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Prospective Optimization of Malignancy Risk Prediction in Indeterminate Thyroid Nodules: Diagnostic Synergy of ACR TI-RADS and the 2023 Bethesda System

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Background: Risk stratification of indeterminate thyroid nodules (Bethesda III–IV) remains difficult and often triggers unnecessary procedures. Ultrasound-based ACR TI-RADS and the 2023 Bethesda System are widely used, but the incremental value of combining them and the role of size thresholds needs prospective validation. Objective: The objective of this study was to prospectively compare the diagnostic performance of ACR TI-RADS and the 2023 Bethesda System, alone and in combination, for predicting malignancy in thyroid nodules, with dedicated analyses of indeterminate lesions (Bethesda categories III–IV), including subtypes of Bethesda III (nuclear atypia vs. other atypia), and the impact of nodule size. Methods: Histopathology was available for 131 nodules. Diagnostic metrics (sensitivity, specificity, PPV, NPV), ROC curves (DeLong comparison), and Youden indices were calculated for individual and combined thresholds; a 16 mm size cut-off was explored. Results: Malignancy was confirmed in 105/131 nodules (80.2%). Bethesda outperformed TI-RADS (AUC 0.87 vs. 0.69; DeLong p = 0.041). Malignancy rates rose with higher categories (e.g., TI-RADS 5: 93.6%; Bethesda category V: 100%; Bethesda category VI: 100%) and were markedly elevated in the histologically confirmed subset for Bethesda category III (32/41; 78.0%) and IV (6/8; 75.0%). The combined requirement of TI-RADS ≥ 4 and Bethesda ≥ 4 maximized specificity (96.2%) and PPV (98.4%) with a high Youden J (0.552), supporting a rule-in strategy in category IV of Bethesda. Size alone was a weak discriminator (AUC 0.66); within Bethesda III–IV nodules, malignancy did not differ significantly by the 16 mm threshold (p = 1.00). ROC using continuous tumor size yielded AUC = 0.66; the ROC-derived optimal cut-off was 16 mm. Applying this split produced sensitivity 0.80 and specificity 0.50. Conclusions: Integrating ACR TI-RADS with Bethesda cytology significantly improves specificity and PPV for indeterminate thyroid nodules, supporting a morphology-driven approach over traditional size-based thresholds. Incorporation of combined sonographic–cytologic criteria into management algorithms may reduce unnecessary interventions and optimize patient care.

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  • Research Article
  • Cite Count Icon 9
  • 10.15537/smj.2022.43.5.20220045
Clinical and ultrasonographic features in cancer risk stratification of indeterminate thyroid nodules
  • May 1, 2022
  • Saudi Medical Journal
  • Saad M Alqahtani + 7 more

Objectives:To estimate the risk of malignancy in indeterminate thyroid nodules and to determine whether certain clinical or radiological parameters can predict the risk of malignancy.Methods:This retrospective study enrolled all adult patients (age ≥14 years) with a cytological diagnosis of atypia/follicular lesion of undetermined significance and follicular neoplasm/suspicious for a follicular neoplasm between January 2014 and January 2020. Fifty patients with surgically treated primary thyroid nodules, documented final histological diagnosis, and ultrasound examination records were included. Thyroid nodules were evaluated radiologically using Thyroid Imaging Reporting and Data System introduced by the American College of Radiology (2017).Results:Forty-two (84.0%) female and 8 (16.0%) male patients were enrolled in the study. The malignancy risks were 44.8% for Bethesda III and 28.6% for Bethesda IV. The malignancy risks for the Thyroid Imaging Reporting and Data System categories were 33.3% (TR2), 39.1% (TR3), 35.3% (TR4), and 50% (TR5). No significant associations were observed between age, gender, Bethesda category, and Thyroid Imaging Reporting and Data System and the risk of malignancy.Conclusion:None of the clinical or radiological characteristics evaluated in this study contributed to the cancer risk stratification of thyroid nodules with indeterminate cytology. A prospective multicenter study is needed to better understand cytologically indeterminate thyroid nodules.

