Evaluation and Management of Indeterminate Thyroid Nodules

In accordance with National Guidelines, we currently follow a linear approach to the diagnosis of thyroid nodules, with management decision based primarily on a cytological diagnosis following fine-needle aspiration biopsy. However, 25% of these biopsies render an indeterminate cytology, leaving uncertainty regarding appropriate management. Individualizing the risk of malignancy of these nodules could improve their management significantly. We summarize the current evidence on the relevance of clinical information, radiological features, cytological features, and molecular markers tests results and describe how these can be integrated to personalize the management of thyroid nodules with indeterminate cytology. Several factors can be used to stratify the risk of malignancy in thyroid nodules with indeterminate cytology. Male gender, large tumors (>4 cm), suspicious sonographic patterns, and the presence of nuclear atypia on the cytology are all associated with an increased cancer prevalence. The added value of current molecular markers in the risk stratification process needs further study because their performance seems compromised in some clinical settings and remains to be validated in others. Risk stratification is possible in thyroid nodules with indeterminate cytology using data that are often underused by current guidelines. Future guidelines should integrate these factors and personalize the recommended diagnostic and therapeutic approaches accordingly.

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Preoperative detection of malignancy in fine-needle aspiration cytology (FNAC) smears with indeterminate cytology (Bethesda III, IV) by a combined molecular classifier

Journal of Clinical Pathology ◽

10.1136/jclinpath-2020-206445 ◽

2020 ◽

Vol 73 (11) ◽

pp. 722-727 ◽

Cited By ~ 1

Author(s):

Sergei Titov ◽

Pavel S Demenkov ◽

Sergei A Lukyanov ◽

Sergei V Sergiyko ◽

Gevork A Katanyan ◽

...

Keyword(s):

Differential Diagnosis ◽

Molecular Markers ◽

Fine Needle Aspiration ◽

Predictive Value ◽

Thyroid Nodules ◽

Needle Aspiration ◽

Cytological Analysis ◽

Fine Needle ◽

Risk Of Malignancy ◽

Indeterminate Cytology

AimsAnalysis of molecular markers in addition to cytological analysis of fine-needle aspiration (FNA) samples is a promising way to improve the preoperative diagnosis of thyroid nodules. Previously, we have developed an algorithm for the differential diagnosis of thyroid nodules by means of a small set of molecular markers. Here, we aimed to validate this approach using FNA cytology samples of Bethesda categories III and IV, in which preoperative detection of malignancy by cytological analysis is impossible.MethodsA total of 122 FNA smears from patients with indeterminate cytology (Bethesda III: 13 patients, Bethesda IV: 109 patients) were analysed by real-time PCR regarding the preselected set of molecular markers (the BRAF V600E mutation, normalised concentrations of HMGA2 mRNA, 3 microRNAs, and the mitochondrial/nuclear DNA ratio). The decision tree–based classifier was used to discriminate between benign and malignant tumours.ResultsThe molecular testing detected malignancy in FNA smears of indeterminate cytology with 89.2% sensitivity, 84.6% positive predictive value, 92.9% specificity and 95.2% negative predictive value; these characteristics are comparable with those of more complicated commercial tests. Residual risk of malignancy for the thyroid nodules that were shown to be benign by this molecular method did not exceed the reported risk of malignancy for Bethesda II histological diagnosis. Analytical-accuracy assessment revealed required nucleic-acid input of ≥5 ng.ConclusionsThe study shows feasibility of preoperative differential diagnosis of thyroid nodules of indeterminate cytology using a small panel of molecular markers of different types by a simple PCR-based method using stained FNA smears.

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Contemporary Management of Thyroid Nodules

Annual Review of Medicine ◽

10.1146/annurev-med-042220-015032 ◽

2021 ◽

Vol 73 (1) ◽

Author(s):

Kristen Kobaly ◽

Caroline S. Kim ◽

Susan J. Mandel

Keyword(s):

