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Background: Thyroid fine-needle aspiration (FNA) surfaced as a vital first-line diagnostic tool to categorize them into benign or malignant, thereby reducing unnecessary surgeries in benign nodules. The Bethesda system for reporting thyroid cytopathology (TBSRTC) has established a standardized, category-based reporting system and since then it has been widely adopted by cytopathologists in worldwide. It has been shown that thyroid pathology contributes significantly to second-opinion discrepancies for cytopathology specimens. Aims and Objectives: To establish the reproducibility of TBSRTC in diagnosing thyroid lesions. To determine the interobserver variation in thyroid cytopathology using the 2023 TBSRTC. Materials and Methods: This was a 2-year retrospective study conducted in the Department of Pathology, from January 2018 to December 2019. Previous archived slides of thyroid FNA cytology were examined by three trained pathologists in a double-blinded fashion and were reclassified according to the 2023 TBSRTC. The results were evaluated for interobserver variability using Cohen's kappa statistics and Statistical Package for the Social Sciences software version 24.0. Results: The present study included a total of 156 patients with a female: male ratio of 3: 0.1 and the mean age of 37.8±2.4 years. The interobserver agreement, calculated using Kappa statistics, for observer 1 and observer 2 was 0.735; for observer 1 and 3 was 0.841; and for observer 2 and 3 was 0.838. These values together showed substantial interobserver agreement. Conclusion: The 2023 TBSRTC gives a distinctive, universal, and homogeneous terminology for reporting the thyroid cytology and its execution should be promoted due to its virtual ease of reproducibility. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusions: 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. Assessing the atypia of undetermined significance rate in the context of positive call rate and time serves as a valuable metric for evaluating cytopathologists proficiency and overall laboratory performance and helps identify trends to provide valuable feedback. [ABSTRACT FROM AUTHOR]

Interobserver variability remains a major challenge for cytopathologists despite the development of standardized reporting and classification systems. Indeed, whereas moderate‐to‐good interobserver agreement is generally achievable when the differential diagnosis between benign and malignant entities is straightforward, high levels of variability make the diagnostic interpretation of atypical and suspicious samples not consistent. This review explores the landscape of interobserver agreement in cytopathology across different anatomical sites. [ABSTRACT FROM AUTHOR]

This review article describes nuclear features of a range of thyroid lesions to enable confident diagnosis in a multidisciplinary thyroid cancer setting. It is hoped that this will serve as a handy aide-mémoire when faced with diagnosis of thyroid FNA (fine needle aspiration) cytology in day-to-day practice. The existing literature has been reviewed to give the reader an overview of the classification systems in thyroid cytology and various entities described therein. The lesions are broadly categorised as benign, malignant, and indeterminate. The comparison to ultrasound imaging classification is given, with a view to have a broader understanding of the clinico-radiological context. Photographs with descriptions in each category are included together with a detailed description of nuclear features, pitfalls, and challenges in diagnosis. This article is designed for practising and trainee cytopathologists as a useful tool for everyday practice. [ABSTRACT FROM AUTHOR]

Thyroid nodules are a common occurrence in the Indian population. The current management involving an individualized approach is increasingly becoming relevant instead of a broad diagnostic and management algorithm. The consensus statements derived in this article aim to provide a summary of the current medical evidence for the diagnosis and management of thyroid nodules, which assists in optimizing recommendations in the Indian setting. The task force of experts has provided inputs to address specific clinical questions in this consensus. The statements are formulated after a thorough analysis of several published studies and guidelines to address the screening, diagnosis, and management of thyroid nodules. A well-defined grading system is used to appraise the evidence and grade the strength of recommendations. This guideline covers risk stratification of thyroid nodules (differentiating benign from malignant lesions) and a guide to the use of fine-needle aspiration cytology to improve definitive management. The guideline covers evidence-based recommendations for the management of benign, cytologically indeterminate, and malignant thyroid nodules. The panel has also touched upon the aspects of nondiagnostic thyroid nodule management and intraoperative neuromonitoring. These evidence-based expert consensus statements can provide useful and practical insights to aid the practicing clinician. [ABSTRACT FROM AUTHOR]

Purpose: The utility of repeating ultrasound-guided fine-needle aspiration (US-FNAB) in the follow-up of benign (THY2) thyroid nodules is still debated. The aim of this study was to retrospectively investigate the diagnostic value of re-biopsy of thyroid nodules following an initially benign result. Methods: We retrospectively analyzed US-FNABs performed at the Unit of Endocrinology of Modena from 2006 to 2009. The firstly benign cytological result was compared with the cytological results of subsequent US-FNABs (2nd and/or 3rd) executed on the same nodule. Results: Among 10449 US-FNABs, 6270 (60%) received a THY2 cytological categorization. Of them, 278 (4.43%) underwent a subsequent US-FNAB: 86.7% maintained the same cytology, 32 (11.5%) changed to THY3 (indeterminate) and 5 (1.8%) to THY4 (suspicious of malignancy). Among the 24 nodules addressed to surgery, 9 (37%) were histologically malignant, with an overall miss rate of 3.2%. Male patients had higher risk of discordant results at subsequent US-FNAB (p = 0.005, OR:3.59, 95%CI:1.453–7.769) while dimensional increase above 5 mm was predictive of concordant benign cytology (p = 0.036, OR:0.249, 95%CI:0.068–0.915). Age, suspicious US characteristics, and distance between US-FNABs resulted not predictive. Conclusions: Re-biopsy of benign nodules confirmed the benign nature in most cases. In case of discordant cytology, relocation in indeterminate category was the most common. The histological diagnosis of cancer occurred in one quarter of nodules surgically removed, with a low overall clinically significant miss rate. Thus, a small percentage of false negatives exists; males and subjects with US suspicious nodules should be carefully followed-up, considering case by case re-biopsy possibility. [ABSTRACT FROM AUTHOR]

Objective: Gray-scale ultrasound (US) is the standard-of-care for evaluating thyroid nodules (TNs). However, the performance is better for the identification of hypoechoic malignant TNs (such as classic papillary thyroid cancer) than isoechoic malignant TNs. Quantitative ultrasound (QUS) utilizes information from raw ultrasonic radiofrequency (RF) echo signal to assess properties of tissue microarchitecture. The purpose of this study is to determine if QUS can improve the cancer risk stratification of isoechoic TNs. Methods: Patients scheduled for TN fine needle biopsy (FNB) were recruited from the Thyroid Health Clinic at Boston Medical Center. B-mode US and RF data (to generate QUS parameters) were collected in 274 TNs (163 isoechoic, 111 hypoechoic). A linear combination of QUS parameters (CQP) was trained and tested for isoechoic [CQP(i)] and hypoechoic [CQP(h)] TNs separately and compared with the performance of conventional B-mode US risk stratification systems. Results: CQP(i) produced an ROC AUC value of 0.937+/- 0.043 compared to a value of 0.717 +/- 0.145 (p >0.05) for the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS) and 0.589 +/- 0.173 (p >0.05) for the American Thyroid Association (ATA) risk stratification system. In this study, CQP(i) avoids unnecessary FNBs in 73% of TNs compared to 55.8% and 11.8% when using ACR TI-RADS and ATA classification system. Conclusion: This data supports that a unique QUS-based classifier may be superior to conventional US stratification systems to evaluate isoechoic TNs for cancer and should be explored further in larger studies. [ABSTRACT FROM AUTHOR]

Background: Fine-Needle Aspiration Cytology (FNAC) is a valuable, minimally invasive diagnostic tool for discerning benign and malignant thyroid lesions. In the realm of thyroid cytopathology, both the traditional approach and the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) are widely utilized for diagnosing and categorizing these lesions. Aims and Objectives: This study aims to classify thyroid cytology smears using both the conventional method and the Bethesda system and to compare their findings with histopathological diagnoses. Method and Materials: A hospital-based cross-sectional study was conducted over one year, spanning from February 1, 2022, to January 31, 2023. We included 191 cases of FNAC thyroid lesions and categorized them following the guidelines of both the conventional system and the Bethesda system for reporting thyroid cytopathology. Sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy for both systems were calculated, with histopathology serving as the gold standard for comparison. Furthermore, we calculated the Risk of Malignancy (ROM) for each category within the Bethesda system. Results: The Bethesda system exhibited a notably high sensitivity of 83.33%, surpassing the conventional method's sensitivity of 50%, while both systems shared the same specificity of 90%. The diagnostic accuracy of the Bethesda system, at 89.13%, outperformed that of the conventional method, which stood at 84.78%. Conclusion: This study demonstrates a strong positive correlation with histopathology, indicating high sensitivity, specificity, and accuracy when employing TBSRTC, in contrast to the conventional method. [ABSTRACT FROM AUTHOR]