  • Research Article
  • Cite Count Icon 3
  • 10.55133/eji.290415
Serum IgG4 level for malignancy prediction in indeterminate thyroid nodules among patients with or without autoimmune thyroid disease
  • Oct 1, 2022
  • Egyptian journal of Immunology
  • Rahma Elshaer + 5 more

The incidence of thyroid nodules (TNs) has increased nowadays, and it is critical to properly differentiate between malignant and benign nodules to prevent unneeded thyroidectomy as well as complications related to surgery. IgG4 significantly contributes to various cancer-associated processes. The present study aimed to assess the value of serum IgG4 level in predicting malignancies in indeterminate thyroid nodules (ITN) among patients with and without autoimmune thyroid disease (AITD). A total of 67 patients with indeterminate cytology thyroid nodules (Bethesda III and IV, according to Bethesda system for reporting thyroid cytopathology) were selected. Preoperative serum thyroid profile, IgG4, anti-thyroglobulin (TG) and anti-thyroid peroxidase (TPO) antibody levels were determined. After total thyroidectomy, patients were categorized based on the postoperative histopathology outcome into two groups. Group (I): confirmed benign nodules (n=55) and Group (II): confirmed malignant TNs (n=12). IgG4 levels were significantly elevated among malignant TNs patients than in benign TNs patients, with a median (IQR) of 194.5 mg/dl (183 - 214) vs. 91 mg/dl (60 - 113), respectively (P=0.001). The cut-off value for differentiation between malignant and benign TNs was >180 mg/dl with a sensitivity of 75% and specificity of 100%. There was a significant positive correlation between thyroid antibodies and IgG4 levels (P=0.001). AITD patients had significantly higher level of IgG4 compared with those without AITD 189 mg/dl (153 - 208) vs 89 mg/dl (58 - 112), respectively (P =0.001). Eighty percent (12/15) of patients with AITD had malignant TNs with IgG4 >180 mg/dl, while 20% (3/15) of patients with benign TNs showed IgG4 levels < 180 mg/dl. In conclusion, IgG4 level can be proposed as a predictor of malignant TNs.

  • Research Article
  • Cite Count Icon 32
  • 10.1007/s12022-011-9159-6
Value of Ultrasound and Cytological Classification System to Predict the Malignancy of Thyroid Nodules with Indeterminate Cytology
  • May 6, 2011
  • Endocrine Pathology
  • Frederico Fernandes Ribeiro Maia + 4 more

Although fine-needle aspiration cytology is considered the gold standard for evaluating thyroid nodules, in about 10-30% of the cases, cytology is indeterminate. This study aimed to determine the value of cytological classification system and ultrasound (US) to predict malignancy in indeterminate thyroid nodule. This retrospective analysis enrolled 80 patients surgically treated at a single center, 75% (60) with benign vs. 25% (20) with malignant lesions at final histology. The clinical, scintigraphic, sonographic, and cytological classification (Bethesda) variables were analyzed in these selected cases of indeterminate cytology, and a prediction model was designed after the multivariate analysis. There was a 25% prevalence of malignancy (20/80). There were no differences in gender, serum thyroid-stimulating hormone and FT4 levels, thyroid auto-antibodies, thyroid dysfunction, and scintigraphic results between benign and malignant nodule groups. The border irregularity in sonographic study was at increased risk for malignancy. The cytological analysis based on Bethesda System (category IV) was an independent predictor for malignancy in indeterminate thyroid nodules. After the multivariate analysis, the model obtained showed border irregularity and Bethesda System category IV as predictive factors of malignancy in indeterminate thyroid nodules, featuring 76.9% of accuracy. This study confirmed a significant increase of risk for malignancy in thyroid nodules with indeterminate cytology showing Bethesda System category IV and suspicious features at US. These findings enhance our current limited predictive armamentarium and can be used to guide surgical decision making.

