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.

Individual Ultrasonographic Characteristics of Thyroid Nodules and Their Cytopathological Correlation to Determine Malignancy Risk.

Background Ultrasonographic evaluation of thyroid nodules is challenging due to their high frequency and low malignancy rate. The risk stratification system developed by the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) focuses on addressing the primary contemporary objectives for these lesions, aiming to decrease unnecessary biopsies while maintaining a similar specificity compared with other risk stratification systems. Generally, when indicative of malignancy by ultrasound findings, the next best step in management is an evaluation by fine needle aspiration biopsy (FNAB) and cytological analysis with The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) results that determine further evaluation requirements, actions that are based on the risk of malignancy (ROM) of the assigned category, which could include surgical intervention. Objectives To validate and analyze the individual impact of each ultrasonographic finding indicative of malignancy in the ACR TI-RADS guidelines based on their respective correlation with results obtained by TBSRTC. Materials and method Reports for 212 thyroid ultrasound-guided FNABs from 2018 to 2020 were assessed. Only 117 had both ACR TI-RADS and TBSRTC reports available and were analyzed. Nodules were divided into two groups: ROM < 5% (Bethesda 1, 2; n = 58), and ROM > 5% (Bethesda 3, 4, 5, 6; n = 59). Statistical analysis was performed using the x2 test and bivariate logistic regression model for each characteristic included in ACR TI-RADS. Results Individual ultrasound characteristics with a more pronounced distribution towards the Bethesda > 5% malignancy group were: solid or almost completely solid composition (n=53, 62.3%), very hypoechoic echogenicity (n=3, 75%), wider-than-tall shape (n=50, 50.5%), lobulated or irregular margin (n=23, 65.7%), punctate echogenic foci (n=18, 72%), and thyroid isthmus location (n=6, 75%). Statistically significant individual ultrasonographic characteristics indicative of malignancy included solid or almost completely solid (p = 0.005), very hypoechoic echogenicity (p = 0.046), margin lobulated or irregular (p = 0.031), and punctate echogenic foci (p = 0.015). No significant association was found in the taller-than-wide shape for differentiating malignant from benign lesions (p = 0.969). Conclusions Specific ultrasound characteristics identified in the ACR TI-RADS system demonstrate a stronger correlation with an increased risk of malignancy when compared with cytologic evaluation results. These characteristics include a solid composition, lobulated or irregular margins, punctate echogenic foci, and very hypoechoic echogenicity. Our findings revealed that the scale points for the taller-than-wide characteristic do not adequately represent its true influence on the risk of malignancy.

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.

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.

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.

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.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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.

Incidence and malignancy rates classified by The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) - An 8-year tertiary center experience in Thailand.

Incidence and Malignancy Rates Classified by The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) - An 8-year Tertiary Center experience in Thailand. BACKGROUND: Fine-needle aspiration (FNA) of the thyroid is considered the best diagnostic tool for preoperative evaluation of thyroid nodules. The introduction of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) in 2010 provided the opportunity to establish worldwide standard for reporting and terminology guidelines for diagnostic categories. It is recommended that every institution evaluates the risk of malignancy (ROM) in each category for quality improvement process. AIM: To assess the effectiveness of TBSRTC method at our institution using cyto-histological correlation. METHOD: A retrospective 8-year (2010-2017) audit of thyroid FNA done by thyroid specialists at Theptarin hospital. The FNA results were classified according to TBSRTC. Histopathology reports for operated cases were used to correlate cytology and final histopathology. RESULTS: A total of 2735 thyroid FNA from 2115 patients (mean age 45.7 ±â€¯13.1 years, female 89.8%) were examined. The rates of non-diagnostic, benign, atypia of undetermined significance (AUS), follicular neoplasm, suspected for malignancy, and malignant cases were 21.1%, 66.6%, 4.7%, 2.4%, 1.8%, and 3.3% respectively. There were 188 patients (9%) who underwent surgical resection with available histopathology. Malignancy rates in operated thyroid nodules were 20.0%, 4.2%, 9.4%, 23.5%, 57.1%, and 90.3% for categories 1 to 6, respectively. The sensitivity, specificity, negative predictive value, and positive predictive value were 96.6%, 88.5%, 95.8%, and 90.3, respectively. CONCLUSIONS: Preoperative diagnosis of thyroid nodules using TBSRTC in our hospital was comparable with other studies. The uniform diagnostic criteria of the Bethesda System help avoid misinterpretation while sharing local experience with international benchmarks.