Despite advancements in diagnostic methods, the classification of indeterminate thyroid nodules still poses diagnostic challenges not only in pre-surgical evaluation but even after histological evaluation of surgical specimens. Proteomics, aided by mass spectrometry and integrated with artificial intelligence and machine learning algorithms, shows great promise in identifying diagnostic markers for thyroid lesions. This review provides in-depth exploration of how proteomics has contributed to the understanding of thyroid pathology. It discusses the technical advancements related to immunohistochemistry, genetic and proteomic techniques, such as mass spectrometry, which have greatly improved sensitivity and spatial resolution up to single-cell level. These improvements allowed the identification of specific protein signatures associated with different types of thyroid lesions. Among all the proteomics approaches, spatial proteomics stands out due to its unique ability to capture the spatial context of proteins in both cytological and tissue thyroid samples. The integration of multi-layers of molecular information combining spatial proteomics, genomics, immunohistochemistry or metabolomics and the implementation of artificial intelligence and machine learning approaches, represent hugely promising steps forward toward the possibility to uncover intricate relationships and interactions among various molecular components, providing a complete picture of the biological landscape whilst fostering thyroid nodule diagnosis. [ABSTRACT FROM AUTHOR]

ObjectiveGray-scale ultrasound (US) is the standard-of-care for evaluating thyroid nodules (TNs). However, the performance is better for the identification of hypoechoic malignant TNs (such as classic papillary thyroid cancer) than isoechoic malignant TNs. Quantitative ultrasound (QUS) utilizes information from raw ultrasonic radiofrequency (RF) echo signal to assess properties of tissue microarchitecture. The purpose of this study is to determine if QUS can improve the cancer risk stratification of isoechoic TNs.MethodsPatients scheduled for TN fine needle biopsy (FNB) were recruited from the Thyroid Health Clinic at Boston Medical Center. B-mode US and RF data (to generate QUS parameters) were collected in 274 TNs (163 isoechoic, 111 hypoechoic). A linear combination of QUS parameters (CQP) was trained and tested for isoechoic [CQP(i)] and hypoechoic [CQP(h)] TNs separately and compared with the performance of conventional B-mode US risk stratification systems.ResultsCQP(i) produced an ROC AUC value of 0.937+/- 0.043 compared to a value of 0.717 +/- 0.145 (p >0.05) for the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS) and 0.589 +/- 0.173 (p >0.05) for the American Thyroid Association (ATA) risk stratification system. In this study, CQP(i) avoids unnecessary FNBs in 73% of TNs compared to 55.8% and 11.8% when using ACR TI-RADS and ATA classification system.ConclusionThis data supports that a unique QUS-based classifier may be superior to conventional US stratification systems to evaluate isoechoic TNs for cancer and should be explored further in larger studies.

Thyroid cancer is the most common malignancy of the endocrine system. Fine-needle aspiration (FNA) biopsy of thyroid nodules has become the gold standard procedure, in terms of cost and efficacy, for guiding clinicians towards appropriate patients' management. One challenge for cytopathologists is to accurately classify cytological specimens as benign or malignant based on cytomorphological features. In fact, with a frequency ranging from 10% to 30%, nodules are diagnosed as indeterminate. In recent years, the mutational landscape of thyroid tumors has been extensively described, and two molecular profiles have been identified: RAS-like (NRAS, HRAS, and KRAS mutations; EIF1AX mutations; BRAF K601E mutation; and PPARG and THADA fusions) and BRAFV600E-like (including BRAFV600E mutation and RET and BRAF fusions). The purpose of this review is to discuss the latest molecular findings in the context of indeterminate thyroid nodules, highlighting the role of molecular tests in patients' management. [ABSTRACT FROM AUTHOR]

Indeterminate follicular thyroid lesions (Thyr 3A and 3B) account for 10% to 30% of all cytopathologic diagnoses, and their unpredictable behavior represents a hard clinical challenge. The possibility to preoperatively predict malignancy is largely advocated to establish a tailored surgery, preventing diagnostic thyroidectomy. We analyzed the role of the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR) and the lymphocyte-to-monocyte ratio (LMR) as prognostic factors of malignancy for indeterminate thyroid nodules. In patients affected by cytological Thyr 3A/3B nodules, NLR, PLR and LMR were retrospectively compared and correlated with definitive pathology malignancy, utilizing student's t-test, ROC analysis and logistic regression. One-hundred and thirty-eight patients presented a Thyr 3A and 215 patients presented a Thyr 3B. After the logistic regression, in Thyr 3A, none of the variables were able to predict malignancy. In Thyr 3B, NLR prognosticated thyroid cancer with an AUC value of 0.685 (p < 0.0001) and a cut-off of 2.202. The NLR results were also similar when considering the overall cohort. The use of cytological risk stratification in addressing the management of indeterminate thyroid nodules in patients is not always reliable. NLR is an easy and reproducible inflammatory biomarker capable of improving the accuracy of preoperative prognostication of malignancy. [ABSTRACT FROM AUTHOR]

This review outlines how the alterations in the 5th edition of the WHO Classification of Endocrine and Neuroendocrine Tumors of the thyroid gland are likely to impact thyroid cytopathology. It is important to note that WHO subclassifies thyroid tumors into several new categories based on increased comprehension of the cell of origin, pathologic features (including cytopathology), molecular classification, and biological behavior. The 3rd edition of the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) will debut in the near future and will include changes in diagnostic category designations. The changes in the 5th edition of the WHO will in some instances subtly, and in other instances significantly, impact the cytological diagnoses. Moreover, these changes will also affect other thyroid FNA classification schemes used internationally for classifying thyroid FNA specimens. [ABSTRACT FROM AUTHOR]

Introduction: Thyroid cytopathology, particularly in cases of atypia of undetermined significance/follicular lesions of undetermined significance (AUS/FLUS), suffers from suboptimal sensitivity and specificity challenges. Recent advancements in digital pathology and artificial intelligence (AI) hold promise for enhancing diagnostic accuracy. This systematic review included studies that focused on diagnostic accuracy in AUS/FLUS cases using AI, whole slide imaging (WSI), or both., Methods: Of the 176 studies from 2000 to 2023, 13 met the inclusion criteria. The datasets range from 145 to 964 WSIs, with an overall number of 494 AUS cases ranging from eight to 254. Five studies used convolutional neural networks (CNNs), and two used artificial neural networks (ANNs). The preparation methods included Romanowsky-stained smears either alone or combined with Papanicolaou-stained or H&E and liquid-based cytology (ThinPrep). The scanner models that were used for scanning the slides varied, including Leica/Aperio, Alyuda Neurointelligence Cupertino, and PANNORAMIC™ Desk Scanner. Classifiers used include Feedforward Neural Networks (FFNNs), Two-Layer Feedforward Neural Networks (2L-FFNNs), Classifier Machine Learning Algorithm (MLA), Visual Geometry Group 11 (VGG11), Gradient Boosting Trees (GBT), Extra Trees Classifier (ETC), YOLOv4, EfficientNetV2-L, Back-Propagation Multi-Layer Perceptron (BP MLP), and MobileNetV2., Results: The available studies have shown promising results in differentiating between thyroid lesions, including AUS/FLUS. AI can be especially effective in removing sources of errors such as subjective assessment, variation in staining, and algorithms. CNN has been successful in processing WSI data and identifying diagnostic features with minimal human supervision. ANNs excelled in integrating structured clinical data with image-derived features, particularly when paired with WSI, enhancing diagnostic accuracy for indeterminate thyroid lesions., Conclusion: A combined approach using both CNN and ANN can take advantage of their strengths. While AI and WSI integration shows promise in improving diagnostic accuracy and reducing uncertainty in indeterminate thyroid cytology, challenges such as the lack of standardization need to be addressed., (© 2025 S. Karger AG, Basel.)

Introduction: Thyroid lesions are one of the most common diseases observed in clinical practice in the North India. These diseases have distinct cytological morphology and thus FNAC is done frequently. Here we report a case of adenomatoid goitre mimicking adenoid cystic carcinoma (ACC) of salivary gland on cytology. Such close resemblance on morphology makes this a case of unusual morphological presentation of a very common condition., Case Summary: We report here a case of a 60-year-old female who developed a right anterior neck swelling six years back. Systemic clinical findings were unremarkable. Routine laboratory investigations, including thyroid function test were within normal limits. A High-resolution ultrasound of neck was performed, and a TIRADS-IV lesion measuring 28.8 × 22.9 mm was reported. Fine needle aspiration was done. Seven smears were made and stained with MGG, H&E and PAP stains. Smears were moderately cellular and abundant globular, amorphous material was observed with lesional cells forming three-dimensional rosette-like structures around them, producing an ACC-like pattern. A second consultation and immunohistochemistry on cell block we performed which led to a diagnosis of adenomatoid goitre, confirmed later histologically., Conclusion: Benign lesions of thyroid can sometime mimic adenoid cystic carcinomas of salivary glands. Misdiagnosing any such case based solely on morphology can lead to wrong prognostication and thus wrong treatment. Extensive review of literature and a second consultation with an experienced pathologist should be done. Whenever needed a cell block preparation and a complete immunohistochemistry panel should be performed., (© 2024 Wiley Periodicals LLC.)