  • Discussion
  • 10.1067/j.cpsurg.2018.12.002
In Brief
  • Dec 21, 2018
  • Current Problems in Surgery
  • Nicholas G Farkas + 5 more

In Brief

  • Research Article
  • 10.71000/qw785274
DIAGNOSTIC ACCURACY OF ULTRASOUND IN CHARACTERIZATION OF THYROID NODULES ON THE BASIS OF TIRADS CLASSIFICATION KEEPING FNAC AS GOLD STANDARD
  • Jul 19, 2025
  • Insights-Journal of Health and Rehabilitation
  • Fatima Safina + 2 more

Background: Thyroid nodules are increasingly common and pose a diagnostic challenge, particularly in distinguishing benign from malignant lesions. In low-resource settings like Pakistan, effective and accessible diagnostic tools are essential to guide appropriate clinical management and avoid unnecessary invasive procedures. The Thyroid Imaging Reporting and Data System (TIRADS) offers a standardized ultrasonographic approach for risk stratification of thyroid nodules. However, its validation in local populations remains limited. Objective: To assess the diagnostic performance of TIRADS in differentiating benign and malignant thyroid nodules in a Pakistani population, using fine-needle aspiration cytology (FNAC) as the reference standard. Methods: A cross-sectional validation study was conducted at Jinnah Postgraduate Medical Centre, Karachi, from April to September 2024. A total of 100 patients with thyroid nodules were enrolled. Ultrasound examinations were performed by an experienced radiologist using a 7–15 MHz transducer. Nodules were categorized according to TIRADS, and all participants underwent FNAC for histological confirmation. Diagnostic metrics—sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy—were calculated. Stratified analysis was conducted based on gender, age, location, and thyroid function status. Results: The mean age of participants was 46.91 ± 18.25 years, with a slight female predominance (56%). Malignancy was identified in 64% of cases on ultrasound and 78% on FNAC. TIRADS demonstrated 80.8% sensitivity, 95.5% specificity, 98.4% PPV, 58.3% NPV, and 84.0% overall accuracy. TIRADS 5 was the most frequent category (24%). Higher sensitivity was noted among rural residents (85.7%) and females (84.1%), while specificity declined in patients over 60 years (80%). Conclusion: TIRADS offers high diagnostic accuracy in confirming thyroid malignancy and is a valuable triage tool in resource-limited settings. However, its limited NPV warrants cautious interpretation of low-risk classifications. Local validation and radiologist training are essential for optimized use. Background: Thyroid nodules are increasingly common and pose a diagnostic challenge, particularly in distinguishing benign from malignant lesions. In low-resource settings like Pakistan, effective and accessible diagnostic tools are essential to guide appropriate clinical management and avoid unnecessary invasive procedures. The Thyroid Imaging Reporting and Data System (TIRADS) offers a standardized ultrasonographic approach for risk stratification of thyroid nodules. However, its validation in local populations remains limited. Objective: To assess the diagnostic performance of TIRADS in differentiating benign and malignant thyroid nodules in a Pakistani population, using fine-needle aspiration cytology (FNAC) as the reference standard. Methods: A cross-sectional validation study was conducted at Jinnah Postgraduate Medical Centre, Karachi, from April to September 2024. A total of 100 patients with thyroid nodules were enrolled. Ultrasound examinations were performed by an experienced radiologist using a 7–15 MHz transducer. Nodules were categorized according to TIRADS, and all participants underwent FNAC for histological confirmation. Diagnostic metrics—sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy—were calculated. Stratified analysis was conducted based on gender, age, location, and thyroid function status. Results: The mean age of participants was 46.91 ± 18.25 years, with a slight female predominance (56%). Malignancy was identified in 64% of cases on ultrasound and 78% on FNAC. TIRADS demonstrated 80.8% sensitivity, 95.5% specificity, 98.4% PPV, 58.3% NPV, and 84.0% overall accuracy. TIRADS 5 was the most frequent category (24%). Higher sensitivity was noted among rural residents (85.7%) and females (84.1%), while specificity declined in patients over 60 years (80%). Conclusion: TIRADS offers high diagnostic accuracy in confirming thyroid malignancy and is a valuable triage tool in resource-limited settings. However, its limited NPV warrants cautious interpretation of low-risk classifications. Local validation and radiologist training are essential for optimized use.

