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Importance This proof-of-concept paper demonstrates that driver mutations can be detected in plasma in differentiated thyroid tumors, and we were able to detect mutations in upto 80% malignant thyroid nodules. Additionally, cancer subtypes could also be predicted using a 8-gene panel. In almost 90% follicular adenoma, rat sarcoma virus (RAS) mutations were detectable. There was a strong agreement between driver mutations found in plasma samples, FNAC materials, and histopathology samples. This has potential as a noninvasive, preoperative diagnostic tool (particularly of clinical importance in indeterminate nodules) and may help in detection of residual tumor after surgery. Future research is warranted to test the role of this tool to detect tumor recurrence. Objective Ultrasonographic (USG) evaluation and fine-needle aspiration (FNA) are cornerstone for evaluation of thyroid neoplasm. Molecular technique including detection of driver mutation from FNA cytology (FNAC) material is an established modality. In this study, we explored the feasibility of using plasma cell–free nucleic acids to identify known driver mutations in differentiated thyroid neoplasm. Design Patients presenting with thyroid nodules underwent USG with Thyroid Image Reporting and Data Systems scoring and FNAC (Bethesda classification). All patients in Bethesda 3, 4, 5, 6 underwent surgery and histopathological confirmation. Patients in Bethesda 2 (cosmetic concerns, compressive symptoms) underwent surgery, and rest were presumed benign on the basis of USG, FNAC features, and clinical followup.). Setting Endocrinology clinic. Participants Subjects with thyroid nodule. Intervention(s) or Exposure(s) None. Main Outcome(s) and Measure(s) Plasma sample, FNA, and histopathology material were evaluated for driver mutations (8-gene panel comprising BRAF-V600E, RET/PTC3, RET/PTC1, TERT promoter, HRAS, NRAS, KRAS, and PAX8-PPARG). Results A total of 223 subjects were recruited; of these 154 were benign and 69 had differentiated thyroid cancer. We were able to detect driver mutation from plasma in 55 subjects (79.71%) of all malignant patients, and 11 patients in benign category had RAS mutation (follicular adenoma). Rest of the benign nodules did not have any detectable driver mutations. Conclusions and Relevance Plasma might be a viable noninvasive alternative source for detection of driver mutations (8-gene panel) in subjects with differentiated thyroid tumors and may have significant clinical utility.

Background Molecular testing is increasingly used to identify malignancy in thyroid nodules (especially indeterminate category). Measurement of cell-free DNA (cfDNA) levels from plasma has been useful in diagnosis of cancers of other organs/tissues; herein we analyze cfDNA levels in patients with thyroid nodules to explore the possibility of establishing a cutoff for identification of malignancy. Methods Patients underwent ultrasonography (USG) and USG-guided fine needle aspiration as well as surgery, where indicated. Cell-free DNA was extracted from plasma and quantified. In initial analysis (determination of cutoff), cfDNA levels were compared between Bethesda 2 and Bethesda 5 &6 to establish a cutoff value that could differentiate malignant from benign nodules. In the subsequent analysis, the aforementioned cutoff was applied (validation of cutoff) to those with indeterminate nodules to check ability to predict malignancy. Results Fine needle aspiration (n = 119) yielded patients with Bethesda 2 (n = 69) Bethesda 5 & 6 (n = 13) who underwent histopathological confirmation. Cell-free DNA levels in these 2 groups were 22.85 ± 1.27 and 96.20 ± 8.31 (ng/mL) respectively. A cfDNA cutoff of 67.9 ng/mL, with area under the curve of 0.992 (95% CI, 0.97-1.0) with 100% sensitivity and 93% specificity was established to identify malignant lesions. Indeterminate group (Bethesda 3 & 4) underwent surgery (malignant n = 24), (benign n = 13), and using the previously identified cutoff for cfDNA, we were able to identify malignant lesions with a sensitivity of 100% and specificity of 92.3%. There was a very strong agreement between cfDNA-based classification with histopathology-based classification of benign and malignant nodules (Cohen’s kappa 0.94; P Conclusion Plasma cfDNA estimation could help differentiate malignant from benign thyroid nodules.

Background: High resolution ultrasonography (USG) is the first-line investigation in evaluation of euthyroid nodules. Thyroid imaging reporting and data system (TIRADS) is an USG-based risk stratification system for classifying thyroid nodules. Subjects with high-risk category of TIRADS undergo fine needle aspiration cytology (FNAC) and FNAC findings are reported according to Bethesda classification. Bethesda categories are used for determining risk of malignancy. Data regarding sonographic classification of thyroid nodule and its cytological association with respect to final histopathological diagnosis remains scarcely available in India. Aims and Objective: The study evaluated euthyroid nodules for risk of malignancy and compared sonographic features and FNAC (Bethesda classification) findings with histopathology of excised samples. Material and Methods: This was a single-center observational study on 137 consecutive subjects of solitary euthyroid nodule. All subjects underwent USG according to TIRADS and FNAC where applicable. Surgical biopsy report was used as a gold standard. Results: The sensitivity, specificity, accuracy, positive predictive and negative predictive value of FNAC were 80%, 90%, 85%, 86%, and 86.6% and TIRADS were 80%, 47.2% 61%, 51.3%, and 77.3%, respectively. FNAC classification was equally sensitive and more specific than TIRADS. Among individual USG parameters, micro-calcification was most sensitive (80%) and specific (86%). Irregular margin and taller-than-wider shape had a specificity of 89% and 92%, respectively. 3 patients (14.28%) with benign cytology and suspicious USG features (specifically TIRADS 4 & 5) undergoing surgery had malignancy in final HPE. Conclusions: USG and FNAC are equally sensitive in diagnosing malignant thyroid nodule but FNA is more specific (90%). It's a minimally invasive method which can be used to distinguish malignant from benign lesions with a high degree of accuracy (85%). In patient having high risk feature on USG, a benign cytology needs to be repeat FNAC and they should undergo surgical biopsy for confirmation.