Significance of RAS Mutations in Thyroid Benign Nodules and Non-Medullary Thyroid Cancer

Thyroid nodules are detected in up to 60% of people by ultrasound examination. Most of them are benign nodules requiring only follow up, while about 4% are carcinomas and require surgery. Malignant nodules can be diagnosed by the fine-needle aspiration cytology (FNAC), which however yields an indeterminate result in about 30% of the cases. Testing for RAS mutations has been proposed to refine indeterminate cytology. However, the new entity of non-invasive follicular thyroid neoplasm, considered as having a benign evolution and frequently carrying RAS mutations, is expected to lower the specificity of this mutation. The aggressive behavior of thyroid cancer with RAS mutations, initially reported, has been overturned by the recent finding of the cooperative role of TERT mutations. Although some animal models support the carcinogenic role of RAS mutations in the thyroid, evidence that adenomas harboring these mutations evolve in carcinomas is lacking. Their poor specificity and sensitivity make the clinical impact of RAS mutations on the management of thyroid nodules with indeterminate cytology unsatisfactory. Evidence suggests that RAS mutation-positive benign nodules demand a conservative treatment. To have a clinical impact, RAS mutations in thyroid malignancies need not to be considered alone but rather together with other genetic abnormalities in a more general context.

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Highly Sensitive and Specific Molecular Test for Mutations in the Diagnosis of Thyroid Nodules: A Prospective Study of BRAF-Prevalent Population

International Journal of Molecular Sciences ◽

10.3390/ijms21165629 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5629 ◽

Cited By ~ 1

Author(s):

Yoon Young Cho ◽

So Young Park ◽

Jung Hee Shin ◽

Young Lyun Oh ◽

Jun-Ho Choe ◽

...

Keyword(s):

Thyroid Cancer ◽

Prospective Study ◽

Thyroid Nodules ◽

Needle Aspiration ◽

Genetic Alterations ◽

Braf V600e ◽

Molecular Testing ◽

Molecular Test ◽

Indeterminate Cytology ◽

A Prospective Study

Molecular testing offers more objective information in the diagnosis and personalized decision making for thyroid nodules. In Korea, as the BRAF V600E mutation is detected in 70–80% of thyroid cancer specimens, its testing in fine-needle aspiration (FNA) cytology specimens alone has been used for the differential diagnosis of thyroid nodules until now. Thus, we aimed to develop a mutation panel to detect not only BRAF V600E, but also other common genetic alterations in thyroid cancer and to evaluate the diagnostic accuracy of the mutation panel for thyroid nodules in Korea. For this prospective study, FNA specimens of 430 nodules were obtained from patients who underwent thyroid surgery for thyroid nodules. A molecular test was devised using real-time PCR to detect common genetic alterations in thyroid cancer, including BRAF, N-, H-, and K-RAS mutations and rearrangements of RET/PTC and PAX8/PPARr. Positive results for the mutation panel were confirmed by sequencing. Among the 430 FNA specimens, genetic alterations were detected in 293 cases (68%). BRAF V600E (240 of 347 cases, 69%) was the most prevalent mutation in thyroid cancer. The RAS mutation was most prevalently detected for indeterminate cytology. Among the 293 mutation-positive cases, 287 (98%) were diagnosed as cancer. The combination of molecular testing and cytology improved sensitivity from 72% (cytology alone) to 89% (combination), with a specificity of 93%. We verified the excellent diagnostic performance of the mutation panel applicable for clinical practice in Korea. A plan has been devised to validate its performance using independent FNA specimens.

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Benign Aspirates on Follow-Up FNA May Be Enough in Patients with Initial Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance

International Journal of Endocrinology ◽

10.1155/2014/354612 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Ga Ram Kim ◽

Jung Hyun Yoon ◽

Eun-Kyung Kim ◽

Hee Jung Moon ◽

Jin Young Kwak

Keyword(s):