  • Research Article
  • Cite Count Icon 22
  • 10.1007/s12070-021-02380-8
Correlation of TIRADS and Bethesda Scoring Systems with Final Histopathology of Thyroid Nodules - An Institutional Experience.
  • Jan 21, 2021
  • Indian Journal of Otolaryngology and Head &amp; Neck Surgery
  • Nebu Abraham George + 10 more

Fine needle aspiration cytology (FNAC) reduces the number of unnecessary thyroid surgeries for patients with benign nodules and appropriately triages patients with thyroid cancer to appropriate treatment. This was a observational study done on cases presenting with clinical suspicion of thyroid malignancy which underwent ultrasonography followed by FNAC of thyroid nodule. Ultrasonographic characterization of nodules was based on Thyroid Imaging Reporting and Data System (TIRADS) and cytology reporting was based on Bethesda system. All recruited patients underwent thyroidectomy. Pre-operative cytology and ultrasonography features were compared with final histopathology report. In our study, Bethesda system of cytology reporting for thyroid nodules had a better sensitivity, specificity and diagnostic accuracy than TIRADS system of ultrasound reporting. Bethesda system in FNAC had a larger area under the ROC curve (0.91) as compared to ultrasound TIRADS (0.70). Malignancy rate of TIRADS 5 nodules was 97.1% with significant p value (0.022). 100% of Bethesda VI lesions were malignant according to final histopathology report. Ultrasound TIRADS could pre-operatively predict malignancy in 63.6% of indeterminate thyroid nodules which were malignant according to post-operative histopathology. The overall concordance of ultrasound TIRADS, Bethesda system and histopathology was 69.8%. Higher TIRADS and Bethesda scoring among thyroid nodules was associated with increased risk of malignancy. US TIRADS is a good predictor of malignancy in indeterminate thyroid nodules.

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  • Research Article
  • 10.1186/s43162-025-00582-y
Evaluation of circulating microRNA-221 as a predictor of malignancy in indeterminate thyroid nodules among euthyroid patients
  • Dec 29, 2025
  • The Egyptian Journal of Internal Medicine
  • Asmaa Kassem + 5 more

While most thyroid nodules are benign, approximately 5–15% carry a risk of malignancy. Fine-needle aspiration cytology (FNAC) remains a standard diagnostic tool; however, indeterminate cytological categories (Bethesda III and IV) pose a significant clinical challenge. Recently, circulating microRNAs (miRNAs), especially microRNA-221 (miR-221), have been identified as potential non-invasive biomarkers for differentiating between benign and malignant thyroid nodules, offering new strategies to reduce diagnostic uncertainty and unnecessary surgeries. The study aimed to assess the diagnostic utility of serum microRNA-221 expression in euthyroid Egyptian patients with indeterminate thyroid nodules, and to investigate its correlation with histopathological outcomes, Bethesda classification, TI-RADS scoring, and clinical data. Increasing TI-RADS and Bethesda scores were significantly associated with higher malignancy risk (p = 0.027). Serum miR-221 expression was significantly elevated in malignant cases, with a sensitivity of 83.3%, a specificity of 75%, and a negative predictive value (NPV) of 90%. Circulating microRNA-221 is a promising non-invasive biomarker for predicting malignancy in indeterminate thyroid nodules, supporting its potential integration into diagnostic algorithms.

  • Research Article
  • Cite Count Icon 1
  • 10.32412/pjohns.v38i2.1703
Stratifying Indeterminate Cytology Thyroid Nodules by Combining Thyroid Imaging Reporting and Data Systems (TI-RADS) and The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC)
  • Nov 20, 2023
  • Philippine Journal of Otolaryngology Head and Neck Surgery
  • Steve Marlo Cambe + 3 more