Thyroid Nodules ◽

Cervical Lymphadenopathy ◽

Standard Technique ◽

Clinical History ◽

Needle Aspiration ◽

Annual Review ◽

Publication Date ◽

Molecular Testing ◽

Risk Of Malignancy ◽

Indeterminate Cytology

Thyroid nodules are common in the general population, with higher prevalence in women and with advancing age. Approximately 5% of thyroid nodules are malignant; the majority of this subset represents papillary thyroid cancer. Ultrasonography is the standard technique to assess the underlying thyroid parenchyma, characterize the features of thyroid nodules, and evaluate for abnormal cervical lymphadenopathy. Various risk stratification systems exist to categorize the risk of malignancy based on the ultrasound appearance of a thyroid nodule. Nodules are selected for fine-needle aspiration biopsy on the basis of ultrasound features, size, and high-risk clinical history. Cytology results are classified by the Bethesda system into six categories ranging from benign to malignant. When cytology is indeterminate, molecular testing can further risk-stratify patients for observation or surgery. Surveillance is indicated for nodules with benign cytology, indeterminate cytology with reassuring molecular testing, or non-biopsied nodules without a benign sonographic appearance. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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ACR TI-RADS and ATA US scores are helpful for the management of thyroid nodules with indeterminate cytology

BMC Endocrine Disorders ◽

10.1186/s12902-019-0429-5 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 11

Author(s):

Thayse Lozovoy Madsen Barbosa ◽

Cleo Otaviano Mesa Junior ◽

Hans Graf ◽

Teresa Cavalvanti ◽

Marcus Adriano Trippia ◽

...

Keyword(s):

Thyroid Nodules ◽

Clinical Decision Making ◽

Clinical Decision ◽

Needle Aspiration ◽

Molecular Testing ◽

American Thyroid Association ◽

Institutional Review ◽

The Us ◽

Risk Of Malignancy ◽

Indeterminate Cytology

Abstract Background Cytologically indeterminate thyroid nodules currently present a challenge for clinical decision-making. The main aim of our study was to determine whether the classifications, American College of Radiology (ACR) TI-RADS and 2015 American Thyroid Association (ATA) guidelines, in association with The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), could be used to stratify the malignancy risk of indeterminate thyroid nodules and guide their clinical management. Methods The institutional review board approved this retrospective study of a cohort of 140 thyroid nodules in 139 patients who were referred to ultrasound-guided fine-needle aspiration cytology (FNAC) from January 2012 to June 2016 with indeterminate cytological results (44 Bethesda III, 52 Bethesda IV and 44 Bethesda V) and in whom pre-FNAC thyroid US images and histological results after surgery were available. Each included nodule was classified by one radiologist blinded to the cytological and histological diagnoses according to the ACR TIRADS scores and the US patterns as recommended in the 2015 ATA guidelines. The risk of malignancy was estimated for Bethesda, TI-RADS scores, ATA US patterns and their combination. Results Of the 140 indeterminate thyroid nodules examined, 74 (52.9%) were histologically benign. A different rate of malignancy (p < 0.001) among Bethesda III, IV and V was observed. The rate of malignancy increased according to the US suspicion categories (p < 0.001) in both US classifications (TI-RADS and ATA). Thyroid nodules classified as Bethesda III and the lowest risk US categories (very low, low and intermediate suspicion by ATA and 2, 3 and 4a by TI-RADS) displayed a sensitivity of 95.3% for both classifications and a negative predictive value of 94.3 and 94.1%, respectively. The highest risk US categories (high suspicion by ATA and 4b,4c and 5 by TI-RADS) were significantly associated with cancer (odds ratios [ORs] 14.7 and 9.8, respectively). Conclusions Ultrasound classifications, ACR TI-RADS and ATA guidelines, may help guide the management of indeterminate thyroid nodules, suggesting a conservative approach to nodules with low-risk US suspicion and Bethesda III, while molecular testing and surgery should be considered for nodules with high-risk US suspicion and Bethesda IV or V.

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Diagnostic Performance of Different Thyroid Imaging Reporting and Data Systems (Kwak-TIRADS, EU-TIRADS and ACR TI-RADS) for Risk Stratification of Small Thyroid Nodules (≤10 mm)

Journal of Clinical Medicine ◽

10.3390/jcm9010236 ◽

2020 ◽

Vol 9 (1) ◽

pp. 236 ◽

Cited By ~ 3

Author(s):

Simone Schenke ◽

Rigobert Klett ◽

Philipp Seifert ◽

Michael C. Kreissl ◽

Rainer Görges ◽

...