The Italian SIAPEC-AIT 2014 classification, the 2017 Bethesda System for Reporting Thyroid Cytology (TBSRTC), the 2016 UK Royal College of Pathologists (RCPath) thyroid reporting system, and the 2019 Japanese reporting system for thyroid aspiration cytology (JRSTAC2019) represent the most widely used reporting systems among clinicians and pathologists for the purpose of cytologically diagnosing, estimating the potential risk of malignancy (ROM), and defining the most appropriate treatment for a patient with a thyroid nodule. Although all the systems use overlapping diagnostic categories and morphologic criteria, they differ on the basis of the criteria for inclusion in the cytologic categories, which may, in turn, affect the ROM of a given category and the clinical management of the patient, particularly with regard to the “indeterminate” categories. The aim of this review is to analyze the main differences that emerge between the systems and to propose possible solutions for a comprehensive reporting system that integrates and harmonizes all the criteria of the Italian classification and the Bethesda system, also taking into account the impact that the new tumor entity NIFTP (non-invasive follicular tumor with papillary-like nuclear features) that has, in many instances, replaced the non-invasive form of the follicular variant of papillary carcinoma, has had on the modification of malignancy risks.

Purpose: To evaluate whether quantitative [18F]FDG-PET/CT assessment, including radiomic analysis of [18F]FDG-positive thyroid nodules, improved the preoperative differentiation of indeterminate thyroid nodules of non-Hürthle cell and Hürthle cell cytology. Methods: Prospectively included patients with a Bethesda III or IV thyroid nodule underwent [18F]FDG-PET/CT imaging. Receiver operating characteristic (ROC) curve analysis was performed for standardised uptake values (SUV) and SUV-ratios, including assessment of SUV cut-offs at which a malignant/borderline neoplasm was reliably ruled out (≥ 95% sensitivity). [18F]FDG-positive scans were included in radiomic analysis. After segmentation at 50% of SUVpeak, 107 radiomic features were extracted from [18F]FDG-PET and low-dose CT images. Elastic net regression classifiers were trained in a 20-times repeated random split. Dimensionality reduction was incorporated into the splits. Predictive performance of radiomics was presented as mean area under the ROC curve (AUC) across the test sets. Results: Of 123 included patients, 84 (68%) index nodules were visually [18F]FDG-positive. The malignant/borderline rate was 27% (33/123). SUV-metrices showed AUCs ranging from 0.705 (95% CI, 0.601–0.810) to 0.729 (0.633–0.824), 0.708 (0.580–0.835) to 0.757 (0.650–0.864), and 0.533 (0.320–0.747) to 0.700 (0.502–0.898) in all (n = 123), non-Hürthle (n = 94), and Hürthle cell (n = 29) nodules, respectively. At SUVmax, SUVpeak, SUVmax-ratio, and SUVpeak-ratio cut-offs of 2.1 g/mL, 1.6 g/mL, 1.2, and 0.9, respectively, sensitivity of [18F]FDG-PET/CT was 95.8% (95% CI, 78.9–99.9%) in non-Hürthle cell nodules. In Hürthle cell nodules, cut-offs of 5.2 g/mL, 4.7 g/mL, 3.4, and 2.8, respectively, resulted in 100% sensitivity (95% CI, 66.4–100%). Radiomic analysis of 84 (68%) [18F]FDG-positive nodules showed a mean test set AUC of 0.445 (95% CI, 0.290–0.600) for the PET model. Conclusion: Quantitative [18F]FDG-PET/CT assessment ruled out malignancy in indeterminate thyroid nodules. Distinctive, higher SUV cut-offs should be applied in Hürthle cell nodules to optimize rule-out ability. Radiomic analysis did not contribute to the additional differentiation of [18F]FDG-positive nodules. Trial registration number: This trial is registered with ClinicalTrials.gov: NCT02208544 (5 August 2014), https://clinicaltrials.gov/ct2/show/NCT02208544. [ABSTRACT FROM AUTHOR]

Purpose: To assess the impact of an [18F]FDG-PET/CT-driven diagnostic workup to rule out malignancy, avoid futile diagnostic surgeries, and improve patient outcomes in thyroid nodules with indeterminate cytology. Methods: In this double-blinded, randomised controlled multicentre trial, 132 adult euthyroid patients with scheduled diagnostic surgery for a Bethesda III or IV thyroid nodule underwent [18F]FDG-PET/CT and were randomised to an [18F]FDG-PET/CT-driven or diagnostic surgery group. In the [18F]FDG-PET/CT-driven group, management was based on the [18F]FDG-PET/CT result: when the index nodule was visually [18F]FDG-positive, diagnostic surgery was advised; when [18F]FDG-negative, active surveillance was recommended. The nodule was presumed benign when it remained unchanged on ultrasound surveillance. In the diagnostic surgery group, all patients were advised to proceed to the scheduled surgery, according to current guidelines. The primary outcome was the fraction of unbeneficial patient management in one year, i.e., diagnostic surgery for benign nodules and active surveillance for malignant/borderline nodules. Intention-to-treat analysis was performed. Subgroup analyses were performed for non-Hürthle cell and Hürthle cell nodules. Results: Patient management was unbeneficial in 42% (38/91 [95% confidence interval [CI], 32–53%]) of patients in the [18F]FDG-PET/CT-driven group, as compared to 83% (34/41 [95% CI, 68–93%]) in the diagnostic surgery group (p < 0.001). [18F]FDG-PET/CT-driven management avoided 40% (25/63 [95% CI, 28–53%]) diagnostic surgeries for benign nodules: 48% (23/48 [95% CI, 33–63%]) in non-Hürthle cell and 13% (2/15 [95% CI, 2–40%]) in Hürthle cell nodules (p = 0.02). No malignant or borderline tumours were observed in patients under surveillance. Sensitivity, specificity, negative and positive predictive value, and benign call rate (95% CI) of [18F]FDG-PET/CT were 94.1% (80.3–99.3%), 39.8% (30.0–50.2%), 95.1% (83.5–99.4%), 35.2% (25.4–45.9%), and 31.1% (23.3–39.7%), respectively. Conclusion: An [18F]FDG-PET/CT-driven diagnostic workup of indeterminate thyroid nodules leads to practice changing management, accurately and oncologically safely reducing futile surgeries by 40%. For optimal therapeutic yield, application should be limited to non-Hürthle cell nodules. Trial registration number: This trial is registered with ClinicalTrials.gov: NCT02208544 (5 August 2014), https://clinicaltrials.gov/ct2/show/NCT02208544. [ABSTRACT FROM AUTHOR]

The American College of Radiology (ACR) Thyroid Imaging Reporting and Data Systems (TI-RADS) was developed to standardize thyroid ultrasound reports and predict the likelihood of malignancy. In our study, we aimed to correlate indeterminate thyroid fine needle aspiration cytology cases with preceding ultrasound (US) ACR TI-RADS scores and concurrent molecular testing results to examine how well the use of the ACR TI-RADS in our institution predicted which patients with indeterminate cytology might harbor molecular alterations. We performed a retrospective review of thyroid nodules. Patients with US reports that included TI-RADS scores, fine needle aspiration specimens with indeterminate cytology (Bethesda class III-V), and molecular testing results were included. A total of 46 indeterminate cytology cases had had preceding US reports with TI-RADS scores and molecular testing (Bethesda class III, n = 37; Bethesda class IV, n = 6; Bethesda class V, n = 3). Most of the indeterminate cases had had a TI-RADS score of TR4 (31 of 46; 67.39%) or TR5 (9 of 46; 19.57%). RAS mutations were the most common alteration (n = 12). Of the 46 cases, 22 (47.85%) showed no alterations. Ten cases proceeded to surgery, of which seven displayed malignancies. Molecular testing in cytologically indeterminate thyroid nodules provided valuable information for TR4 and TR5 lesions; however, the TR2 and TR3 lesions often had no molecular alterations. These findings highlight the potential value of including US imaging features when assessing the significance of indeterminate cytology findings. • We found that molecular testing provided important information regarding malignancy in higher risk ACR TI-RADS lesions (TR4 and TR5). • The findings in our study underscore the potential contribution of ultrasound imaging findings to the assessment of thyroid nodules even after FNA is performed. [ABSTRACT FROM AUTHOR]