Objective: To determine the risk of malignancy of Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) indeterminate Thyroid Nodules (Bethesda III, IV and V) by combining cytologic (TSBRTC) and Thyroid Imaging Reporting and Data Systems (TI-RADS) ultrasonographic features based on final histopathology. Methods:Design: Retrospective review of recordsSetting: Tertiary Private Training HospitalParticipants: 551 recordsResults: Among 81 eligible participants, 59 out of 84 nodules (70.24%) wer malignant on histopathology. The malignancy risk of Bethesda classification was 60.87% (28 out of 46) for Bethesda III, 57.14% (8 out of 14) for Bethesda IV and 95.83% for Bethesda V. The malignancy risk for TI-RADS categories was 0 % (0/1) for TI-RADS 2, 50% (10 out of 20) for TI-RADS 3, 71.05 % for TI-RADS 4 and 91.67 % for TI-RADS 5. The highest risk of malignancy (100%) was associated with [Bethesda IV/TI-RADS 1, 2, and 3], [Bethesda V/TI-RADS 1, 2 and 3 [Bethesda IV and V/TI-RADS 1, 2 and 3] and [Bethesda IV/TI-RADS 5]. The lowest risk of malignancy (33.33%) was associated with [Bethesda III/TI-RADS1, 2 and 3]. A high Bethesda classification (Bethesda V) was almost 5x more likely to have a malignant anatomorphology compared with Bethesda III (p = .05) while a TI-RADS 4 or 5 category was almost 5x more likely to have a malignant anatomorphology compared to TI-RADS 1, 2 or 3 (p = .026). Conclusion: This study showed that TI-RADS scoring is a sensitive diagnostic classification in recognizing patients with thyroid cancer and combining Bethesda classification and TI-RADS scoring increases the sensitivity in the diagnosis of malignant thyroid nodules. A higher likelihood of malignancy is associated with higher Bethesda classification and TI-RADS scoring.

  • Research Article
  • Cite Count Icon 2
  • 10.4103/trp.trp_5_24
The diagnosis and management of thyroid nodules: Consensus statement of the Indian Thyroid Society
  • May 1, 2024
  • Thyroid Research and Practice
  • Rajesh Rajput + 13 more

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.

  • Research Article
  • Cite Count Icon 8
  • 10.1089/ve.2020.0173
Diagnosis of Thyroid Nodule with New Ultrasound Imaging Modalities
  • Mar 1, 2020
  • VideoEndocrinology
  • Ghobad Azizi + 4 more

Introduction: B-mode ultrasound (US) technology is an integral part of diagnosing and assessing risk stratification of thyroid nodules (TNs). The addition of shear wave elastography and three-dimensional (3D) US imaging may improve risk stratification for thyroid cancer (TC).Materials and Methods: The patient was evaluated in our clinic with US imaging including B-mode, shear wave elastography, 3D-US, and fine needle aspiration biopsy (FNAB). Laboratory measurements were performed at LabCorp. The patient gave informed consent.Case: A 20-year-old female referred for hypothyroidism who was on levothyroxine 25µg daily. Her thyroid-stimulating hormone (TSH) was 3.870 (0.45–4.5 µIU/mL). Thyroid peroxidase antibody and thyroglobulin antibody were elevated, suggestive of Hashimoto's thyroiditis. Her thyroid ultrasongraph showed a heterogeneous thyroid gland with a hypoechoic TN in the right lobe measuring 9.2 × 8.9 × 9 mm. Shear wave elastography examination was suggestive of a hard TN. The shear wave velocity (SWV) measurements for the target TN was 3.9 m/s. 3D-US examination demonstrated a hypoechoic TN with irregular margins and a volume of 0.322 cm3. FNAB of right TN was performed. The cytopathology was read as malignant (Bethesa Category VI), diagnostic for papillary thyroid cancer (PTC). She underwent total thyroidectomy. Surgical pathology report showed an 8 mm PTC in the right lobe and 2 mm PTC in the left lobe with a background of Hashimoto's thyroiditis. There were 3/10 positive lymph nodes (LNs) for metastases. The largest metastatic LN measured 5 mm at level 6.Discussion: This case illustrates recent advances in US technology. For decades, clinicians relied on B-mode US to assess the risk for TC. This case illustrates important challenges and advances in US technology. Current ACR-TIRADS guideline for TN management is based on B-mode US features and TN size.1 In our experience, including additional factors such as elastography, 3D-US, and laboratory evaluation helps to improve our diagnostic accuracy. In this case, her laboratory was suggestive of autoimmune thyroid disease. This information was helpful to put this patient in a higher risk category. Recent large studies reported an association between differentiated TC and autoimmune thyroid disease and/or TSH when all Bethesda classifications were included.2–4 Shear wave elastography examination showed that this TN had a high SWV, suggestive of a hard TN, which is suspicious for malignancy. Several recent publications have reported that elastography can assess the malignant potential of TN.5–10 In our prospective study, we reported that in a single cutoff analysis for predicting malignancy in TNs, a maximum SWV of 3.54 m/s had the best sensitivity. With greater SWV values, specificity increased but sensitivity decreased.6 3D-US technology enhances our ability to visualize the target lesion because of adding a new dimension, coronal view, to the existing B-mode that consists of transverse and longitudinal views. In this case, irregular margins of the TN are seen much better with 3D-US. This is a preliminary report, and more studies need to be done.Conclusion: Adding SWE and 3D-US technology to B-mode US may enhance our ability for risk stratification for TN before FNAB. 3D-US may improve our ability to visualize the margins of TN.No competing financial interests exist.Runtime of video: 2 mins 5 secs

