Molecular testing of <i>BRAF, RAS</i> and <i>TERT</i> on thyroid FNAs with indeterminate cytology improves diagnostic accuracy

Decaussin‐Petrucci, Myriam; Descôtes, Françoise; Depaepe, L.; Lapras, V.; Denier, Marie-Laure; Borson‐Chazot, Françoise; Lifante, Jean Christophe; Lopez, Jonathan

doi:10.1111/cyt.12493

Cited by 54 publications

(60 citation statements)

References 34 publications

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“…Most publications included in our study accrued patients before the formal recognition of NIFTP, and these neoplasms would have been labeled follicular variant of PTCs and considered malignant. Of the publications in our analysis that reported NIFTP histology in their results (22,27,37,46,48,53,54,63,69), we considered them as ''malignant'' for statistical purposes, consistent with the current desire that they undergo surgical resection as opposed to in situ observation. Thus, PPVs in our study estimate the combined probably of cancer or NIFTP.…”

Section: Limitationsmentioning

confidence: 99%

Molecular Variants and Their Risks for Malignancy in Cytologically Indeterminate Thyroid Nodules

Goldner

Angell

McAdoo

et al. 2019

Thyroid

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Background: Gene panels are routinely used to assess predisposition to hereditary cancers by simultaneously testing multiple susceptibility genes and/or variants. More recently, genetic panels have been implemented as part of solid tumor malignancy testing assessing somatic alterations. One example is targeted variant panels for thyroid nodules that are not conclusively malignant or benign upon fine-needle aspiration (FNA). We systematically reviewed published studies from 2009 to 2018 that contained genetic data from preoperative FNA specimens on cytologically indeterminate thyroid nodules (ITNs) that subsequently underwent surgical resection. Pooled prevalence estimates per gene and variant, along with their respective positive predictive values (PPVs) for malignancy, were calculated. Summary: Our systematic search identified 540 studies that were supplemented by 18 studies from bibliographies or personal files. Sixty-one studies met all inclusion criteria and included >4600 ITNs. Overall, 26% of nodules contained at least 1 variant or fusion. However, half of them did not include details on the specific gene, variant, and/or complete fusion pair reported for inclusion toward PPV calculations. The PPVs of genomic alterations reported at least 10 times were limited to BRAF V600E (98%, 95% confidence interval [CI 96-99%]), PAX8/ PPARG (55% [CI 34-78%]), HRAS Q61R (45% [CI 22-72%]), BRAF K601E (42% [CI 19-68%]), and NRAS Q61R (38% [CI 23-55%]). Excluding BRAF V600E , the pooled PPV for all other specified variants and fusions was 47%. Multiple variants within the same nodule were identified in *1% of ITN and carried a cumulative PPV of 77%. Conclusions: The chance that a genomic alteration predicts malignancy depends on the individual variant or fusion detected. Only five alterations were reported at least 10 times; BRAF V600E had a PPV of 98%, while the remaining four had individual PPVs ranging from 38% to 55%. The small sample size of most variants and fusion pairs found among ITNs, however, limits confidence in their individual PPV point estimates. Better specific reporting of genomic alterations with cytological category, histological subtype, and cancer staging would facilitate better understanding of cancer prediction, and the independent contribution of the genomic profile to prognosis.

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Section: Limitationsmentioning

confidence: 99%

Molecular Variants and Their Risks for Malignancy in Cytologically Indeterminate Thyroid Nodules

Goldner

Angell

McAdoo

et al. 2019

Thyroid

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“…Although >90% of thyroid nodules are non-neoplastic, 10 In this study, we reported the results of a prospective molecular analysis on 141 cytological samples of thyroid nodules with an indeterminate or frankly malignant cytological diagnosis to attempt a better management of the patients. Although this study concerns a small case series compared to more extensive studies, [28][29][30] possibility to perform molecular tests with an innovative, easy and low-cost method.…”

Section: Discussionmentioning

confidence: 99%

Impact of ultrasonographic features, cytomorphology and mutational testing on malignant and indeterminate thyroid nodules on diagnostic accuracy of fine needle cytology samples: A prospective analysis of 141 patients