Introduction: The diagnosis of Primary Thyroid Lymphoma (PTL) and its distinction from Florid Lymphocytic Thyroiditis (FLT) is often difficult on Fine Needle Aspirate (FNA). The sensitivity is low for Low Grade Lymphoma (LGL) and the distinction of PTL is important as they are treated by chemotherapy rather than surgery. We studied the efficacy of FNA for thyroid lymphoproliferative disorders which includes thyroid lymphoma and lymphocytic thyroditis and detection of cytomorphological features differentiating between thyroiditis and lymphoma. Aim: To find out interobserver variation in cytological diagnosis of thyroid lymphomas and thyroiditis with evaluation of the cytomorphological pointers of lymphoma on thyroid cytology. Materials and Methods: Thirty-three cases of FNA thyroid with lymphoid proliferation in which histological confirmation with Immunohistochemistry (IHC) was available were retrieved and studied for various cytomorphological features by three pathologists. The findings were correlated with the final histopathology diagnosis. Results: Of the total 33 cases that had significant lymphoid infiltrate on thyroid FNA, 28 cases were confirmed as NonHodgkin’s lymphoma, three cases as thyroiditis and two case of carcinoma on histology. All the lymphoma cases were positive for CD20 antibody on histology. The percentage of cases of thyroid lymphoma was high in present study because only selected type of cases were included (FNA thyroid with lymphoid proliferation) and it does not refer to true incidence of thyroid lymphoma. Among three observers, two observers (observer 1&2) diagnosed 18 cases of HGL, two cases of FLT and one observer (observer 3) diagnosed 15 cases of HGL and one cases of FLT correctly on FNA, five cases of LGL were correctly diagnosed by all the three observers. The diagnostic accuracy was 76.1% with high specificity (80%) and sensitivity (94.7%) for HGL and high concordance among the three pathologists (Kappa= 0.8). LGL and FLT had low sensitivity (55.6% and 66.7%) and least interobserver correlation (kappa – 0.21). Monomorphism, large cells, absent plasma cells, macrophages were significantly associated with diagnosis of lymphoma. Conclusion: Cytological features of thyroid lymphoma are diagnostic in HGL, however the features are more non-specific in LGLs. High cellularity, relatively monomorphic population and frequent occurrence of lymphoglandular bodies were common in LGL compared to FLT. It is challenging to diagnose PTLs, especially low grade on FNA. For this reason, it should be kept in mind that patients with chronic lymphocytic thyroiditis should be evaluated carefully and possibility of LGL should not rule out on cytology. The role of FNA is limited but it is simple safe and cost effective for initial workup in centres lacking facility of flow cytometry and immunocytochemistry

Abstract Objective To evaluate our institutional experience with molecular diagnostics (MD) on thyroid cytology smears, evaluate the costs and describe MD guided clinical management of indeterminate Bethesda III/V thyroid nodules. Methods We performed a retrospective review of 164 Bethesda III or V thyroid cytopathology reports subjected to MD from 2013 to 2020, that altered Bethesda classification or management. MD consisted of mutation and gene fusion analysis by next‐generation sequencing (NGS) of morphologically analysed and selected cytological slides. Findings were modelled to nationwide data on Bethesda incidences from ‘the Dutch Pathology Registry’ PALGA, and costs were estimated. Results 82 of 164 cases received an upgrade in Bethesda class. Twenty cases changed from Bethesda III to IV/V, 62 from Bethesda III or V to VI, and 72 remained unaltered. We estimate net savings with implementing MD, by preventing 454 repeat cytology and 326 (diagnostic) hemithyroidectomies, to be at least 2 million Euro annually in the Netherlands. Per Bethesda III and V patient, net savings would be about 100 Euro and 4100 Euro, respectively. Conclusion NGS‐based MD on nucleic acids extracted directly from cytology slides is a feasible and cost saving tool for personalized management in indeterminate Bethesda III/V thyroid cytology. Based on the interpretation of our retrospective data, we assume that this approach results in less disease burden for the patient, reduced surgical interventions and complication risks, reduced sick leave, among others. Further evaluation of structural implementation of the presented approach in routine thyroid Bethesda III/V cytology in a prospective setting is warranted.

Objective: To evaluate our institutional experience with molecular diagnostics (MD) on thyroid cytology smears, evaluate the costs and describe MD guided clinical management of indeterminate Bethesda III/V thyroid nodules. Methods: We performed a retrospective review of 164 Bethesda III or V thyroid cytopathology reports subjected to MD from 2013 to 2020, that altered Bethesda classification or management. MD consisted of mutation and gene fusion analysis by next‐generation sequencing (NGS) of morphologically analysed and selected cytological slides. Findings were modelled to nationwide data on Bethesda incidences from 'the Dutch Pathology Registry' PALGA, and costs were estimated. Results: 82 of 164 cases received an upgrade in Bethesda class. Twenty cases changed from Bethesda III to IV/V, 62 from Bethesda III or V to VI, and 72 remained unaltered. We estimate net savings with implementing MD, by preventing 454 repeat cytology and 326 (diagnostic) hemithyroidectomies, to be at least 2 million Euro annually in the Netherlands. Per Bethesda III and V patient, net savings would be about 100 Euro and 4100 Euro, respectively. Conclusion: NGS‐based MD on nucleic acids extracted directly from cytology slides is a feasible and cost saving tool for personalized management in indeterminate Bethesda III/V thyroid cytology. Based on the interpretation of our retrospective data, we assume that this approach results in less disease burden for the patient, reduced surgical interventions and complication risks, reduced sick leave, among others. Further evaluation of structural implementation of the presented approach in routine thyroid Bethesda III/V cytology in a prospective setting is warranted. [ABSTRACT FROM AUTHOR]

Background: Molecular testing (MT) refines risk stratification for thyroid nodules that are indeterminate for cancer by fine needle aspiration (FNA) cytology. Criteria for selecting nodules for MT vary and remain largely untested, raising questions about the best strategy for maximizing the usefulness of MT while minimizing the harms of overtesting. We used a unique data set to examine the effects of repeat FNA cytology-based criteria for MT on management decisions and nodule outcomes. Methods: This was a study of adults (age 25–90 years; 281 women and 72 men) with cytologically indeterminate (Bethesda III/IV) thyroid nodules who underwent repeat FNA biopsy and Afirma Gene Expression Classifier (GEC) testing (N = 363 nodules from 353 patients) between June 2013 and October 2017 at a single institution, with follow-up data collected until December 2019. Subgroup analysis was performed based on classification of repeat FNA cytology. Outcomes of GEC testing, clinical/sonographic surveillance of unresected nodules, and histopathologic diagnoses of thyroidectomies were compared between three testing approaches: (i) Reflex (MT sent on the basis of the initial Bethesda III/IV FNA), (ii) SemiRestrictive (MT sent if repeat FNA is Bethesda I–IV), and (iii) Restrictive (MT sent only if repeat FNA is Bethesda III/IV) testing approaches. Results: Restricting MT to nodules that remain Bethesda III/IV on repeat FNA would have missed 4 low-risk cancers and 3 noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) (collectively 2% of the test population) but would have avoided diagnostic surgery for 42 benign nodules (12% of the test population). The Restrictive testing strategy was more specific (delta 0.126 confidence interval [CI 0.093 to 0.159] and 0.129 [CI 0.097 to 0.161], respectively) but less sensitive (delta −0.339 [CI −0.424 to −0.253] and −0.340 [CI −0.425 to −0.255], respectively) than the Reflex and SemiRestrictive approaches for detecting NIFTP or cancer. Conclusions: Repeat FNA cytology can guide the selection of cytologically indeterminate thyroid nodules that warrant MT. The Restrictive model of performing Afirma GEC only on nodules with two separate biopsies showing Bethesda III/IV cytology would reduce the rate of diagnostic surgery for histologically benign nodules while missing only rare low-risk tumors. Given the low but nontrivial risks of thyroidectomy, the higher specificity of the Restrictive testing approach disproportionately outweighs the potential harms. [ABSTRACT FROM AUTHOR]

