Role of Ultrasonographic/Clinical Profile, Cytology, and BRAF V600E Mutation Evaluation in Thyroid Nodule Screening for Malignancy: A Prospective Study

Abstract Context: Ultrasound (US)-guided fine-needle aspiration biopsy (FNAB) is the most reliable nonsurgical test for distinguishing benign from malignant thyroid nodules. However, there is no consensus on which nodules should undergo FNAB. Aims: The aims of this study were to evaluate the utility of US-guided FNAB in the diagnostic assessment of nodules with or without clinical/US features suggestive for malignancy and to investigate the additional contribution of BRAF V600E mutation analysis in the detection of differentiated thyroid cancer. Design and Methods: Thyroid cytoaspirates from 2421 nodules at least 4 mm in diameter were performed in 1856 patients who underwent cytological evaluation and biomolecular analysis. Results: Cytology showed high positive predictive value and specificity for the diagnosis of malignant lesions. BRAF V600E mutation was found in 115 samples, 80 of which were also cytologically diagnosed as papillary thyroid cancer. BRAF mutation analysis significantly enhanced the diagnostic value of cytology, increasing FNAB diagnostic sensitivity for malignant nodules by approximately 28%. Micro PTC (63% of diagnosed papillary thyroid carcinoma) showed a high prevalence of multifocality, extrathyroidal extension, and lymph node metastases, underlining the malignant potential of thyroid microcarcinomas. Each investigated US/clinical characteristic of suspected malignancy correlated with the presence of a thyroid cancer in thyroid nodules with diameter of at least 4 mm. Conclusions: These data indicate that nodules of at least 4 mm may underlie a thyroid cancer independently of US/clinical characteristics of suspected malignancy, suggesting the need to perform FNAB. The diagnostic sensitivity for thyroid cancer is significantly increased by BRAF V600E mutation analysis, indicating that the screening for BRAF mutation in FNAB samples has a relevant diagnostic potential.

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Association Between BRAF V600E Mutation and Recurrence of Papillary Thyroid Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2014.56.8253 ◽

2015 ◽

Vol 33 (1) ◽

pp. 42-50 ◽

Cited By ~ 238

Author(s):

Mingzhao Xing ◽

Ali S. Alzahrani ◽

Kathryn A. Carson ◽

Young Kee Shong ◽

Tae Yong Kim ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Multicenter Study ◽

Braf Mutation ◽

Prognostic Value ◽

Braf V600e Mutation ◽

Braf V600e ◽

Disease Stage ◽

Papillary Thyroid ◽

Recurrence Rates

Purpose To investigate the prognostic value of BRAF V600E mutation for the recurrence of papillary thyroid cancer (PTC). Patients and Methods This was a retrospective multicenter study of the relationship between BRAF V600E mutation and recurrence of PTC in 2,099 patients (1,615 women and 484 men), with a median age of 45 years (interquartile range [IQR], 34 to 58 years) and a median follow-up time of 36 months (IQR, 14 to 75 months). Results The overall BRAF V600E mutation prevalence was 48.5% (1,017 of 2,099). PTC recurrence occurred in 20.9% (213 of 1,017) of BRAF V600E mutation–positive and 11.6% (125 of 1,082) of BRAF V600E mutation–negative patients. Recurrence rates were 47.71 (95% CI, 41.72 to 54.57) versus 26.03 (95% CI, 21.85 to 31.02) per 1,000 person-years in BRAF mutation–positive versus –negative patients (P < .001), with a hazard ratio (HR) of 1.82 (95% CI, 1.46 to 2.28), which remained significant in a multivariable model adjusting for patient sex and age at diagnosis, medical center, and various conventional pathologic factors. Significant association between BRAF mutation and PTC recurrence was also found in patients with conventionally low-risk disease stage I or II and micro-PTC and within various subtypes of PTC. For example, in BRAF mutation–positive versus –negative follicular-variant PTC, recurrence occurred in 21.3% (19 of 89) and 7.0% (24 of 342) of patients, respectively, with recurrence rates of 53.84 (95% CI, 34.34 to 84.40) versus 19.47 (95% CI, 13.05 to 29.04) per 1,000 person-years (P < .001) and an HR of 3.20 (95% CI, 1.46 to 7.02) after adjustment for clinicopathologic factors. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories. Conclusion This large multicenter study demonstrates an independent prognostic value of BRAF V600E mutation for PTC recurrence in various clinicopathologic categories.

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Significance of BRAF V600E Mutation and Cytomorphological Features for the Optimization of Papillary Thyroid Cancer Diagnostics in Cytologically Indeterminate Thyroid Nodules

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-0588-4885 ◽

2018 ◽

Vol 127 (04) ◽

pp. 247-254 ◽

Cited By ~ 2

Author(s):

Augustas Beiša ◽

Mindaugas Kvietkauskas ◽

Virgilijus Beiša ◽

Mindaugas Stoškus ◽

Elvyra Ostanevičiūtė ◽

...