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  • Research Article
  • Cite Count Icon 9
  • 10.3389/fendo.2020.00053
A Novel Risk Stratification System for Thyroid Nodules With Indeterminate Cytology—A Pilot Cohort Study
  • Feb 18, 2020
  • Frontiers in Endocrinology
  • Cristiane J Gomes-Lima + 12 more

Background: Thyroid ultrasound (US), fine needle aspiration biopsy (FNAB), and molecular testing have been widely used to stratify the risk of malignancy in thyroid nodules. The goal of this study was to investigate a novel diagnostic approach for cytologically indeterminate thyroid nodules (ITN) based upon a combination of US features and genetic alterations.Methods: We performed a pilot cohort study of patients with ITN (Bethesda III/IV), who underwent surgical treatment. Based on standardized sonographic patterns established by the American Thyroid Association (ATA), each ITN received an US score (XUS), ranging between 0 and 0.9 according to its risk of thyroid cancer (TC). DNA and RNA were extracted from pathologic material, available for all patients, and subjected to Oncomine™ Comprehensive Assay v2 (OCAv2) next-generation sequencing. Each genetic alteration was annotated based on its strength of association with TC and its sum served as the genomic classifier score (XGC). The total risk score (TRS) was the sum of XUS and XGC. ROC curves were generated to assess the diagnostic accuracy of XUS, XGC, and TRS.Results: The study cohort consisted of 50 patients (39 females and 11 males), aged 47.5 ± 14.8 years. Three patients were excluded due to molecular testing failure. Among the remaining 47 patients, 28 (59.6%) were diagnosed with TC. BRAFV600E was the most common mutation in papillary TC, PAX8-PPARG fusion was present in NIFTP, pathogenic variants of SLX4, ATM, and NRAS were found in Hürthle cell TC and RET mutations in medullary TC. The diagnostic accuracy of XGC and TRS was significantly higher compared with XUS (88 vs. 62.5%, p < 0.001; 85.2 vs. 62.5%, p < 0.001, respectively). However, this increased accuracy was due to significantly better sensitivity (80.7 vs. 34.6%, p < 0.001; 84.6 vs. 34.6%, p < 0.001, respectively) without improved specificity (94.7 vs. 90%, p = 0.55; 85.7 vs. 90%, p = 0.63, respectively).Conclusion: Molecular testing might not be necessary in ITN with high-risk US pattern (XUS = 0.9), as specificity of TC diagnosis based on Xus alone is sufficient and not improved with molecular testing. OCAv2 is useful in guiding the management of ITN with low-to-intermediate risk US features (XUS < 0.9), as it increases the accuracy of TC diagnosis.