INTRODUCTION: This study aims to evaluate the diagnostic reliability of the American College of Radiology Thyroid Imaging Report and Data System (ACR-TIRADS) and Total Malignancy Score (TMS) scoring system, in differentiating benign and malignant thyroid nodules. MATERIALS AND METHODS: This is a cross-sectional study involving patients with thyroid nodules treated at Hospital Canselor Tuanku Muhriz from October 2017 until October 2019. Ultrasound findings were scored according to the ACRTIRADS and TMS scoring system. They were then correlated with the FNAC or histopathology report. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy of both scoring system were calculated for analysis. RESULTS: A total of 150 patients with 223 thyroid nodules were included. 17% or 38 nodules were found to be malignant. The sensitivity, specificity, PPV, NPV and accuracy of ACR-TIRADS and TMS were 97.37% vs. 84.21 %, 52.97% vs. 62.70%, 29.84% vs. 31.68%, 98.99% vs. 95.08% and 61% vs. 66% respectively. According to the ACR-TIRADS, only hypoechoic nodules was a strong predictor of malignancy. Comparatively, in the TMS, strong predictors of malignancy include single nodule, hypoechogenicity, irregular margin, and nodules with peri and intranodular vascularity. CONCLUSION: Both ACR-TIRADS and TMS score had good diagnostic accuracy in predicting malignant thyroid nodule. TMS is comparable and not inferior to ACRTIRADS however, the latter is more practical for use as growth and Doppler characteristic are not included in the assessment. [ABSTRACT FROM AUTHOR]

The purpose of this prospective study is to evaluate if the association of Bethesda system and a 3-categories Ultrasonography (US) risk stratification system proposed by the American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi improves the performance of cytology alone in III or IV categories and if further variables such as US provider (radiologist; endocrinologist, or endocrine surgeon both coming from a dedicated team) influence the accuracy of the diagnostic. 570 consecutive patients with complete clinical records, affected by Bethesda III or IV nodules, have been addressed to two public referral surgical centers of Western Sicily. Age, sex, autoimmunity, nodule size, and US provider were recorded. Fisher's exact test was used for the univariate analysis; Odd's ratios were calculated for the multivariate analysis. 248 patients had malignancy at histology, 322 were benign. The mean age was 52 years for the malignancy group and 58 y for the benign group (P < 0.001). At univariate analysis, autoimmunity was correlated with benign group (P < 0.001), and US risk 2 and 3 were correlated with malignancy (nearly 10-folds, P < 0.001); In addition, no difference was found concerning nodule size. At multivariate analysis, US risk 2 and 3 were strong predictors of malignancy (P < 0.0001) especially if cytology was Bethesda IV; endocrinologist and surgeon were more accurate in predicting malignancy compared with the radiologist (P < 0.01). In the context of indeterminate nodules, the American College of Endocrinology/American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi US risk stratification system strongly improves the results of Bethesda system especially when performed from dedicated endocrinologist or endocrine surgeon. [ABSTRACT FROM AUTHOR]

Introduction: Fine needle aspiration cytology (FNAC), along with thyroid ultrasound, is an important tool in evaluation of thyroid nodules that helps in further management of these patients in making a decision of surgical intervention vs follow‐up. The Bethesda System for Reporting Thyroid Cytopathology category III of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) has risk of malignancy (ROM) ranging from 5% to 15%. The aim of the present study was to describe the frequency of AUS/FLUS in thyroid gland FNACs and the surgical outcomes of these cases. Methods: The integrated laboratory management system retrieved the thyroid FNACs from 2010 to 2018 and subsequent surgical pathology specimens. For the AUS/FLUS cases, data regarding patient demographics, cytology and histological diagnoses were recorded. The results were tabulated as the overall frequency of AUS/FLUS in thyroid FNACs, cytohistological correlation (benign and malignant) and ROM. Results: Over a period of 9 years, 256 (10.9%) cases out of 2342 thyroid FNACs were reported as AUS/FLUS at our institution. Mean age was 43.5 years. The majority (70.3%) of patients were female. Seventy‐two of 104 resection specimens (69.2%) were reported as benign and 32 cases (30.7%) had malignant diagnosis. Upper‐bound ROM was 30.7% (32 cases with malignant diagnosis out of 104 resection specimens). Lower‐bound ROM was calculated as 12.5% (32 cases with malignant diagnosis out of 256 total AUS diagnosis). Conclusion: The AUS/FLUS category of thyroid cytology and associated ROM remain an evolving area. Individual institutions should monitor the frequency and include ROM in the dashboard indicators to remain within the recommended range. This study describes the frequency of AUS/FLUS in thyroid gland fine needle aspiration cytology in a single institute in Pakistan and correlates this with the surgical outcomes of these cases. All institutions should monitor their performance and aim to be within the recommended range. [ABSTRACT FROM AUTHOR]

Objectives: Fine-needle aspiration (FNA) of thyroid bed lesions after thyroidectomy is challenging to evaluate. We determined the sensitivity, specificity, and positive and negative predicative value of thyroid bed FNA (TB-FNA) for detecting local recurrence of thyroid carcinoma.Methods: A retrospective search was conducted for TB-FNAs from patients with a prior thyroid resection and subsequent ipsilateral FNA from the thyroid bed. Clinical and pathologic data were retrieved from the medical record. Patients were ultimately classified as "malignant" or "benign" based on the worst pathology identified and follow-up available.Results: Forty-two cases were included, and the prior thyroidectomy pathology included 36 papillary thyroid carcinomas, two follicular carcinomas, one medullary carcinoma, and three benign cases. TB-FNA was adequate in 38 (90.5%) cases and interpreted as positive for malignancy (n = 22; 52.4%), suspicious for follicular neoplasm (n = 3; 7.1%), atypia of unknown significance (n = 2; 4.8%), and benign (n = 10; 23.8%). Twenty-seven patients had histologic follow-up, and 24 (87.5%) showed recurrent malignancy. The cytology sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 96%, 100%, 100%, 92.3%, and 97.4%, respectively, for identification of recurrent malignancy.Conclusions: Most TB-FNA cases ultimately were diagnosed with malignancy on follow-up, although there may be sampling bias, as not all clinically benign cases had surgical follow-up. [ABSTRACT FROM AUTHOR]

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 x 2 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., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Comité de Investigación Centro Médico ABC issued approval CMABC-24-05 dated January 8, 2024. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Castilla Villanueva et al.)

Introduction: The cytological diagnosis of follicular‐patterned thyroid lesions is challenging, especially since the World Health Organisation classification has recognised non‐invasive follicular thyroid neoplasm with papillary‐like features. These entities are often classified as indeterminate on cytology. Molecular testing has been proposed to help classify indeterminate nodules. RAS and K601E BRAF mutations are mostly encountered in follicular‐patterned lesions, but their diagnostic value is not well established. Nuclear scores have also been proposed to help classify indeterminate lesions. Objective: To investigate the correlation between cytological features and histology and to assess nuclear scores in a series of indeterminate RAS or BRAF K601E positive thyroid nodules. Methods: The cytological parameters of 69 indeterminate RAS or BRAF K601E‐positive thyroid nodules were evaluated. The Strickland and Maletta scores and a new nuclear score were assessed. Diagnosis of malignant, benign or indolent neoplasms was confirmed in each case by histology. Malignant and indolent nodules were considered surgical nodules, and adenomas non‐surgical nodule. Results: Surgical nodules were associated with the presence of ground glass nuclei (P =.001), grooves (P <.001) or irregular nuclear membranes (P =.01) on cytology. Nuclear scores were more often ≥2 in surgical nodules compared to benign ones (P <.001), with high sensitivity, but a low negative predictive value. Conclusions: Analysis of nuclear features is useful to distinguish non‐surgical from surgical nodules in indeterminate FNAs. Although nuclear scores are not ideal rule‐out tests for indeterminate RAS or BRAF K601E positive nodules, they seem useful to screen non‐molecular tested or non‐mutated indeterminate FNAs. This work shows that meticulous analysis of nuclear features on cytological specimens can be useful to distinguish non‐surgical nodules (adenoma) from surgical nodules in indeterminate FNAs. Although nuclear scores are not rule‐out tests for indeterminate RAS or BRAF K601E positive nodules, they are useful in screening non‐molecular tested or non‐mutated indeterminate FNAs for surgery. This work shows that meticulous analysis of nuclear features on cytological specimens can be useful to distinguish non‐surgical nodules (adenoma) from surgical nodules in indeterminate FNAs. Although nuclear scores are not rule‐out tests for indeterminate RAS or BRAF K601E positive nodules, they are useful in screening non‐molecular tested or non‐mutated indeterminate FNAs for surgery. [ABSTRACT FROM AUTHOR]