Thyroid Nodules ◽

Surgical Excision ◽

Needle Aspiration ◽

Risk Of Malignancy ◽

Benign Nodules ◽

Benign Thyroid Nodules ◽

Benign Thyroid ◽

Undetermined Significance

Background.Management of thyroid nodules with benign aspirates following atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) is not well established. We reviewed the risk of malignancy and the role of ultrasound (US) features among thyroid nodules with benign results following initial AUS/FLUS diagnoses.Methods.From December 2009 to February 2011, a total of 114 nodules in 114 patients diagnosed as benign on follow-up fine-needle aspiration (FNA) after AUS/FLUS results were included in our study. Eight among 114 nodules were confirmed pathologically and 106 were clinically observed by a follow-up FNA or US. Suspicious US features were defined as markedly hypoechogenicity, irregular or microlobulated margin, presence of microcalcifications, and taller than wide shape.Results.There were 110 (96.5%) benign nodules and 4 (3.5%) malignant nodules. Two (4.8%) among 42 nodules without suspicious US features and 2 (2.8%) out of 72 nodules with suspicious US features were confirmed as malignancy, but there were no significant associations between the malignancy rate and US features (P=0.625).Conclusion.Clinical follow-up instead of surgical excision or continuous repeat FNA may be enough for benign thyroid nodules after AUS/FLUS. The role of US features might be insignificant in the management of these nodules.

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FNAC IN THE MANAGEMENT OF SOLITARY THYROID NODULE

The Professional Medical Journal ◽

10.29309/tpmj/2006.13.04.4934 ◽

2006 ◽

Vol 13 (04) ◽

pp. 596-603

Author(s):

SOHAIL RAZA ◽

HAMAD RAZA ◽

ZAHID SAEED ◽

Mubasher Ahmed

Keyword(s):

Thyroid Nodule ◽

Thyroid Nodules ◽

Fine Needle Aspiration Biopsy ◽

Cost Effective ◽

Needle Aspiration ◽

Military Hospital ◽

Solitary Thyroid Nodule ◽

Benign Nodules ◽

Histopathological Results

Objective: To determine the significant role of FNAC upon other diagnosticmodalities in pre-operative investigations of patients presenting with solitary thyroid nodules and to compare the postoperative histopathological results with the results of FNAC. Design: A Comparative study. Place and Duration ofStudy: Department of Surgery Combined Military Hospital Quetta and Combined Military Hospital Rawalpindi fromDecember 1999 to December 2001. Patients and Methods: In this study 46 patients with solitary thyroid nodule werestudied. Only 2 patients were toxic while remaining 44 were with euthyroid. In this study only one case was suspectedto be malignant clinically out of 5 malignant cases. All 46 patients under went thyroid scanning, ultrasound examinationand fine needle aspiration biopsy and the diagnostic accuracy was assessed. Results: 36 patients (78.26%) wereoperated while 10(21.73%) were managed conservatively. There were 5(10.86%) malignant nodules while 41(89.13%)were benign. All the 5 cases with malignancy were with ‘cold’ nodules on scan as most of others, while ‘solid’ onultrasound examination and so were most of other benign nodules. All cases diagnosed malignant pre-operatively onFNAC, proved to be malignant on histopathology after surgery and the others diagnosed as benign on FNAC provedto be benign. Conclusion: This study shows that conventional investigations for evaluation of solitary thyroid nodulesare inaccurate in identifying the malignant from the benign nodules and their routine use in such patients should beabandoned, while the use of FNAC should be encouraged more in our hospitals as this technique is with high degreeof sensitivity and specificity, cost effective and safe.

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Ultrasound Microvascular Blood Flow Evaluation: A New Tool for the Management of Thyroid Nodule?

International Journal of Endocrinology ◽

10.1155/2019/7874890 ◽

2019 ◽

Vol 2019 ◽

pp. 1-6 ◽

Cited By ~ 5

Author(s):

Carlo Cappelli ◽

Ilenia Pirola ◽

Elena Gandossi ◽

Fiorella Marini ◽

Alessandra Cristiano ◽

...

Keyword(s):

