.