Fulciniti

Campanile

Malzone³

et al. 2019

Clinical Endocrinology

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractObjective: Fine needle cytology (FNC) is the first-line diagnostic method to determine the benign or malignant nature of thyroid nodules. The gray zone of cytological classifications remains, however, a crucial and challenging area for cytopathologists. Design, patients and measurements:In the present study, 141 thyroid cytological samples, with ultrasonographic suspicious features, have been prospectively analysed. Molecular analyses were performed by an innovative technology using two multiplex PCRs for the amplification of BRAF, N-H-K-RAS and RET exon genes. RNA samples were studied for RET/PTC1 and RET/PTC3 rearrangements by PCR amplification, and the conditions were set-up to study, with a single experiment, both wildtype PAX8 and PAX8/PPARɣ rearrangements. In total, 111 samples were examined for BRAF, N-H-K-RAS and RET genes. An ultrasonographic, cytological and molecular correlation was also carried out in an attempt to suggest a possible way to manage the patients with thyroid nodules. Cyto-histological correlation was available in 115 cases, and it was used to verify the global diagnostic accuracy of this combined approach.Results: According to the histopathological diagnosis, FNC accuracy was 100% for TIR5 and metastases; 89% for TIR4; 84% for TIR3A and 58% for TIR3B. About 11% of the studied samples showed either RET-PTC1 or RET/PTC3 chromosomal rearrangements, and only one sample simultaneously presented RET/PTC1 and RET/PTC3 rearrangements. PAX8/PPARɣ rearrangement was found in 6% of the samples. Conclusions:A multidisciplinary approach to the thyroid is therefore necessary to develop innovative methods suitable for an improved diagnostic and prognostic definition of thyroid cancer.

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“…All of them were diagnosed with thyroid carcinoma, although it was not statistically significant due to the small sample size. Decaussin-Petrucci, et al 14) reported that neuroblastoma rat sarcoma (NRAS), harvey rat sarcoma (HRAS), and telomerase reverse transcriptase (TERT) gene mutations are strong predictors of malignancy regardless of the cytological classification according to the Bethesda system. According to the study in 61 AUS nodules, NRAS/HRAS mutations were significantly more frequent in malignant nodules and BRAF V600E mutation was not.…”

Section: Discussionmentioning

confidence: 99%

“…Although some previous reports suggested possible predictive factors, these studies enrolled very small patient numbers. 13,14) A large cohort study of AUS nodules followed by surgical pathologic confirmation providing statistically significant predictors for malignancy has not yet been reported.…”

Section: Introductionmentioning

confidence: 99%

BRAFV600E Mutation is a Strong Preoperative Indicator for Predicting Malignancy in Thyroid Nodule Patients with Atypia of Undetermined Significance Identified by Fine Needle Aspiration

Choi¹,

Choi²,

Cho³

et al. 2018

Korean J Otorhinolaryngol-Head Neck Surg

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Background and Objectives This study aimed to identify a reliable preoperative predictive factor for the development of thyroid cancer in patients with atypia of undetermined significance (AUS) identified by fine needle aspiration biopsy (FNAB). Subjects and Method This was a retrospective cohort study. Two hundred and ninety-nine patients diagnosed with AUS by preoperative FNAB who underwent curative thyroid surgery at our institution between September 2005 and February 2014 were analyzed. Clinical, radiological and molecular features were investigated as preoperative predictors for postoperative permanent malignant pathology. Results The final pathologic results revealed 36 benign tumors including nodular hyperplasia, follicular adenoma, adenomatous goiter, nontoxic goiter, and lymphocytic thyroiditis, as well as 263 malignant tumors including 1 follicular carcinoma and 1 invasive follicular carcinoma; the rest were papillary thyroid carcinomas. The malignancy rate was 87.9%. The following were identified as risk factors for malignancy by univariate analysis: BRAF V600E gene mutation, specific ultrasonographic findings including smaller nodule size, low echogenicity of the nodule, and irregular or spiculated margin (p＜0.05). Multivariate analysis revealed that only BRAF V600E mutation was a statistically significant risk factor for malignancy (p＜0.05). When BRAF V600E mutation was positive, 98.5% of enrolled patients developed malignant tumors. In addition, the diagnostic rate of malignancy in these cases was approximately 16-fold higher than BRAF-negative cases. Conclusion Patients with AUS thyroid nodules should undergo BRAF V600E gene mutation analysis to improve diagnostic accuracy and if the mutation is confirmed, surgery is recommended due to the high risk of malignancy.

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Molecular testing of BRAF, RAS and TERT on thyroid FNAs with indeterminate cytology improves diagnostic accuracy

Abstract: Mutation profiling can be successfully performed on thyroid LB-FNA without any dedicated sample in a pathology laboratory. It is an easy way to improve diagnostic accuracy of routine LB-FNA and may help to better select patients for surgery and to avoid unnecessary thyroidectomies.

Cited by 54 publications

References 34 publications

Molecular Variants and Their Risks for Malignancy in Cytologically Indeterminate Thyroid Nodules

Molecular Variants and Their Risks for Malignancy in Cytologically Indeterminate Thyroid Nodules

Impact of ultrasonographic features, cytomorphology and mutational testing on malignant and indeterminate thyroid nodules on diagnostic accuracy of fine needle cytology samples: A prospective analysis of 141 patients

BRAFV600E Mutation is a Strong Preoperative Indicator for Predicting Malignancy in Thyroid Nodule Patients with Atypia of Undetermined Significance Identified by Fine Needle Aspiration

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