Thyroid Cancer ◽

Thyroid Nodules ◽

Univariate Analysis ◽

Power Doppler ◽

Needle Aspiration ◽

Microvascular Blood Flow ◽

Microvascular Flow ◽

Multivariate Logistic Model ◽

Needle Aspiration Cytology ◽

Benign Nodules

Background. Toshiba Medical System has developed a new Doppler technique [Superb Microvascular Imaging (SMI)] that has improved microvascular flow imaging. SMI depicts perinodular and intranodular thyroid microvascular flow in higher detail compared to standard colour Doppler (CD) and power Doppler (PD) imaging. Objective. Assess the nodular microvascular architecture by SMI compared to CD and PD features in a series of thyroid nodules submitted to fine needle aspiration cytology, in order to evaluate the potential of SMI in detecting thyroid cancer. Materials and Methods. From April 2016 to July 2017, 254 patients with thyroid nodules, evaluated as at high risk for malignancy in agreement with AACE/ACE/AME guidelines, were submitted to cytology. All nodules were previously submitted to ultrasound grayscale, CD, PD, and SMI evaluation. Benign and malignant nodules were stratified in accordance to the number of vessels visualised by SMI: score 1 with a maximum of two blood vessels and score 2 with three or more vessels. Results. Score 1 was found in 59.6% of benign nodules and in 17.9% of malignant nodules, whereas score 2 was found in 40.4% and in 82.1%, respectively (sensitivity 81.7%; specificity 60.5%, p<0.001). Variables significantly associated with malignancy in the univariate analysis were gender (OR, 0.18; 95% CI, 0.08-0.37; p<0.001), vascularity (OR, 1.91; 95% CI, 1.65-3.89; p<0.001), and SMI (OR, 6.72; 95% CI, 3.89-11.59; p<0.001); multivariate logistic model confirmed SMI score 2 as an independent risk factor for malignancy (OR, 6.99; 95% CI, 3.46-12.09; p<0.001). Conclusions. This prospective pilot study showed that SMI can depict intranodular flow in higher detail compared to CDI and PDI, thus improving thyroid cancer detection.

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Estimation of The Fractal Dimension of Thyroid Nodules As A Complementary Diagnostic Tool For Predicting Malignancy

10.21203/rs.3.rs-504905/v1 ◽

2021 ◽

Author(s):

Philippe Lothaire ◽

Pierrick Uzureau ◽

Karim Zouaoui Boudjelta ◽

Nathalie Nagy ◽

Carine Michiels ◽

...

Keyword(s):

Fractal Dimension ◽

Thyroid Cancer ◽

Thyroid Nodules ◽

Thyroid Tissue ◽

High Sensitivity ◽

Needle Aspiration ◽

Ultrasound Images ◽

Visual Interpretation ◽

Normal Tissues ◽

Benign Nodules

Abstract PurposeUltrasound-guided fine-needle aspiration is the most sensitive investigation procedure in the evaluation of patients with thyroid nodules; however, despite the level of achieved precision, it is still impossible to preoperatively discriminate between follicular adenomas and carcinomas. Thus, no current detection tool of thyroid nodule has both high sensitivity and high positive predictive value for the diagnosis of thyroid cancer. Ultrasound images provide information that are currently missed due to visual interpretation, including the roughness of the echotexture. However, such information can be retrieved using the measurement of the fractal dimension (FD).Material and methodsAccording to the box-counting method, we measured the FD of the echotexture of ultrasound images of 13 benign thyroid nodules and 14 malignant thyroid nodules compared to normal thyroid tissue from 10 men and 16 women (mean age 40).ResultsThe difference of the FD value between malignant nodules (median FD 2.31) and corresponding normal tissues (median FD 2.184) was significant (p<0.001) while the FD values for the benign nodules (median FD 2.21) and for corresponding normal tissues (median FD 2.231) could not be distinguished (p=0.78).ConclusionsThis preliminary work revealed that FD would be an additional feature to discriminate benign from malignant nodules. A larger sampling is now required to confirm the possible utilization of FD in the thyroid cancer diagnosis in clinical practice.

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Malignancy Analyses of Thyroid Nodules in Patients Subjected to Surgery with Cytological- and Ultrasound-Based Risk Stratification Systems

Endocrines ◽

10.3390/endocrines1020010 ◽

2020 ◽

Vol 1 (2) ◽

pp. 102-118

Author(s):

Stefania Giuliano ◽

Maria Mirabelli ◽

Eusebio Chiefari ◽

Margherita Vergine ◽

Rita Gervasi ◽

...