Cytological Diagnoses Associated with Noninvasive Follicular Thyroid Neoplasms with Papillary-Like Nuclear Features According to the Bethesda System for Reporting Thyroid Cytopathology: A Systematic Review and Meta-Analysis.

BACKGROUND: The recent introduction of noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) in the World Health Organization classification of thyroid tumors has significantly modified the risk of malignancy of cytological diagnoses. In fact, while this tumor was previously classified as a carcinoma (the encapsulated, noninvasive form follicular variant of papillary thyroid carcinoma), it is now considered a neoplasm with low malignant potential. Given that the cytological features of NIFTP are not specific and overlap with other pathologic entities, there is no specific cytological diagnostic category for NIFTP. To obtain more robust information about the cytological findings associated with NIFTP, published articles were systematically reviewed, and a meta-analysis of the data was conducted. METHODS: The review was conducted according to PRISMA guidelines. A comprehensive literature search of the PubMed/MEDLINE and Scopus databases was conducted using a combination of terms "noninvasive," "encapsulated," "follicular variant," "NIFTP," and "thyroid cancer." The search was updated to June 2018, and references of the retrieved articles were also screened. Only original articles reporting the classification of histologically proven NIFTPs with cytological findings according to The Bethesda System for Reporting Thyroid Cytopathology were eligible for inclusion. RESULTS: The literature search revealed 117 articles, of which 15 were included in the study. All studies were retrospective. A total of 915 NIFTP cases were retrieved. The incidence of cases cytologically classified according to the Bethesda system was as follows: non-diagnostic 3%, benign 10%, atypia of undetermined significance or follicular lesion of undetermined significance 30%, follicular neoplasm or suspicious for a follicular neoplasm 21%, suspicious for malignancy 24%, and malignant 8%. Mild heterogeneity between the studies was found. Publication bias was absent. CONCLUSIONS: This meta-analysis shows that the cytological diagnoses associated with NIFTP by fine-needle aspiration cytology includes a wide spectrum of findings. The majority of cases are cytologically indeterminate, and the remainder may be read as non-diagnostic, benign, or malignant. In order to develop an accurate presurgical diagnosis of these cases, further cytological and/or molecular characteristics need to be identified.

Current Status of Thyroid Fine-Needle Aspiration Practice in Thailand.

Thyroid carcinoma is one of the leading malignancies in Thailand increasingly prevalent in the female population. Fine-needle aspiration (FNA) cytology is a widely used diagnostic tool for evaluation of thyroid nodules and thyroid cancer. Thyroid FNA is a routine procedure universally performed in Thai hospitals by a variety of clinical specialists. Manual guidance is the first-line choice complemented by ultrasound assistance in selected cases. Despite national guidelines recommendations, the diagnostic criteria and terminology of the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) was slowly adopted in the local settings. Currently, the Bethesda system is actively promoted by the local professional societies as a uniform reporting system. Experience with thyroid FNA has been rarely reported to date-only a handful of publications are available in local journals. Our review, in addition to presenting various aspects of thyroid FNA in Thailand, established for the first time national references for a certain statistical outputs of TBSRTC based on the original multi-institutional cohort. The risk of malignancy in 2,017 operated thyroid nodules collected from three tertiary thyroid cancer centers was 21.7%, 14.7%, 35.9%, 44.4%, 76.7%, and 92.6% for categories I to VI, respectively. The malignancy risk in several diagnostic categories (II to IV) was higher than the risk estimated by TBSRTC and recent meta-analysis studies. We endorse the use of uniform terminology of the Bethesda system in Thailand, which will help facilitate communication among diverse medical professionals involved in the management of patients with thyroid nodules, to share local experience with the international audience.

Thyroid Fine-Needle Aspiration Practice in the Philippines.