Keyword(s):

Risk Stratification ◽

Predictive Value ◽

Diagnostic Performance ◽

Thyroid Nodules ◽

Cohort Analysis ◽

Medullary Carcinoma ◽

Data Systems ◽

Thyroid Imaging ◽

Promising Tool ◽

Risk Of Malignancy

Due to the widespread use of ultrasound, small thyroid nodules (TNs) ≤ 10 mm are common findings. Standardized approaches for the risk stratification of TNs with Thyroid Imaging Reporting and Data Systems (TIRADS) were evaluated for the clinical routine. With TIRADS, the risk of malignancy in TNs is calculated by scoring the number or combination of suspicious ultrasound features, leading to recommendations for further diagnostic steps. However, there are only scarce data on the performance of TIRADS for small TNs. The aim was to compare three different TIRADS for risk stratification of small TNs in routine clinical practice. We conducted a retrospective cohort analysis of TNs ≤ 10 mm and their available histology. Nodules were classified according to three different TIRADS. In the study, 140 patients (n = 113 female) with 145 thyroid nodules (n = 76 malignant) were included. Most of the malignant nodules were papillary carcinoma (97%), and the remaining 3% were medullary carcinoma. For all tested TIRADS, the prevalence of malignancy rose with increasing category levels. The highest negative predictive value was found for ACR TI-RADS and the highest positive predictive value for Kwak-TIRADS. All tested variants of TIRADS showed comparable diagnostic performance for the risk stratification of small TNs. TIRADS seems to be a promising tool to reliably assess the risk of malignancy of small TNs.

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Ultrasound characterization for thyroid nodules with indeterminate cytology: inter-observer agreement and impact of combining pattern-based and scoring-based classifications in risk stratification

Endocrine ◽

10.1007/s12020-019-02000-0 ◽

2019 ◽

Vol 66 (2) ◽

pp. 278-287 ◽

Cited By ~ 4

Author(s):

Cesar A. Lam ◽

Melissa J. McGettigan ◽

Zachary J. Thompson ◽

Laila Khazai ◽

Christine H. Chung ◽

...

Keyword(s):

Risk Stratification ◽

Thyroid Nodules ◽

Observer Agreement ◽

Indeterminate Cytology

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Thyroid Nodules with Indeterminate Cytology: Utility of the American Thyroid Association Sonographic Patterns for Cancer Risk Stratification

Thyroid ◽

10.1089/thy.2018.0085 ◽

2018 ◽

Vol 28 (8) ◽

pp. 1004-1012 ◽

Cited By ~ 26

Author(s):

Pablo Valderrabano ◽

Melissa J. McGettigan ◽

Cesar A. Lam ◽

Laila Khazai ◽

Zachary J. Thompson ◽

...

Keyword(s):

Cancer Risk ◽

Risk Stratification ◽

Thyroid Nodules ◽

American Thyroid Association ◽

Sonographic Patterns ◽

Indeterminate Cytology

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Do tumor characteristics predict risk of malignancy in thyroid nodules with indeterminate cytology?

Nature Reviews Endocrinology ◽

10.1038/ncpendmet1078 ◽

2009 ◽

Vol 5 (3) ◽

pp. 140-141 ◽

Cited By ~ 1

Author(s):

Jennifer A Sipos ◽

Matthew D Ringel

Keyword(s):

Thyroid Nodules ◽

Tumor Characteristics ◽

Risk Of Malignancy ◽

Indeterminate Cytology

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Risk Stratification in Patients With Follicular Neoplasm on Cytology: Use of Quantitative Characteristics and Sonographic Patterns

Frontiers in Endocrinology ◽

10.3389/fendo.2021.614630 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ming-Hsun Wu ◽

Kuen-Yuan Chen ◽

Min-Shu Hsieh ◽

Argon Chen ◽

Chiung-Nien Chen

Keyword(s):