Keyword(s):

Thyroid Cancer ◽

Risk Stratification ◽

Clinical Features ◽

Fine Needle Aspiration ◽

Thyroid Surgery ◽

Thyroid Nodules ◽

Needle Aspiration ◽

American Thyroid Association ◽

Fine Needle ◽

Indeterminate Cytology

The fine needle aspiration (FNA) cytology is the gold standard for the preoperative diagnosis of thyroid cancer. However, up to 30% of FNA examinations yield nondiagnostic or indeterminate results and this complicates patient management. Clinical features and ultrasound (US) patterns, including US risk stratification systems, could be useful in the preoperative diagnostic workup and prediction of malignancy, but the evidences are not univocal. Methods: 400 consecutive patients subjected to thyroid surgery were retrospectively enrolled at our institution in Calabria, Southern Italy. Preoperative US and FNA cytological descriptions, formulated according to the “Italian consensus for reporting thyroid fine-needle aspiration cytology” (ICCRTC) classification and three US risk stratification systems (those developed by the American Association of Clinical Endocrinologists, American College of Endocrinology and Associazione Medici Endocrinologi (AACE/ACE/AME), American Thyroid Association (ATA), and American College of Radiology (ACR-TIRADS)), were collected, along with histological results. Results: 147 thyroid cancer cases, in large majority papillary carcinomas, were detected on final histological examination. Almost two-thirds of patients subjected to thyroid surgery for either benign or malignant lesions were female. Patient’s age ≤20 years and between 21–30 years were clinical features associated with increased risk of thyroid cancer in logistic regression analyses. US features associated with thyroid cancer included irregular margins, solid composition, microcalcifications, and marked hypoechogenicity. The AACE/ACE/AME, ATA, and ACR-TIRADS risk categories, corresponding to specific US patterns, were strong predictors of malignancy in both genders, but not in nodules with indeterminate cytology. A measured difference between the longitudinal (L) and the anteroposterior (AP) diameter >5 mm, a proxy for a parallel-oriented oval shape of a nodule, emerged as a robust protective factor against thyroid cancer (OR 0.288 (95%CI 0.817–0.443); p < 0.001), regardless of cytological risk. Conclusions: Some, but not all, well-established predictors of TC have been confirmed in this study. Controversy surrounds the diagnostic performance of US risk stratification systems for the detection of thyroid cancer in the subgroup of nodules with indeterminate cytology, suggesting their use only to set the thresholds for FNA. A measured difference between L and AP diameters >5 mm may represent an additional and practical tool for ruling out malignancy in thyroid nodules, with the potential to reduce unnecessary surgical procedures.

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Role of Midkine in Predicting Malignancy in Patient with Solitary Thyroid Nodule

Journal of Cancer and Tumor International ◽

10.9734/jcti/2019/v9i230102 ◽

2019 ◽

pp. 1-10

Author(s):

Nesma A. Ibrahim ◽

Ahmed M. Hamam

Keyword(s):

Thyroid Nodule ◽

Thyroid Nodules ◽

Clinical Problem ◽

Needle Aspiration ◽

Heparin Binding ◽

Significant Difference ◽

Solitary Thyroid Nodule ◽

Needle Aspiration Cytology ◽

Benign Nodules

Background: Solitary thyroid nodules are a common clinical problem. None of sonographic features is sufficient to discard or detect malignancy efficiently. Midkine is a novel heparin-binding growth factor, plays critical roles in carcinogenesis. In this study, we aimed to evaluate serum midkine levels in patients with solitary thyroid nodules to predict malignancy. Methods: A total of 100 patients who had solitary thyroid nodules were enrolled in the study. Serum midkine levels were measured. Fine needle aspiration cytology was done to all nodules (25 suspicious/ malignant and 75 benign). Results: Serum midkine levels were significantly higher in patients who had nodules with the following sonographic features; hypoechoic nodules compared to isoechoic and hyperechoic nodules (P=0.024), nodules with microcalcification compared to nodules with macrocalcification or without calcification (P = 0.011), nodules with irregular borders compared to nodules with regular borders (P = 0.014) and nodules more than 2 cm in length than shorter ones (P = 0.011). Serum midkine levels were also higher in nodules with absent halo compared to those with clear halo but with no significant difference (P = 0.660). Also, levels of serum medikine were significantly higher in suspicious/ malignant nodules than in benign nodules (P < 0.001). Conclusion: Serum midkine can predict malignancy in solitary thyroid nodule and also well correlated with sonographic features of thyroid nodules. We suggest that midkine levels may serve as a novel biochemarker in association with sonographic features in evaluation of solitary thyroid nodules.