The increased frequency of thyroid nodules is paralleled by the rise of thyroid cancer diagnosis. To define the nature of most thyroid nodules, fine needle aspiration (FNA) followed by cytological evaluation is considered the method of choice. About 20% of FNA biopsies on thyroid nodules, however, show indeterminate cytological features and may require diagnostic surgery. Several immunocytochemical and molecular markers have been proposed to improve classification of thyroid nodules, but these tests require adequate cell amount and cytological paraffin inclusion. Polymeric matrices were recently proposed for the collection of cells for diagnostic purposes. In this study, we evaluated the diagnostic use of a new matrix (CytoMatrix). Morphological, molecular and immunohistochemical investigations were carried out on 23 FNA samples included in CytoMatrix and compared with data obtained from the definitive histology of surgical samples. Our results showed that CytoMatrix is suitable to capture and preserve the cellularity of the samples harvested by FNA and that its paraffin sections mimic the morphology of those obtained from real histological tissue. Immunohistochemistry on CytoMatrix samples was consistent with the immunophenotypical profile of the corresponding histological surgical specimens. Mutational analysis of the BRAF (V600E) gene performed on CytoMatrix inclusions and paired surgical tissue matched in all but one cases while matrix immunohistochemistry identified 91.6% of BRAF mutated samples. In conclusion, we suggest that CytoMatrix could be a reliable tool to overcome the current limits of traditional collection methods for the study of thyroid cytology, thereby improving their reliability for a conclusive diagnostic interpretation. [ABSTRACT FROM AUTHOR]

Background: NTRK‐rearranged thyroid carcinomas (NRTC), though rare, harbor a potential therapeutic target. The cytomorphologic features by fine needle aspiration (FNA) and the utility of preoperative molecular testing for NRTC remain largely uncharacterized. We provide a detailed cytomorphologic analysis of an institutional NRTC cohort with clinical, radiologic, histopathologic, and molecular correlations. Methods: Our NRTC FNA cohort included 21 specimens from 19 patients. The mean age and female‐to‐male ratio were 42 years and 2.2:1, respectively. Predominantly alcohol‐stained Papanicolaou smears and liquid‐based preparations were reviewed for 14 patients with available materials, and histologic review of subsequent resections was conducted for all 19 patients. Imaging and clinical data were accessed through electronic medical records. Results: Sonographically, NRTC were hypoechoic (87%), predominantly solid (53%) with limited central vascularity (27%), ill‐defined borders (67%), and microcalcifications (67%). Observed cytomorphologic features include mixed architectural patterns (79%), fibrosis (93%), oncocytic and vacuolated cytoplasm (36% and 43%, respectively), and abundant intranuclear pseudoinclusions (14%). Most NRTC FNAs were classified as suspicious for malignancy or malignant (89%). One case classified as atypia of uncertain significance underwent ThyroSeq sequencing where a NTRK1 fusion was identified. Conclusion: Although NRTC did not show a consistent cytomorphologic signature, mixed architectural patterns, prominent fibrosis and distinct cytoplasmic or nuclear features should raise suspicion for NRTC and, when accompanied by negative BRAFV600E by immunohistochemistry on cell block material, aid in selecting cases for molecular testing. This algorithmic approach may help identify potential NRTC, maximizing treatment options for patients, especially in patients for whom treatment planning is complicated. NTRK‐related thyroid carcinomas (NRTC) are amenable to targeted therapy. Identifying NRTC by preoperative fine‐needle aspiration may modify primary treatment options. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the reliability of 18F-FDG PET/CT in distinguishing differentiated thyroid cancers (DTCs) and follicular neoplasms (FNs) from nodular hyperplasias (NH) in thyroid nodules with indeterminate cytology according to the Italian consensus for the classification and reporting of thyroid cytology (ICCRTC). We also tested whether the 18F-FDG PET/CT result was an independent risk factor for DTCs or FNs when sex, age, nodule dimensions, the European Thyroid Imaging and Reporting Data System (EU-TIRADS) and ICCRTC were considered. Methods: We evaluated all patients with thyroid nodules and indeterminate cytology from September 2015 to May 2019; nodules were classified as low risk (TIR3A) and high risk (TIR3B) according to the ICCRTC. Neck ultrasonography features according to EU-TIRADS were re-evaluated and 18F-FDG PET/CT performed. All these patients were surgically treated. Results: We included 111 patients; 67 nodules were classified as TIR3A and 44 as TIR3B. Overall, we found 27 DTCs, 57 NHs and 27 FNs. Among 73 FDG-negative nodules, we found four low-risk papillary thyroid cancers. All follicular thyroid cancers were identified by 18F-FDG-PET/CT. All TIR3A with low-risk US and negative 18F-FDG-PET/CT were NH. In TIR3A nodules, the sensitivity, specificity, negative and positive predictive values (NPV, PPV) of 18F-FDG PET/CT and EU-TIRADS for DTCs were 77.8%, 41.4%, 92.3%, 17.1% and 66.7%, 56.9%, 91.7%, 19.4%, respectively. In TIR3B nodules, the sensitivity, specificity, NPV and PPV of 18F-FDG PET/CT and EU-TIRADS for DTCs were 88.9%, 38.5%, 83.3%, 50% and 88.2%, 58.3%, 87.5%, 60%, respectively. On multivariate analysis, 18F-FDG-PET/CT (OR 9.04), ICCRTC (O.R. 7.57) and EU-TIRADS (OR 4.41) were all independent risk factors associated to DTCs and FNs. Conclusion: 18F-FDG-PET/CT is a reliable rule-out test for DTC even in thyroid nodules with indeterminate high-risk results. In this subgroup, PPV also tends to be considerable. 18F-FDG-PET/CT results, ICCRTC and EU-TIRADS proved independent risk factors associated to DTCs and FNs. [ABSTRACT FROM AUTHOR]

Classification schemes for reporting thyroid cytology of fine needle aspiration (FNA) of thyroid nodules are largely used in clinical practice, but the level of inter-observer agreement among cytopathologists is poorly acknowledged. The present study aimed to explore the inter-observer agreement among the experienced authors of the 2014 Italian Consensus for Classification and Reporting of Thyroid Cytology (ICCRTC). A stratified randomization was performed in order to obtain a sample homogeneously distributed and representative of all ICCRTC classes. Four high-experience raters were randomly selected among the extensors of the Italian consensus. They independently reviewed 60 FNA samples blindly of the initial cytological report and clinical features. Their overall agreement was evaluated according to Fleiss' kappa. The overall inter-observer agreement was moderate (κ 0.46). Specifically, a good agreement was found when the samples were consistent for malignancy (TIR5) or were not adequate for diagnosis (TIR1) (κ 0.67 and κ 0.73, respectively). A moderate agreement was present for suspicious-for-malignant category (TIR4), and a fair agreement was recorded in the two intermediate ones (TIR3A and TIR3B) (κ 0.36 and κ 0.35, respectively). For clinical purposes, the agreement was good (κ 0.74) in differentiating cases with surgical indication (TIR4/TIR5) from those in which surgery is not essential or requires limited extension (TIR3B/TIR3A/TIR2). In conclusion, the present study confirms the reliability of ICCRTC. These data represent a reference for cytopathologists using this system and are useful for the practice of clinicians and surgeons. [ABSTRACT FROM AUTHOR]

Background: Ultrasound has become the initial approach to evaluating thyroid nodules, facilitating the distinction between benign and malignant nodules based on composition, echogenicity, nodule border or margin, shape, the presence of calcifications, and nodule dimensions. The American College of Radiology (ACR) recommended the Thyroid Imaging Reporting and Data System (TI‐RADS) as a classification system to standardize thyroid ultrasound reports and to predict the probability of malignancy in thyroid nodules using a scoring system (TR1‐TR5) based on multiple ultrasound characteristics and nodule size. Fine‐needle aspiration (FNA) is recommended as the next step for nodules that warrant further workup. The authors assessed the accuracy of the ACR TI‐RADS based on the corresponding FNA cytology results (Bethesda system diagnoses I‐VI). Methods: ACR TI‐RADS ultrasound reports and corresponding FNA cytology diagnoses from January 1, 2018 to August 30, 2018 were evaluated. Results: From January 1, 2018 to August 30, 2018, 2306 thyroid ultrasound‐guided FNAs were performed at our institution. Of 2306 cases, 361 had ACR TI‐RADS reports available. The majority of FNAs were TR4 (180; 49.9%) or TR3 (108; 29.9%). No TR2 or TR3 nodules were associated with Bethesda category V or VI diagnoses. The majority of TR4 nodules (142 of 180; 78.9%) and TR5 nodules (42 of 65; 64.6%) exhibited benign (Bethesda category II) cytology. Fourteen TR5 cases (21.5%) had malignant (Bethesda category VI) cytology. Conclusions: Although there were no TR2 or TR3 malignant (Bethesda category VI) diagnoses, and there were only a few malignancies in the TR4 and TR5 categories, the current results reassert the notion that the ACR TI‐RADS scoring system shows at least some correlation between benign or malignant cytology diagnoses, as illustrated by the greater number of malignant cases in the higher ACR TI‐RADS categories. Particular ultrasound features from the American College of Radiology's Thyroid Imaging Reporting and Data System (TI‐RADS) scoring system are quantified and correlated with the fine‐needle aspiration diagnosis. Although no cases are positive for malignancy (Bethesda category VI) in the TI‐RADS 2 (TR2) and TR3 categories, and only small percentages are positive in the TR4 and TR5 categories, the current results reassert the notion that this scoring system shows at least some correlation between benign or malignant cytology diagnoses, as illustrated by the increased number of malignant cases in the higher TI‐RADS categories. [ABSTRACT FROM AUTHOR]

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.

