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Molecular testing improves the diagnostic accuracy of thyroid cancer. Whether specific molecular testing results are associated with tumor phenotype or provide prognostic information needs further delineation.Consecutive thyroid cancer patients after index thyroidectomy with ThyroSeq version 3 (Rye Brook, NY) molecular testing obtained on preoperative fine-needle aspiration or thyroidectomy specimens from patients with thyroid cancer were categorized into 3 molecular risk groups based on detected mutations, fusions, copy number alterations, and/or gene expression alterations and correlated with histopathology and recurrence, defined as biochemical or structural.Of 578 patients, 49.9%, 37.5%, and 12.6% had molecular risk group-low, molecular risk group-intermediate, and molecular risk group-high cancers, respectively. With a median 19-month follow-up, 9.1% patients recurred. Compared with molecular risk group-low, molecular risk group-intermediate cancers were diagnosed in younger patients and more often had microscopic extrathyroidal extension, involved margins, and nodal disease. Compared with molecular risk group-intermediate, molecular risk group-high cancers were diagnosed in older patients and more often had gross extrathyroidal extension and vascular invasion. In multivariable analysis, recurrence was more likely in molecular risk group-high cancers than in molecular risk group-intermediate (hazard ratio = 4.0; 95% confidence interval, 1.9-8.6; P.001) and more likely in molecular risk group-intermediate than in molecular risk group-low (hazard ratio = 5.0; 95% confidence interval, 2.0-12.5; P.001).Using modern comprehensive genotyping, the genetic profile of thyroid cancers can be categorized into 3 novel molecular risk groups that were associated with histopathologic phenotype and recurrence in short-term follow-up.

Recent guidelines from the American Thyroid Association recommend thyroid lobectomy for intrathyroidal differentiated thyroid cancers4 cm. Our aim was to examine histology from patients with cytologic results that were positive or suspicious for malignancy to assess the extent of initial thyroidectomy based on criteria from the 2015 American Thyroid Association guidelines.We studied consecutive patients who had either a positive or suspicious for malignancy cytologic diagnosis and under prior American Thyroid Association guidelines underwent initial total thyroidectomy ± lymphadenectomy.Among 447 patients, high-risk features necessitating total thyroidectomy were present in 19% (72/380) of positive and 15% (10/67) of suspicious for malignancy patients (P = .5). Intermediate-risk features on histology were identified postoperatively in 46% (175/380) with positive and 15% (18/67) with suspicious for malignancy fine-needle aspiration results. In multivariable analysis, preoperative factors associated with intermediate-risk disease included age ≥45 years, women, larger tumor size, positive fine-needle aspiration cytology, and BRAF V600E or RET/PTC positivity.When patients are considered for lobectomy under the 2015 American Thyroid Association guidelines, ~ 60% with positive and 30% with suspicious for malignancy cytology would need completion thyroidectomy based on intermediate-risk disease. The cost and risk implications of the new American Thyroid Association strategy were substantial and better tools are needed to improve preoperative risk stratification.

Background In thyroid nodule fine-needle aspiration (FNA) cytology, the atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) category has a 5–15% malignancy risk that increases to 85–99% when mutation testing for BRAF , RAS , RET/PTC , or PAX8/PPARγ is positive. However, negative testing does not exclude malignancy. The study objective was to identify clinical and imaging features that predict cancer in mutation–negative AUS/FLUS thyroid nodules. Methods All patients were reviewed (April 2007 to April 2009) who had AUS/FLUS cytology, negative prospective molecular testing of FNA, and histopathology. Results Of the 230 nodules, 12 (5.2%) were malignant in 11 of 190 patients, and known clinical risk factors for thyroid cancer did not predict malignancy. On preoperative imaging, ≥1 suspicious ultrasound feature was identified in 33% of nodules and occurred regardless of histology ( P = .23). Malignant mutation-negative AUS/FLUS nodules were larger than benign nodules (mean maximum diameter, 33.6 vs 24.0 mm; P = .007). On multivariate analysis, nodule size remained an independent predictor of malignancy (odds ratio, 1.043; P = .018). We observed no malignancies in 88 mutation-negative AUS/FLUS nodules Conclusion Size is an independent predictor of malignancy in mutation-negative AUS/FLUS nodules and the risk increased 4.3% with every millimeter increase in nodule size. Selected patients with small, mutation-negative AUS/FLUS thyroid nodules may be managed with ultrasound surveillance in lieu of thyroidectomy.

Background Preoperative detection of RAS mutations can contribute to cancer risk assessment in indeterminate thyroid nodules, although RAS is not always associated with malignancy. Methods Fine-needle aspiration samples classified in 1 of 3 indeterminate cytology categories were prospectively tested for N-, H-, and K-RAS mutations using next-generation sequencing assay. Results In the study, 93 patients with 94 nodules had preoperative RAS detected, of whom 86 patients had an operation (69% total thyroidectomy, 29% lobectomy). In total, 76% of RAS-positive nodules were malignant and follicular variant papillary thyroid cancer was the most common cancer type (83%). HRAS mutations had the greatest risk of cancer (92%) followed by NRAS (74%) and KRAS (64%; P = .05). No preoperative variables were associated with malignancy including age (P = .07), sex (P = .49), RAS isoform (P = .05), mutational allelic frequency (P = .49), nodule size (P = .14), cytology category (P = .63), or ultrasound bilaterality (P = .24), multifocality (P = .23), or presence of ≥1 suspicious feature (P = .86). Only 60% of patients with a unifocal nodule on ultrasound had single focus low-risk encapsulated follicular variant papillary thyroid cancer or benign disease. Conclusion Preoperative RAS mutation detection in thyroid nodules carries a substantial risk of cancer with a greater risk associated with HRAS and NRAS. Most RAS malignancies are follicular variant papillary thyroid cancer, which may inform the extent of operation.

Background High false-negative rates for fine needle aspiration biopsy (FNAB) of thyroid nodules greater than 3 cm have prompted recommendations for diagnostic lobectomy. We considered the presence of a greater than 4 cm nodule an independent indication for thyroidectomy regardless of FNAB results. Methods We reviewed clinical data from 223 patients with thyroid nodules greater than or equal to 4 cm operated on from July 2003 to November 2006. Unifocal micropapillary cancer was considered clinically insignificant. Results Clinically significant thyroid cancer was frequent, occurring in 57 of 223 patients (26%). Subgroup analysis showed that 43 of 223 patients (19.3%) had carcinoma within the mass and that 7 of 223 patients (3.1%) had significant carcinoma elsewhere in the resected thyroid. Multifocal micropapillary cancer was found in an additional 7 of 223 patients (3.1%). Preoperative FNAB was read incorrectly as benign in 9 of 71 patients with cancer (13%) (16% including multifocal micropapillary carcinoma). Benign FNAB results failed to identify 24 (34%) follicular lesions (including 7 cancers). In patients with preoperative FNAB results categorized as indeterminate lesions, 17 of 43 patients (40%) had carcinoma of the mass on final pathology. Conclusions In thyroid nodules greater than or equal to 4 cm, the incidence of carcinoma is high with a high false-negative rate for preoperative benign cytology. Thyroid nodules greater than or equal to 4 cm should be considered for diagnostic lobectomy regardless of FNAB results.