Abstract
BackgroundMutations involving BRAF and TERT are important predictors of disease severity in thyroid cancer, but molecular testing is limited by cost and lack of adequate tissue sample. This study aimed to assess the utility of BRAFV600E and TERT testing using droplet digital PCR (ddPCR) as a diagnostic and prognostic tool for thyroid fine needle aspirate biopsy (FNAB).MethodsPatients with thyroid nodules were prospectively enrolled from March 2015 to September 2018. Pre-operative FNAB was collected for standard cytology and molecular testing. BRAFV600E and TERT levels were analyzed by ddPCR. Cytology (Bethesda system) and ddPCR results were correlated to surgical pathology.ResultsA total of 222 patients were enrolled, of which 124 received thyroid surgery. Pre-operative cytology alone with Bethesda ≥5 was 100% specific and 70% sensitive for malignancy on final surgical pathology. BRAFV600E positivity or TERT overexpression was 100% specific and 60.0% sensitive. Combining cytology (Bethesda ≥5) with BRAFV600E and TERT testing increased the sensitivity of a malignant diagnosis to 80.0%. High TERT levels and/or BRAFV600E was associated with aggressive or advanced stage pathology.ConclusionsCombining cytology with ddPCR analysis of BRAFV600E and TERT can improve the diagnostic accuracy of thyroid FNAB, and help predict aggressive pathology.
Highlights
Mutations involving BRAF and telomerase reverse transcriptase (TERT) are important predictors of disease severity in thyroid cancer, but molecular testing is limited by cost and lack of adequate tissue sample
The 2015 American Thyroid Association (ATA) guidelines recommend workup of thyroid nodules using ultrasound followed by fine needle aspirate biopsy (FNAB) if warranted Bethesda cytopathologic categories are used to risk stratify thyroid nodules and guide management; this system is limited in its diagnostic accuracy [6]
Determination of BRAFV600E and TERT levels by droplet digital PCR (ddPCR) was performed by MK, who was blinded to clinical and pathologic characteristics associated with FNAB samples
Summary
Mutations involving BRAF and TERT are important predictors of disease severity in thyroid cancer, but molecular testing is limited by cost and lack of adequate tissue sample. TERT expression can be upregulated through several mechanisms including promoter mutations, TERT gene copy number alterations, increased promoter methylation and histone modifications [14,15,16,17,18] These TERT-related genetic aberrations have been implicated in thyroid cancer with particular prevalence in aggressive subtypes [15, 16]. They have a high specificity and positive predictive value for thyroid cancer [19] and have been associated with poorer patient outcomes, including a greater risk of death [14, 15, 20]
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