Performance of a Genomic Sequencing Classifier for the Preoperative Diagnosis of Cytologically Indeterminate Thyroid Nodules

Patel, Kepal N.; Angell, Trevor E.; Babiarz, Joshua E.; Barth, Neil M.; Blevins, Thomas; Duh, Quan‐Yang; Ghossein, Ronald; Harrell, R. Mack; Huang, Jing; Kennedy, Giulia C.; Kim, Su Yeon; Kloos, Richard T.; LiVolsi, Virginia A.; Randolph, Gregory W.; Sadow, Peter M.; Shanik, Michael H.; Sosa, Julie Ann; Traweek, S. Thomas; Walsh, P. Sean; Whitney, Duncan; Yeh, Michael W.; Ladenson, Paul W.

doi:10.1001/jamasurg.2018.1153

Cited by 278 publications

(310 citation statements)

References 50 publications

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“…The actual incidence of thyroid cancer in these nodules is quite low. Only 5‐15% of cases are confirmed to be malignant . With its high sensitivity and specificity, FNA is now standard of care .…”

Section: Introductionmentioning

confidence: 99%

“…The Afirma Thyroid FNA Analysis is a proprietary test developed by Veracyte, Inc. (San Francisco, CA). It encompasses the original Gene Expression Classifier (GEC) and the newly modified Genomic Sequencing Classifier (GSC) . Since 2012, Afirma has been the pioneer in commercial testing platforms offered as a molecular adjunct to indeterminate aspirates …”

Section: Introductionmentioning

confidence: 99%

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Risk of malignancy and neoplasia predicted by three molecular testing platforms in indeterminate thyroid nodules on fine‐needle aspiration

Partyka

Trevino

Randolph

et al. 2019

Diagnostic Cytopathology

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BACKGROUND The management of thyroid nodules with indeterminate cytology is challenging. Recently, molecular testing on fine‐needle aspirates (FNAs) has been advocated to determine whether clinical follow‐up or surgery is warranted for patients. Three different testing platforms were performed on aspirates from our institution (Afirma Thyroid FNA Analysis, RosettaGX Reveal, and Interpace ThyGenX/ThyraMIR). This study compares their diagnostic efficacy. METHODS We conducted a retrospective analysis of indeterminate thyroid FNAs with correlating molecular testing over 4 years (2015‐2018). The aspirates included diagnoses of follicular lesion of undetermined significance, follicular neoplasm, or suspicious for malignancy (SM). Based on cases that underwent surgical resection (Afirma, n = 37; Rosetta, n = 19; Interpace, n = 14), we calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for risk of malignancy and neoplasia. RESULTS The three tests performed similarly when predicting risk of malignancy. They showed high sensitivity (80‐100%) and NPV (90‐100%) but lower specificity (10‐64%) and PPV (21‐44%). When assessing their value to predict neoplasia, each test had a high PPV (76‐89%) but low NPV (20‐33%). The sensitivity for neoplasm was intermediate to high (50‐93%), and the specificity remained extremely variable (11‐67%). CONCLUSION Overall, these molecular platforms performed similarly, displaying high NPV but low to intermediate PPV for malignancy and low NPV but high PPV for neoplasm. The risk of neoplasm is a good index for surgery, and we argue that many of the neoplasms are low‐risk tumors. We endorse conservative treatment with lobectomy for cases that are indeterminate at FNA but suspicious by molecular testing.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Risk of malignancy and neoplasia predicted by three molecular testing platforms in indeterminate thyroid nodules on fine‐needle aspiration

Partyka

Trevino

Randolph

et al. 2019

Diagnostic Cytopathology

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“…7-10 RAS mutations, the most common type in thyroid nodules, have been reported to have variable positive and negative predictive value for malignancy, often occurring in benign nodules. [18][19][20] A messenger RNA risk classifier can help to rule out the need for surgery in indeterminate nodules due to its high negative predictive value for malignancy. 16,17 Multiple studies have described the ability of RNA-based risk classifiers to help resolve diagnostic uncertainty in indeterminate thyroid nodules.…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14][15] Furthermore, residual risk of malignancy (5%-25%) is present in patients who lack any detectable mutational change. 19,20 However, its less than optimal positive predictive value limits the ability to rule in the need for surgery, especially in AUS/FLUS nodules, where malignancy rates are low. [18][19][20] A messenger RNA risk classifier can help to rule out the need for surgery in indeterminate nodules due to its high negative predictive value for malignancy.…”

Section: Introductionmentioning

confidence: 99%

“…16,17 Multiple studies have described the ability of RNA-based risk classifiers to help resolve diagnostic uncertainty in indeterminate thyroid nodules. [19][20][21] Comparatively, non-coding microRNA based risk classifiers have shown similarly high negative predictive value (NPV) for malignancy and superior positive predictive value when used in combination with analysis for oncogenic mutations and messenger RNA fusion transcripts. 19,20 However, its less than optimal positive predictive value limits the ability to rule in the need for surgery, especially in AUS/FLUS nodules, where malignancy rates are low.…”

Section: Introductionmentioning

confidence: 99%

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Clinical impact of testing for mutations and microRNAs in thyroid nodules