Keyword(s):

Logistic Regression ◽

Thyroid Cancer ◽

Logistic Regression Model ◽

Thyroid Nodules ◽

Needle Aspiration ◽

Braf V600e Mutation ◽

Braf V600e ◽

Papillary Thyroid ◽

Mutation Status ◽

Fine Needle

Abstract Background Ultrasound guided fine needle aspiration biopsy with cytologic analysis is an initial step in diagnostic of thyroid nodules. Unfortunately, up to 30% of biopsies are indeterminate and diagnostic surgery is required. The aim of this study was to estimate the diagnostic value of BRAF V600E mutation status combined with cytomorphological features for diagnosis of papillary thyroid cancer (PTC) in cytologically indeterminate thyroid nodules. Methods A prospective study analyzed patients who had ultrasound suspicious thyroid nodules, underwent fine needle aspiration and cytological examination, and were classified according to the Bethesda system. Patients from indeterminate diagnostic categories were examined for BRAF V600E mutation and 22 cytomorphological features, and underwent thyroid surgery. A binary logistic regression model was used to evaluate the diagnostic utility. Results A total of 219 patients met study criteria. After histological examination, 77 (35.2%) patients were diagnosed with PTC and 142 (64.8%) with benign nodular thyroid disease. According to logistic regression model, significant features for PTC diagnosis were: liquid colloid consistency, papillary structures, eosinophilic colloid bodies, and BRAF V600E mutation. Risk groups classified by this model have sensitivity of 80.5% (95% CI: 69.9 to 88.7), specificity of 99.3% (95% CI: 96.1 to 100), positive predictive value of 98.4% (95% CI: 89.8 to 99.8), negative predictive value of 90.4% (95% CI: 85.7 to 93.7), and accuracy of 92.7% (95% CI: 88.4 to 95.8) for PTC diagnosis. Conclusions Evaluation of BRAF V600E mutation status combined with cytomorphological features for diagnosis of PTC in cytologically indeterminate thyroid nodules can significantly improve diagnostic accuracy and reduce the number of diagnostic operations (calculator available at www.ptc-calc.we2host.lt).

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Correlation between F18-FDG PET/CT Imaging and BRAF V600E Genetic Mutation for the Early Assessment of Treatment Response in Papillary Thyroid Cancers

Journal of Personalized Medicine ◽

10.3390/jpm10020052 ◽

2020 ◽

Vol 10 (2) ◽

pp. 52

Author(s):

Andra Piciu ◽

Maria-Iulia Larg ◽

Doina Piciu

Keyword(s):

Thyroid Cancer ◽

Prognostic Factors ◽

Papillary Thyroid Cancer ◽

Genetic Mutation ◽

Braf V600e Mutation ◽

Braf V600e ◽

Papillary Thyroid ◽

Early Assessment ◽

Pet Ct ◽

Ct Evaluation

In thyroid neoplastic pathology, the BRAF V600E mutation is shown to be involved in the oncogenesis of papillary thyroid cancer and its subtypes. The purpose of this study is to evaluate the correlation between the mutation of the BRAF V600E oncogene and the pathological standardized uptake values (SUV) at the F18-fluorodeoxyglucose (F18-FDG) positron emission tomography/computed tomography (PET/CT) evaluation, for a group of 20 patients with radically treated (total thyroidectomy and radioiodine therapy) papillary thyroid cancer, with subclinical persistent disease, at 6 months after the initial treatment. We analyzed the correlations between the values of SUV and the presence of the BRAF mutation as well with other prognostic factors such as stage, age, specific tumor markers (thyroglobulin and anti-thyroglobulin), extrathyroid extension, the presence of metastatic lymph nodes or distant metastasis. The value of SUV in the case of BRAF+ (positive) patients was higher than in the negative ones, but without statistical significance, thus, the values of the SUV cannot be a predictable factor for the presence of the genetic mutation. There was a statistically significant correlation in BRAF+ subgroup between the SUV values and the positive resection limit following surgery, showing a higher SUV value in the PET/CT evaluation. No correlation was observed between the aforementioned prognostic factors involved in papillary thyroid cancer and the BRAF V600E mutation.