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Can sonographic features of microcalcification predict thyroid nodule malignancy? a prospective observational study

Egyptian Journal of Radiology and Nuclear Medicine ◽

10.1186/s43055-021-00498-x ◽

2021 ◽

Vol 52 (1) ◽

Author(s):

Mehrdad Nabahati ◽

Rahele Mehraeen ◽

Zoleika Moazezi ◽

Naser Ghaemian

Keyword(s):

Thyroid Nodule ◽

Roc Analysis ◽

Thyroid Nodules ◽

Area Under The Curve ◽

Positive Association ◽

Needle Aspiration ◽

Northern Iran ◽

Significant Positive Association ◽

Irregular Margin ◽

Benign Nodules

Abstract Background The aim of this study was to investigate the diagnostic accuracy of microcalcification, as well as its associated sonographic features, for prediction of thyroid nodule malignancy. We prospectively assessed the patients with thyroid nodule, who underwent ultrasound-guided fine-needle aspiration during 2017–2020 in Babol, northern Iran. The ultrasonographic characteristics of the nodules, as well as their cytological results, were recorded. We used regression analysis to evaluate the relation between sonographic findings and nodule malignancy. A receiver operator characteristics (ROC) analysis was also used to estimate the ability of ultrasound to predict the characteristic features of malignancy, as estimated by the area under the curve (AUC). Results Overall, 1129 thyroid nodules were finally included in the study, of which 452 (40%) had microcalcification. A significant positive association was found between nodule malignancy and microcalcification in both univariate (OR=3.626, 95% CI 2.258–5.822) and multivariable regression analyses (OR=1.878, 95% CI 1.095–3.219). In the nodules with microcalcification, significant positive relations were seen between malignancy and hypoechogenicity (OR=3.833, 95% CI 1.032–14.238), >5 microcalcification number (OR=3.045, 95% CI 1.328–6.982), irregular margin (OR=3.341, 95% CI 1.078–10.352), and lobulated margin (OR=5.727, 95% CI 1.934–16.959). The ROC analysis indicated that AUC for hypoechogenicity, >5 microcalcification number, irregular margin, and lobulated margin were 60%, 62%, 55%, and 60%, respectively, in predicting malignant thyroid nodules. Conclusion The findings indicated that microcalcification can be a potential predictor of thyroid nodule malignancy. Also, the presence of irregular or lobulated margins, multiple intranodular microcalcification (>5 microcalcifications), and/or hypoechogenicity can improve the ability of microcalcification in distinguishing malignant from benign nodules.

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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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Molecular Diagnostics of Thyroid Tumors

Archives of Pathology & Laboratory Medicine ◽

10.5858/2010-0664-rair.1 ◽

2011 ◽

Vol 135 (5) ◽

pp. 569-577 ◽

Cited By ~ 2

Author(s):

Yuri E. Nikiforov

Keyword(s):

Thyroid Cancer ◽

Molecular Markers ◽

Fine Needle Aspiration ◽

Thyroid Nodules ◽

Needle Aspiration ◽

Genetic Alterations ◽

Braf V600e ◽

Fine Needle ◽

Molecular Alterations ◽

Diagnostic Use

Abstract Context.—Thyroid cancer is the most common type of endocrine malignancy and its incidence is steadily increasing. Papillary carcinoma and follicular carcinoma are the most common types of thyroid cancer and represent those tumor types for which use of molecular markers for diagnosis and prognostication is of high clinical significance. Objective.—To review the most common molecular alterations in thyroid cancer and their diagnostic and prognostic utility. Data Sources.—PubMed (US National Library of Medicine)–available review articles, peer-reviewed original articles, and experience of the author. Conclusions.—The most common molecular alterations in thyroid cancer include BRAF and RAS point mutations and RET/PTC and PAX8/PPARγ rearrangements. These nonoverlapping genetic alterations are found in more than 70% of papillary and follicular thyroid carcinomas. These molecular alterations can be detected in surgically resected samples and fine-needle aspiration samples from thyroid nodules and can be of significant diagnostic use. The diagnostic role of BRAF mutations has been studied most extensively, and recent studies also demonstrated a significant diagnostic utility of RAS, RET/PTC, and PAX8/PPARγ mutations, particularly in thyroid fine-needle aspiration samples with indeterminate cytology. In addition to the diagnostic use, BRAF V600E mutation can also be used for tumor prognostication, as this mutation is associated with higher rate of tumor recurrence and tumor-related mortality. The use of these and other emerging molecular markers is expected to improve significantly the accuracy of cancer diagnosis in thyroid nodules and allow more individualized surgical and postsurgical management of patients with thyroid cancer.

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