Sistrunk

Shifrin

Frager

et al. 2019

Diagnostic Cytopathology

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Background We report results of a multicenter clinical experience study examining the likelihood of patients with indeterminate thyroid nodules to undergo surgery or have malignant outcome based on multiplatform combination mutation and microRNA testing (MPT). Methods MPT assessed mutations in BRAF, HRAS, KRAS, NRAS, and PIK3CA genes, PAX8/PPARγ, RET/PTC1, and RET/PTC3 gene rearrangements, and the expression of 10 microRNAs. Baseline clinical information at the time of MPT and clinical follow‐up records were reviewed for 337 patients, of which 80% had negative MPT results. Kaplan Meier analysis for cumulative probability of survival without having a surgical procedure or malignant diagnosis over the course of patient follow‐up was determined for MPT results of 180 patients, among which only 14% had malignancy. Results A negative MPT result in nodules with Bethesda III or IV cytology (2009) conferred a high probability of non‐surgical treatment, with only 11% expected to undergo surgery and a high probability of survival without malignancy (92%) for up to 2 years follow up. A positive MPT result conferred a 57% probability of malignancy and was an independent risk factor for undergoing surgical treatment (Hazard Ratio [HR] 9.2, 95% confidence intervals 5.4‐15.9, P < .0001) and for malignancy (HR 13.4, 95% confidence intervals 4.8‐37.2, P < .0001). For nodules with weak driver mutations, positive microRNA test results supported high risk of cancer while negative results downgraded cancer risk. Conclusion MPT results are predictive of real‐world decisions to surgically treat indeterminate thyroid nodules, with those decisions being appropriately aligned with a patient's risk of malignancy over time.

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Development of a Molecular Assay for Detection and Quantification of theBRAFVariation in Residual Tissue From Thyroid Nodule Fine-Needle Aspiration Biopsy Specimens

Chazen

MacMillan

et al. 2021

JAMA Netw Open

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IMPORTANCE Thyroid cancer, predominantly papillary thyroid carcinoma (PTC), is common, but an estimated 30% of ultrasonography-guided fine-needle aspiration (FNA) biopsies of thyroid nodules are indeterminate. BRAF variation, associated with poor clinicopathological characteristics, is a useful molecular marker for diagnostics. OBJECTIVETo develop a sensitive molecular assay for BRAF V600E detection in remaining tissue of thyroid FNA biopsies to identify patients with cancer carrying a BRAF variation. DESIGN, SETTING, AND PARTICIPANTSThis diagnostic study used tumor tissue from surgical formalin-fixed, paraffin-embedded (FFPE) specimens and residual tissue from thyroid FNA biopsies for genomic DNA extraction. FFPE specimens served as the validation set, and residual tissue from FNA biopsies served as the test set. A molecular assay was developed for accurate detection of BRAF V600E variation using locked nucleic acid (LNA) probe-based droplet digital polymerase chain reaction (dPCR), and the assay was validated by BRAF V600E immunohistochemical staining (IHC). The study was conducted between February 2019 and May 2021. RESULTS A total of 271 specimens, including 77 FFPE specimens (with a follow-up of 48 matched surgical specimens) and 146 residual FNA samples, were collected from 223 patients (mean [SD] age, 53.8 [15.3] years; 174 [78.0%] women; 49 [22.0%] men). The molecular assay by dPCR was first established to specifically and accurately detect and quantify wild-type BRAF and variant BRAF in DNA from human follicular thyroid carcinoma-derived FTC-133 and papillary thyroid carcinomaderived BCPAP cells. The linearity of quantification of BRAF V600E was calculated (y = 0.7339x;R 2 = 0.9996) with sensitivity at 0.02 copies/μL and reproducibility in detecting variant DNA at various dilutions(coefficient of variance in 0.3% DNA, 9.63%; coefficient of variance in 1.0% DNA, 7.41%). In validation testing, the dPCR assay and IHC staining exhibited 100% specificity in concordantly identifying BRAF V600E in PTCs (κ = 0.873; P < .001) and sensitivity of 32.0% (95% CI, 19.1% to 44.9%) in dPCR and 26.0% (95% CI, 13.1% to 38.9%) in IHC staining, with an improvement by 23.08% in dPCR compared with the IHC staining. The dPCR assay further detected BRAF V600E in 39 of 146 residual FNA specimens (26.7%). At short-term follow-up, 48 patients, including 14 of 39 patients with BRAF variation and 34 of 107 patients without BRAF variation on residual FNA specimens, underwent resection. The dPCR assay of BRAF status in the matched surgical specimens showed BRAF V600E variations in 12 patients and wild-type BRAF in 36 patients, with a high agreement to that in residual tissue of FNA specimens (κ = 0.789; P < .001). Among 14 patients with BRAF variations on residual FNA, 13 were diagnosed with PTC and 1 was diagnosed with anaplastic thyroid cancer at the thyroidectomy.

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Performance of a Genomic Sequencing Classifier for the Preoperative Diagnosis of Cytologically Indeterminate Thyroid Nodules

Cited by 278 publications

References 50 publications

Risk of malignancy and neoplasia predicted by three molecular testing platforms in indeterminate thyroid nodules on fine‐needle aspiration

Risk of malignancy and neoplasia predicted by three molecular testing platforms in indeterminate thyroid nodules on fine‐needle aspiration

Clinical impact of testing for mutations and microRNAs in thyroid nodules

Development of a Molecular Assay for Detection and Quantification of theBRAFVariation in Residual Tissue From Thyroid Nodule Fine-Needle Aspiration Biopsy Specimens

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