  • Research Article
  • Cite Count Icon 23
  • 10.1089/thy.2019.0575
Combining the American Thyroid Association's Ultrasound Classification with Cytological Subcategorization Improves the Assessment of Malignancy Risk in Indeterminate Thyroid Nodules.
  • Dec 10, 2020
  • Thyroid
  • Aline Machado Larcher De Almeida + 9 more

Background: The risk of malignancy (RoM) of indeterminate thyroid nodules (ITNs) shows a high variability in interinstitutional cohorts. The RoM is partially associated with the cytological degree of atypia and the ultrasound (US) pattern. This study evaluated the cancer risk of ITNs by jointly considering the cytological subcategory and the American Thyroid Association (ATA)-based US risk classification. Methods: This study features a retrospective cohort from two Brazilian centers comprising 238 ITNs with confirmed outcomes. US classification, according to ATA-based guidelines, and cytological subcategorization were determined. The cytological subgroups were as follows: (1) nuclear atypia (NA) related to papillary thyroid carcinoma (PTC) but insufficient to categorize the cytology as suspicious for malignancy; (2) architectural atypia without NA (AA); (3) both architectural and nuclear atypia (ANA); (4) oncocytic pattern (OP) without NA; and (5) NA not related to PTC (NANP). NA was divided into three subgroups: nuclear size and shape, nuclear membrane appearance, and/or chromatin aspects. Results: The overall frequency of malignancy was 39.5%. Among the cytological subcategories, the highest RoM was related to the NA (43.9%) and to the ANA (43.5%), followed by AA (29.4%), and OP (9.4%). NA was positively and independently associated with cancer (odds ratio [OR]: 4.5; confidence interval [CI: 1.2-16.6]) as was the occurrence of ANA (OR 6.6 [CI 1.5-29.5]). AA and OP were not independently associated with cancer. Both ATA-based high- and intermediate-risk categories showed an independent association with cancer (OR 6.8 [CI 2.9-15.5] and OR: 2.6 [CI 1.1-5.8], respectively). ITNs with cytological findings of NA or ANA when combined with intermediate US patterns had RoM values of 47.5% and 56.7%, respectively. Both cytological subcategories, when combined with the ATA high-suspicion class reached an RoM >70%. The type of NA with the highest odds for cancer was related to the nuclear membrane (OR 11.5). Conclusions: The RoM of ITNs can reach almost 80% when both NA and ATA-based high-risk US features are present. The presence of such cytological features also increased the RoM in the ATA-based intermediate-risk US category. In addition, AA and OP were not independently related to higher cancer risk. These results strengthen the recommendations for combing cytological subcategorization and US risk classification in the workup for ITNs before the decision of a molecular testing, clinical observation, or diagnostic surgery.

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  • Supplementary Content
  • Cite Count Icon 76
  • 10.3389/fendo.2023.1101410
Molecular diagnostics in the evaluation of thyroid nodules: Current use and prospective opportunities
  • Feb 24, 2023
  • Frontiers in Endocrinology
  • Jena Patel + 2 more

Thyroid cancer is the most common endocrine malignancy with an estimated 43,800 new cases to be diagnosed in 2022 and representing the 7th most common cancer in women. While thyroid nodules are very common, being identified in over 60% of randomly selected adults, only 5-15% of thyroid nodules harbor thyroid malignancy. Therefore, it is incumbent upon physicians to detect and treat thyroid malignancies as is clinically appropriate and avoid unnecessary invasive procedures in patients with benign asymptomatic lesions. Over the last 15-20 years, rapid advances have been made in cytomolecular testing to aid in thyroid nodule management. Initially, indeterminate thyroid nodules, those with Bethesda III or IV cytology and approximately a 10-40% risk of malignancy, were studied to assess benignity or malignancy. More recently, next generation sequencing and micro-RNA technology platforms have refined the diagnostic capacity of thyroid nodule molecular testing and have introduced opportunities to glean prognostic information from both cytologically indeterminate and malignant thyroid nodules. Therefore, clinicians can move beyond determination of malignancy, and utilize contemporary molecular information to aid in decisions such as extent of surgery and post-therapy monitoring plans. Future opportunities include molecularly derived information about tumor behavior, neo-adjuvant treatment opportunities and response to thyroid cancer therapies.