Fine-needle aspiration (FNA) is a well accepted initial approach in the management of thyroid lesions. It has come a long way since its introduction for nearly a century ago. In the Philippines, FNA of the thyroid was first introduced 30 years ago and has been utilized until now as a mainstay in the diagnosis of thyroid malignancy. The procedure is performed by pathologists, endocrinologists, surgeons, and radiologists. Most pathologists report the cytodiagnosis using a combination of the aspiration biopsy cytology method that closely resembles the histopathologic diagnosis of thyroid disorders and the six-tier nomenclature of The Bethesda System for Reporting Thyroid Cytopathology. Local endocrinologists and surgeons follow the guidelines of the 2015 American Thyroid Association in the management of thyroid disorders. There is still a paucity of local research studies but available data deal with cytohistologic correlations, sensitivity, specificity, and accuracy rates as well as usefulness of ultrasound-guided FNA. Cytohistologic correlations have a wide range of sensitivity from 30.7% to 73% and specificity from 83% to 100%. The low sensitivity can be attributed to poor tissue sampling since a majority of the thyroid FNA is done by palpation only. The reliability can be improved if FNA is guided by ultrasound as attested in both international and local studies. Overall, FNA of the thyroid has enabled the diagnosis of thyroid disorders with an accuracy of 72.8% to 87.2% and it correlates well with histopathology.

Triage of the indeterminate thyroid aspirate: What are the options for the practicing cytopathologist?

Fine-needle aspiration (FNA) plays a key role in the early evaluation of patients with thyroid nodules; however, from 15% to 30% of FNA specimens are cytologically indeterminate. Molecular testing has proven useful when applied to indeterminate thyroid FNAs, and its use has been endorsed in the American Thyroid Association guidelines. In addition to the noncommercial ("in-house") application of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), rat sarcoma (RAS), rearranged in transformation/papillary thyroid carcinoma (RET/PTC), and peroxisome proliferator-activated receptor γ/paired box gene 8 (PPARγ/PAX8) testing, there are currently 3 commercially available molecular panels that vary in their relative reported performances, strengths, and limitations. Here, we discuss the role of molecular testing for indeterminate thyroid aspirates, taking into consideration the recent reclassification of the encapsulated follicular variant of papillary thyroid carcinoma (PTC) as "noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP)." Cancer Cytopathol 2017;125(6 suppl):477-85. © 2017 American Cancer Society.

An evaluation of the diagnostic efficacy of fine needle aspiration biopsy in patients operated for a thyroid nodular goiter.

BACKGROUND: Thyroid cancer (TC) comprises 1% of all carcinomas and is the most common malignancy of the endocrine system. The disease is more common in women, with its peak morbidity observed in 40-50-year-old patients. The main risk factors include radiation, iodine deficiency, hereditary background, and genetic mutations. Among all diagnosed thyroid nodules, 5%-30% will evolve into cancer. The gold-standard procedure in the preoperative evaluation of a nodular goiter, apart from ultrasonography, is fine needle aspiration (FNA) biopsy. The FNA biopsy is favored for its simplicity, safety, and high specificity and sensitivity rates. AIM: The aim of our study was to evaluate the clinical efficacy of FNA based on the patients' register. MATERIALS AND METHODS: In the Department of Surgery at the 4th Military Teaching Hospital in Wroclaw, 2,133 patients underwent thyroid surgery for thyroid goiter between 1996 and 2015. One hundred and eight cases of TC were diagnosed and of these, 66 patients had a preoperative FNA. RESULTS: Fourteen FNA biopsies (21%) revealed cancer, all of which were confirmed in the postoperative histopathology, although six cases of FNA-diagnosed cancer revealed a different histological type postoperatively. Eighteen FNA biopsies (27%) were suspected of being malignant. A disturbingly high rate of "benign" FNA biopsies (32 cases; 48%) revealed TC after surgery. CONCLUSION: It is of great importance that the quality and quantity of FNA biopsies that are performed have been improved, especially due to the wide adoption of the Bethesda cytological evaluation system. FNA biopsy remains an obligatory and valuable diagnostic tool in thyroid nodules, but it is still insufficient as a standard procedure. A preoperative biopsy should always be related to all the available clinical data in order to provide the best treatment option for each patient individually.