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The BRAF V600E mutation is a predictor of the effect of radioiodine therapy in papillary thyroid cancer

Journal of Cancer ◽

10.7150/jca.33105 ◽

2020 ◽

Vol 11 (4) ◽

pp. 932-939 ◽

Cited By ~ 13

Author(s):

Junshang Ge ◽

Jie Wang ◽

Hui Wang ◽

Xianjie Jiang ◽

Qianjin Liao ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Radioiodine Therapy ◽

Braf V600e Mutation ◽

Braf V600e ◽

Papillary Thyroid

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BRAF V600E Mutation Independently Predicts Central Compartment Lymph Node Metastasis in Patients with Papillary Thyroid Cancer

Annals of Surgical Oncology ◽

10.1245/s10434-012-2611-0 ◽

2012 ◽

Vol 20 (1) ◽

pp. 47-52 ◽

Cited By ~ 78

Author(s):

Gina M. Howell ◽

Marina N. Nikiforova ◽

Sally E. Carty ◽

Michaele J. Armstrong ◽

Steven P. Hodak ◽

...

Keyword(s):

Thyroid Cancer ◽

Lymph Node ◽

Lymph Node Metastasis ◽

Papillary Thyroid Cancer ◽

Central Compartment ◽

Braf V600e Mutation ◽

Braf V600e ◽

Papillary Thyroid ◽

Node Metastasis

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BRAF V600E Mutation Independently Predicts Central Compartment Lymph Node Metastasis in Patients with Papillary Thyroid Cancer

Annals of Surgical Oncology ◽

10.1245/s10434-012-2614-x ◽

2012 ◽

Vol 20 (1) ◽

pp. 3-4 ◽

Cited By ~ 7

Author(s):

Martha A. Zeiger ◽

Eric B. Schneider

Keyword(s):

Thyroid Cancer ◽

Lymph Node ◽

Lymph Node Metastasis ◽

Papillary Thyroid Cancer ◽

Central Compartment ◽

Braf V600e Mutation ◽

Braf V600e ◽

Papillary Thyroid ◽

Node Metastasis

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BRAF V600E Mutation Analysis in Papillary Thyroid Carcinomas by Peptide Nucleic Acid Clamp Real-time PCR

Annals of Surgical Oncology ◽

10.1245/s10434-012-2494-0 ◽

2012 ◽

Vol 20 (3) ◽

pp. 759-766 ◽

Cited By ~ 31

Author(s):

Dongjun Jeong ◽

Yujun Jeong ◽

Ji Hye Park ◽

Sun Wook Han ◽

Sung Yong Kim ◽

...

Keyword(s):

Nucleic Acid ◽

Real Time ◽

Mutation Analysis ◽

Real Time Pcr ◽

Peptide Nucleic Acid ◽

Braf V600e Mutation ◽

Braf V600e ◽

Papillary Thyroid ◽

Thyroid Carcinomas

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Highly accurate NGS-based multi-gene testing in the diagnosis of thyroid nodules with indeterminate cytology.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13579 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13579-e13579

Author(s):

Yuntao Song ◽

Bin Zhang ◽

Tonghui Ma

Keyword(s):

Next Generation Sequencing ◽

Mutation Analysis ◽

Predictive Value ◽

Thyroid Nodules ◽

Braf V600e Mutation ◽

Braf V600e ◽

Gene Testing ◽

Indeterminate Cytology ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

e13579 Background: Thyroid nodules are highly prevalent, Fine-needle aspiration (FNA) is the standard pre-operative tool for diagnosis. However, some of the samples are classified as indeterminate, which leads to unnecessary surgery. BRAF V600E mutation is often used as a diagnostic marker for thyroid cancer, and it is highly specific for papillary thyroid carcinoma (PTC). But BRAF mutation is rarely occurred in thyroid nodules with indeterminate cytology. To diagnose the indeterminate thyroid nodules precisely, some NGS-based multi-gene testing panel has been developed and clinically used in America and Europe, but rare research was reported in China. In this study, we evaluated the value of a next-generation sequencing (NGS) panel to cancer diagnosis in indeterminate thyroid nodules. Methods: From February 2018 to September 2018, 360 patients with thyroid nodules who underwent FNA at Peking University Cancer Hospital were enrolled. And the FNA samples with indeterminate cytology were evaluated using a next-generation sequencing (NGS) assay, including 16 genes analyzed for point mutations and 26 types of gene fusions. Diagnostic performance of this multi-gene testing panel was compared with BRAF V600E single gene mutation analysis. Results: 141 nodules were cytologically indeterminate among 360 patients on FNA biopsy, 72 of which were resected and analyzed by NGS successfully. Histologic analysis after surgery revealed 41 (56.9%) cancers in these 72 patients. The multi-gene testing assay could classify 30/41 cancers correctly, showing a sensitivity of 73.2%, specificity of 96.8%, positive predictive value of 96.8%, and negative predictive value of 73.2%. The diagnostic accuracy of the multi-gene testing was significantly higher than the BRAF V600E mutation analysis (83.3% vs 73.6%, x2= 31.588, p < 0.01). Conclusions: Our study demonstrated that the multi-gene testing provided both high sensitivity and high specificity for cancer detection in thyroid nodules with indeterminate cytology, and its accuracy was much higher than BRAF V600E mutation test.

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