Risk Stratification ◽

Thyroid Nodules ◽

Region Of Interest ◽

Diagnostic Value ◽

Follicular Neoplasm ◽

American Thyroid Association ◽

Cad System ◽

Hospital Patients ◽

Risk Of Malignancy ◽

Us Findings

ObjectivesDifferentiating thyroid nodules with a cytological diagnosis of follicular neoplasm remains an issue. The goal of this study was to determine whether ultrasonographic (US) findings obtained preoperatively from the computer-aided detection (CAD) system are sufficient to further stratify the risk of malignancy for this diagnostic cytological category.MethodsFrom September 2016 to September 2018 in our hospital, patients diagnosed with Bethesda category IV (follicular neoplasm or suspicion of follicular neoplasm) thyroid nodules and underwent surgical excisions were include in the study. Quantification and analysis of tumor features were performed using CAD software. The US findings of the region of interest, including index of composition, margin, echogenicity, texture, echogenic dots indicative of calcifications, tall and wide orientation, and margin were calculated into computerized values. The nodules were further classified into American Thyroid Association (ATA) and American College of Radiology Thyroid Imaging Reporting & Data System (TI-RADS) categories.Results92 (10.1%) of 913 patients were diagnosed with Bethesda category IV thyroid nodules. In 65 patients, the histological type of the nodule was identified. The quantitative features between patients with benign and malignant conditions differed significantly. The presence of heterogeneous echotexture, blurred margins, or irregular margins was shown to have the highest diagnostic value. The risks of malignancy for nodules classified as having very low to intermediate suspicion ATA, non-ATA, and high suspicion ATA patterns were 9%, 35.7%, and 51.7%, respectively. Meanwhile, the risks of malignancy were 12.5%, 26.1%, and 53.8% for nodules classified as TIRADS 3, 4, and 5, respectively. When compared to human observers, among whom poor agreement was noticeable, the CAD software has shown a higher average accuracy.ConclusionsFor patients with nodules diagnosed as Bethesda category IV, the software-based characterizations of US features, along with the associated ATA patterns and TIRADS system, were shown helpful in the risk stratification of malignancy.

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Malignancy Risk in RAS-Mutated Cytologically Indeterminate Thyroid Nodules: Real-World Clinical Experience

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1766 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A865-A865

Author(s):

Joseph Lu ◽

Mark Armin Lupo

Keyword(s):

Surgical Resection ◽

Real World ◽

Thyroid Nodules ◽

Standard Procedure ◽

Molecular Testing ◽

Imaging Features ◽

National Guidelines ◽

Ras Mutations ◽

Risk Of Malignancy

Abstract Introduction: Fine needle biopsy (FNB) is the standard procedure for thyroid nodules meeting criteria for biopsy according to current national guidelines (ATA and ACR). However, 15-25% of biopsies are categorized as indeterminate in the Bethesda Categories III (Atypical/FLUS) or IV (Follicular/Hurthle Neoplasm). Molecular testing is a common way to further risk stratify these nodules for surveillance versus surgical resection. BRAF-like mutations have a high probability of malignancy while RAS-like mutations have a variable risk of malignancy. This study examines the performance of RAS mutations in identifying malignancy or NIFTP in a real-world clinical setting. Methods: 2,372 sequential thyroid FNBs were performed in our center from July 2014 to June 2020. Of these, 367 were subjected to molecular testing with either Thyroseq V2 or V3. 55 RAS-mutated BCIII or IV cases were identified and retrospectively evaluated. NIFTP was considered malignant in the calculations. ATA and ACR ultrasound classification as well as Doppler grade of the study nodule were assessed. Results: 8 cases were excluded due to lack of follow-up or incomplete data. 40 underwent surgical resection based on the cytology and molecular results. 7 did not undergo surgery based on patient preference or comorbidities and had clinical follow up with stable ultrasound for at least 6 months. Surgical pathology results: 67.5% benign, 7.5% NIFTP and 25% malignant. All 4 of the Thyroseq “currently negative” RAS nodules were benign. Of the 36 “positive” cases, 6 with additional mutations had a 66.7% ROM and the 30 RAS-only cases had a 30% ROM. Of the 9 RAS-only cases that were not benign, 3 were NIFTP, 5 FVPTC (2 unencapsulated and 3 encapsulated) and 1 was angio-invasive PTC with extensive extrathyroidal extension (this case had high-risk pre-op imaging features). None had lymph node involvement. Higher allelic frequency, abnormal gene expression (GE) and copy number alterations (CNA) all increased the risk of malignancy/NIFTP; ROM was 50% when both GE and CNA were positive. Nodules that were ATA/ACR moderate and high suspicion had an approximately 40% and 67% ROM respectively with ATA and ACR performing similarly. High intra-nodular vascularity conferred a 46% ROM. Conclusions: RAS mutations represent the most frequent abnormality found in oncogene testing however isolated RAS mutations have a low risk of malignancy and when malignant are generally non-aggressive. When both GE and CNA are positive, the risk increases. US features, including Doppler also contribute to risk assessment. Combining all these features is recommended when counseling patients on active surveillance versus surgical resection of RAS-mutated thyroid nodules.

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