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  • Research Article
  • Cite Count Icon 26
  • 10.1007/s12020-017-1509-9
Shear wave elastography and Afirma\u2122 gene expression classifier in thyroid nodules with indeterminate cytology: a comparison study
  • Jan 1, 2018
  • Endocrine
  • Ghobad Azizi + 6 more

PurposeTo compare shear wave elastography (SWE) and Afirma™ gene expression classifier (GEC) for diagnosis of malignancy in thyroid nodules (TNs) with Bethesda Classification (BC) III or IV indeterminate cytology.MethodsThis preliminary single-center prospective study was approved by the Institutional Review Board. We evaluated 151 consented patients with 151 indeterminate TNs (123 BC III, 28 BC IV) on fine-needle aspiration biopsy (FNAB). B-mode ultrasound, vascularity, and SWE were performed prior to FNAB. TN stiffness was measured as shear wave velocity (SWV) in meters per second (m/s). The stiffest area of the TN was selected for SWV measurement. GEC testing was performed with a second FNAB. Surgery was recommended for GEC-suspicious TNs, or GEC-benign TNs with two or more worrisome B-mode US features.ResultsSurgical pathology confirmed 31 malignant TNs. Among the GEC-suspicious group, 28 of 59 TNs were malignant. The SWV value of ≥3.59 m/s was the best cut-off for malignancy risk based on the receiver operating curve (ROC). Twenty-six malignant TNs had SWV ≥ 3.59 m/s. The sensitivity and specificity for SWV ≥ 3.59 m/s were 83.9 and 79.2%, respectively. Positive predictive value (PPV) was 51.0% and negative predictive value (NPV) was 95.0%. For the GEC-suspicious group, sensitivity, specificity, PPV, and NPV were 90.3, 74.2, 47.5, and 96.7%, respectively. In multivariate analysis, SWV and GEC-suspicious were significant predictors of malignancy, but B-mode features and vascularity were not.ConclusionThis preliminary study indicates that SWE and GEC are independent predictors of malignancy in TNs with BC III or IV.

  • Research Article
  • Cite Count Icon 1
  • 10.2174/0250688203666210111152307
A Retrospective Study Correlating Ultrasound Based Thyroid Imaging Reporting and Data System (TIRADS) with Bethesda System for Thyroid Cytopathology in Thyroid Nodule Risk Stratification
  • Jul 27, 2021
  • New Emirates Medical Journal
  • Rajeev Chaturvedi + 3 more

Objective: To evaluate the efficacy of the ultrasound-based Thyroid Imaging Reporting and Data System (TIRADS) in estimating the risk of malignancy in thyroid nodules by correlating it with the Bethesda system of thyroid cytopathology. Methods: A retrospective single-center study was conducted in a specialty hospital in UAE from November 2017 to November 2019 on 259 thyroid nodules that underwent ultrasound and fine-needle aspiration cytology (FNAC). Thyroid nodules were evaluated using American College of Radiology (ACR) TIRADS and categorized as benign (TR1), not suspicious (TR2), mildly suspicious (TR3), moderately suspicious (TR4), or highly suspicious (TR5) for malignancy. The risk of malignancy associated with each TIRADS category was evaluated by comparing it with the Bethesda classification system of cytopathology. Results: Ultrasound and FNAC data of 259 nodules were reviewed. Out of these, 33 (12.7%) nodules were excluded because FNAC revealed atypia of undetermined significance or follicular lesion of undetermined significance. The estimated risk of malignancy in TR 3 was 13.6%, TR4 was 27%, and TR5 was 63.6%. There was a statistically significant correlation between TIRADS and Bethesda system, which was determined using the Chisquare test (p &lt; 0.001). The receiver operating curve (ROC) analysis revealed specificity of 81.3% [95% CI, 74.9 - 86.6%], NPV of 91% [95% CI, 87.1 – 93.8%] and accuracy of 77.9% [95% CI, 71.9 – 83.1%], when differentiating benign from malignant nodules. Conclusion: The ultrasound-based ACR-TIRADS scoring correlates well with the Bethesda cytopathology in thyroid nodule risk stratification. Thus, it can be used as a simple and effective tool to decide further management and avoid unnecessary FNAC and surgeries in thyroid nodules.

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