Thyroid cancer’s incidence has increased in the last decades, and its diagnosis can be a challenge. Further and complementary testing based in biochemical alterations may be important to correctly identify thyroid cancer and prevent unnecessary surgery. Fourier-transform infrared (FTIR) spectroscopy is a metabolomic technique that has already shown promising results in cancer metabolome analysis of neoplastic thyroid tissue, in the identification and classification of prostate tumor tissues and of breast carcinoma, among others. This work aims to gather and discuss published information on the ability of FTIR spectroscopy to be used in metabolomic studies of the thyroid, including discriminating between benign and malignant thyroid samples and grading and classifying different types of thyroid tumors.

Background: The American Thyroid Association (ATA) sonographic patterns stratify the risk of malignancy of cytologically indeterminate thyroid nodules (ITNs). This study aimed to (1) assess inter-observer agreement for sonographic features and patterns; (2) identify potential sources of disagreement; and (3) evaluate whether the number of suspicious features risk-stratifies non-ATA and high-suspicion patterns. Methods: Three observers independently reviewed the ultrasound images of 463 ITNs with histological follow-up consecutively evaluated between October 2008 and June 2015 at an academic cancer center. Each observer evaluated individual sonographic features. ATA sonographic patterns were derived from the interpretation of sonographic features. Nodules not fitting into any of the proposed patterns were clustered into a non-ATA pattern. Results: The inter-observer agreement for ATA sonographic patterns and echogenicity was fair, moderate for margins, good for composition and echogenic foci, and very good for extrathyroidal extension and lymph node metastasis. The interpretation of each sonographic feature was significantly different between observers, and there was complete disagreement in at least one of the features in 104 (22%) nodules. A total of 169 nodules (37%) were classified into the non-ATA pattern. The number of suspicious features allowed risk stratifying nodules with non-ATA and high-suspicion sonographic patterns. Most Non-invasive Follicular Thyroid Neoplasms with Papillary-like Nuclear Features had 0–1 suspicious features and none had >2. Conclusions: Echogenicity interpretation was the greatest source of disagreement. The number of suspicious features risk-stratifies ITNs with non-ATA or high-suspicion patterns. Future studies attempting to objectivize the interpretation of echogenicity and heterogeneity are needed. [ABSTRACT FROM AUTHOR]

Advances in our understanding of thyroid lesions, especially those entities with an indolent behavior, has led clinicians to question the most appropriate surgical management of such thyroid nodules. Several studies have shown that the non-invasive encapsulated follicular variant of papillary thyroid carcinomas (NI-EFVPC) exhibits poor histopathologic diagnostic reproducibility and have been over-treated as conventional thyroid cancer. In 2015, an international thyroid working group re-evaluated NI-EFVPC and its diagnostic criteria. The new terminology of "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) was accordingly introduced to replace NI-EFVPC. The literature has emphasized that NIFTPs are biologically similar to follicular adenomas lacking lymph node metastases and/or recurrence. While the definition of NIFTP is based on specific morphological parameters, recent studies have questioned whether the criterion allowing less than 1% of true papillae should be revised to a total absence of papillae. The motivation for this revision is the rare finding, in some studies, of lymph nodes with metastatic NIFTP. This review evaluates the existing published series of NIFTP cases, clinical consequences of NIFTP, and emerging changes in the diagnostic criteria for NIFTP. The introduction of NIFTP has resulted in significant impact on the clinical management of thyroid nodules. Recent revisions in the morphological criteria for NIFTP emphasize the need to adhere to very stringent histomorphologic criteria when making a diagnosis of NIFTP. The adoption of NIFTP terminology instead of NI-EFVPC is associated with conservative lobectomy without radioactive iodine treatment in the majority of cases. [ABSTRACT FROM AUTHOR]

Background: The Paris System for Urine Cytopathology (the Paris System) has succeeded in making the analysis of liquid‐based urine preparations more reproducible. Any algorithm seeking to automate this system must accurately estimate the nuclear‐to‐cytoplasmic (N:C) ratio and produce a qualitative "atypia score." The authors propose a hybrid deep‐learning and morphometric model that reliably automates the Paris System. Methods: Whole‐slide images (WSI) of liquid‐based urine cytology specimens were extracted from 51 negative, 60 atypical, 52 suspicious, and 54 positive cases. Morphometric algorithms were applied to decompose images to their component parts; and statistics, including the NC ratio, were tabulated using segmentation algorithms to create organized data structures, dubbed rich information matrices (RIMs). These RIM objects were enhanced using deep‐learning algorithms to include qualitative measures. The augmented RIM objects were then used to reconstruct WSIs with filtering criteria and to generate pancellular statistical information. Results: The described system was used to calculate the N:C ratio for all cells, generate object classifications (atypical urothelial cell, squamous cell, crystal, etc), filter the original WSI to remove unwanted objects, rearrange the WSI to an efficient, condensed‐grid format, and generate pancellular statistics containing quantitative/qualitative data for every cell in a WSI. In addition to developing novel techniques for managing WSIs, a system capable of automatically tabulating the Paris System criteria also was generated. Conclusions: A hybrid deep‐learning and morphometric algorithm was developed for the analysis of urine cytology specimens that could reliably automate the Paris System and provide many avenues for increasing the efficiency of digital screening for urine WSIs and other cytology preparations. [ABSTRACT FROM AUTHOR]

Introduction Accurate cytological assessment is pivotal for managing thyroid lesions and various global reporting systems are in use, such as the globally acclaimed The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), alongside other reporting systems namely, the Japanese Reporting System for Thyroid Aspiration Cytology (JRSTAC), Italian Consensus for the Classification and Reporting of Thyroid Cytology (ICCRTC), the UK Royal College of Pathologists System for Reporting Thyroid Cytopathology (UK RCPath), the Royal College of Pathologists of Australasia and Australian Society of Cytology Classification System (RCPA/ASC). Notably, variations exist among these systems which are influenced by country-specific statistics. Given the lack of large-scale data in India and the difference in prevalence of diagnostic entities compared to the western population, this study aimed to identify reporting systems suitable for the Indian population focusing on distinguishing neoplastic from non-neoplastic lesions. Materials and methods A cross-sectional analysis of 40 thyroid cytology cases with histopathological correlation was conducted. Pathologists independently assessed cytology slides using JRSTAC, ICCRTC, RCPA/ASC, UK RCPath and TBSRTC. Five performance indicators, sensitivity, specificity, positive predictive value (PPV) of neoplastic conditions, negative predictive value (NPV) of non-neoplastic conditions, diagnostic accuracy and two quality indicators, percentage of Atypia of undetermined significance (AUS) and AUS/Malignant ratio were analyzed and compared. Results Among 40 cases, 22 cases were neoplastic (16 papillary thyroid carcinoma, six follicular adenoma) and 18 non-neoplastic (14 multinodular goiter, four lymphocytic thyroiditis). Specific patterns emerged in cases labeled "Non-diagnostic", prompted questions about categorizing inadequately cellular cases as "benign" in light of the presence of specific findings. All reporting systems showed 100% specificity in detecting non-neoplastic and neoplastic conditions in Category 1 and Category 6 respectively. Performance and quality indicators varied among reporting systems with TBSRTC (PPV of neoplastic cases 85.71%, NPV of non-neoplastic cases 70.58%, specificity 85.7%, sensitivity 70.58%, diagnostic accuracy 60%, AUS percentage 22.5% and AUS/Malignant ratio 3%) and RCPA/ASC (PPV of neoplastic cases 76.47%, NPV of non-neoplastic cases 70.58%, specificity 75%, sensitivity 72.2%, diagnostic accuracy 62.5%, AUS percentage 15% and AUS/Malignant ratio 3%) showing better results. Conclusion Among the five thyroid cytology reporting systems studied, TBSRTC and RCPA/ASC showed better overall performance results and quality indicators were close to benchmark. Better performance by TBSRTC 2023 could be due to the detailed criterion mentioned per category with subcategorization of AUS and suspicious for malignancy by features of cytological and architectural atypia. Similarly, RCPA/ASC has subcategorized AUS with defined criteria and certain background features were included as an isolated criterion for the suspicious for malignancy category. These defined criteria outlined in TBSRTC and RCPA/ASC played a crucial role in minimizing and reclassifying cases from the indeterminate categories (AUS and suspicious for malignancy) into well-defined categories with established management protocols., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Ramamoorthy et al.)

Molecular testing is an adjunct test for thyroid fine needle aspirations with indeterminate diagnoses, with certain mutations showing a greater risk of malignancy (ROM). Rat sarcoma (RAS) point mutations are the most common alterations in indeterminate thyroid nodules. While they can have a high ROM, they are also found in benign disease. This study describes the histologic outcomes of indeterminate nodules with RAS mutations. Bethesda III and IV thyroid nodules with ThyroSeq results showing RAS mutations (NRAS, KRAS, and HRAS) were identified between November 1, 2018 and February 28, 2023. Baseline patient characteristics, ThyroSeq results, and surgical diagnoses were collected. We identified 18 nodules with RAS mutations from 17 patients. Fourteen were NRAS (isolated NRAS in 6; NRAS with other abnormalities [NRAS+] in 8); one was isolated KRAS; and three were HRAS with other abnormalities (HRAS+). NRAS Q16R was the most common amino acid change. Twelve cases had follow-up. Two were malignant, a minimally invasive follicular carcinoma (NRAS+) and a papillary thyroid carcinoma, follicular variant (HRAS+). Three were noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), 2 HRAS+ and 1 NRAS+. Four were follicular adenomas, one being atypical (3 NRAS+ and one isolated NRAS). One was an oncocytic adenoma (isolated NRAS). Two were nodular hyperplasias (isolated NRAS and NRAS+, respectively). Twenty-eight percent of our RAS-mutated nodules were malignant or NIFTP. All three HRAS-mutated nodules were malignant or NIFTP. The three isolated RAS mutations with follow up were benign (adenomas or nodular hyperplasia). These findings were in line with the literature., (© 2023 Wiley Periodicals LLC.)

The Bethesda system in thyroid cytology was developed to standardize diagnostic criteria, to facilitate communication among the multidisciplinary team that includes: Endocrinologist, Radiologist, Surgeon, Oncologist and Pathologist. The classification has 6 diagnostic categories which have specific criteria and a possible surgical management and/or follow-up. There are three categories of the Bethesda System for thyroid nodules that are considered "indeterminate" for malignancy, category III, IV and V. Molecular tests are indicated in these categories to determine if the nodule is benign or malignant and thus offer the best therapy to the patient. Recently, these molecular tests have also been used to identify therapeutic targets in thyroid carcinoma. [ABSTRACT FROM AUTHOR]

Background: The 2015 American Thyroid Association (ATA) guidelines recommend using a classification based on sonographic patterns to set the size threshold for biopsies. Each pattern is associated with a distinct estimated rate of malignancy that it was hypothesized should stratify the risk of malignancy of cytologically indeterminate thyroid nodules (ITNs). Methods: Ultrasound images of 463 ITNs (38% atypia/follicular lesions of undetermined significance; 62% follicular neoplasms) with histological follow-up consecutively evaluated between October 2008 and June 2015 at the authors' academic cancer center were independently evaluated by three observers and classified into one of the five sonographic patterns proposed by the ATA. Nodules with sonographic patterns not defined in the classification were grouped into a non-ATA pattern category. Differences in clinical and histological findings between the sonographic patterns were assessed. The prevalence of malignancy and odds ratio for malignancy were calculated for each sonographic pattern (low and intermediate patterns were collapsed for the analysis). Results: The distribution of size and cytological diagnosis was significantly different between sonographic patterns (p < 0.001). The overall rate of malignancy was 27%. The rate of malignancy for the very low, low/intermediate, high, and non-ATA patterns were 0%, 19%, 56%, and 36%, respectively, and were all significantly different. Compared to the low/intermediate suspicion patterns, the odds ratios for malignancy were 2.35 for the non-ATA and 5.18 for the high suspicion patterns (p < 0.001). The odds ratio of the non-ATA pattern was 0.45 over the high suspicion pattern (p = 0.04). Results were similar in both cytological categories and for each observer separately. Sonographic patterns were associated with distinct histopathological profiles (p < 0.001). Conclusions: ATA sonographic patterns are associated with distinct clinical features and pathological outcomes, and effectively stratify the cancer risk in ITNs. Thus, the ATA sonographic patterns should be used not only to set the size threshold for biopsy, but also to personalize management after the biopsy. [ABSTRACT FROM AUTHOR]

Introduction: The Bethesda system is widely accepted for thyroid FNA diagnostics, but has scarcely been analysed in relation to clinical background data. Our aim was to analyse the thyroid FNA diagnostic process in view of clinical data, and to assess the validity of the Bethesda system during the first year of implementation. Methods: There were 415 thyroid FNAs taken from 363 patients during October 2011‐September 2012 in the Pirkanmaa Hospital District, Finland. The median age of the patients was 59 years, and the female‐to‐male ratio 4:1. Clinical data were collected from patient registries, and thyroid FNA and histopathological data from the pathology registry. Results: The Bethesda categories were represented as follows: 94 non‐diagnostic cases (26%); 177 benign (49%); 32 atypia of undetermined significance/follicular lesion of undetermined significance (9%); 31 follicular neoplasm (9%); 20 suspicious for malignancy (5%); and nine malignant cases (2%). Only 23 (24%) of the non‐diagnostic samples and 18 (56%) of the atypia of undetermined significance/follicular lesion of undetermined significance led to repeat FNA. Thyroid cancer was histopathologically diagnosed in 28 cases (8%). When the categories requiring surgical treatment were considered true positive findings, the sensitivity of the Bethesda system was 90%, and specificity was 70%. Interobserver accuracy was 86%. Conclusions: Already during the first year of implementation, the Bethesda system proved reliable in evaluating the risk of thyroid malignancy. Nevertheless, the clinical judgement of the indication of ultrasound/FNA and management according to the FNA findings need improvement. The relatively high proportion of non‐diagnostic FNAs could be diminished by obtaining the samples by radiologists experienced in ultrasound‐guided FNA techniques. [ABSTRACT FROM AUTHOR]

Background: Indeterminate categories of thyroid cytopathology (categories B-III and B-IV of the Bethesda system) are integrated by a heterogeneous spectrum of cytological scenarios that are generally clustered for analysis and management recommendations. It has been suggested that aspirates exhibiting nuclear atypia have a higher risk of malignancy. This study aimed to assess whether cytologically indeterminate thyroid nodules with nuclear atypia have a significantly higher cancer risk than those without nuclear atypia. Methods: On June 30, 2016, PubMed and EMBASE were searched for articles in English or Spanish using a search strategy developed by an endocrinologist and a librarian. Case reports were excluded, and no date limits were used. The references of all included studies were also screened for relevant missing studies. Studies were included if the prevalences of malignancy of cytologically indeterminate thyroid nodules with histological confirmation with and without nuclear atypia were reported. Studies were excluded if they had: (i) nodules suspicious for malignancy; (ii) nodules with non-indeterminate (B-III or B-IV) cytology on repeated biopsy, if performed; (iii) nodules not consecutively evaluated; or (iv) cohorts overlapping with another larger series. Two investigators independently assessed the eligibility and risk of bias of the studies. PRISMA and MOOSE guidelines were followed. Summary data were extracted from published reports by one investigator and independently reviewed by another. Data were pooled using a random-effects model. Heterogeneity was explored using subgroup analysis and mixed-effect model meta-regression. The odds ratio for malignancy of cytologically indeterminate thyroid nodules with nuclear atypia over cytologically indeterminate thyroid nodules without nuclear atypia was calculated. Results: Of 2571 retrieved studies, 20 were eligible. The meta-analysis was conducted on summary data of 3532 cytologically indeterminate thyroid nodules: 1162 with and 2370 without nuclear atypia. The odds ratio for malignancy in cytologically indeterminate thyroid nodules with nuclear atypia was 3.63 [confidence interval 3.06-4.35]. There was no evidence of publication bias, and heterogeneity was insignificant ( I2 < 0.01%, p = 0.40). Conclusions: Nuclear atypia is a significant indicator of malignancy in cytologically indeterminate thyroid nodules and needs to be standardized and implemented into clinical practice. [ABSTRACT FROM AUTHOR]