We propose a management guideline based on a patient's risk-very low, low, moderate, and high-for clinicians to use when delineating those patients who should undergo RAI treatment for initial postoperative management of DTC. A majority of very low-risk and low-risk patients, as well as select cases of patients with moderate risk do not demonstrate survival or disease-free survival benefit from postoperative RAI treatment, and therefore we recommend against postoperative RAI in these cases.

Background: The ThyroSeq v2 next-generation sequencing assay (ThyroSeq) estimates the probability of malignancy in indeterminate thyroid nodules (ITN). Its diagnostic accuracy in different practice settings and patient populations is not well understood. Methods: We analyzed 273 Bethesda III/IV ITN evaluated with ThyroSeq at 4 institutions: 2 comprehensive cancer centers (n=98 and 102), a multicenter healthcare system (n=60), and an academic medical center (n=13). The positive (PPV) and negative predictive values (NPV) of ThyroSeq, and distribution of final pathology were analyzed and compared to values predicted by Bayes Theorem. Results: Across 4 institutions, the PPV was 35% (22-43%), and NPV was 93% (88-100%). Predictive values correlated closely with Bayes Theorem estimates (r2=.84), although PPVs were lower than expected. RAS mutations were the most frequent molecular alteration. Among 84 RAS- mutated nodules, malignancy risk was variable (25%, range 10-37%), and distribution of benign diagnoses differed across institutions (adenoma/hyperplasia 12-85%, NIFTP 5-46%). Conclusions: In a multi-institutional analysis, ThyroSeq PPVs were variable and lower than expected. This is attributable to differences in the prevalence of malignancy, and variability in pathologist interpretations of non-invasive tumors. It is important that clinicians understand ThyroSeq performance in their practice setting when evaluating these results.

IMPORTANCE While well-differentiated papillary thyroid carcinoma (WDPTC) outcomes have been well characterized, the prognostic implications of more aggressive variants are far less defined. The rarity of these subtypes has led to their consolidation as intermediate risk for what are in fact likely heterogeneous diseases.OBJECTIVE To analyze incidence, clinicopathologic characteristics, and outcomes for aggressive variants of papillary thyroid carcinoma (PTC). DESIGN, SETTING, AND PARTICIPANTSThis cohort study used data from 2000 to 2016 from hospital-based and population-based US cancer registries to analyze aggressive PTC variants, including diffuse sclerosing (DSV), tall-cell (TCV), insular, and poorly differentiated (PDTC) subtypes. These variants were compared against WDPTC and anaplastic cases. Data analysis was conducted from January 2019 to October 2019.MAIN OUTCOMES AND MEASURES Age-adjusted incidence was calculated via annual percentage change (APC) using the weighted least-squares method. Overall survival and disease-specific survival were analyzed via Cox regression. Propensity-score matching was used to adjust survival analyses for clinical and demographic covariates.RESULTS Collectively, 5447 aggressive PTC variants were identified (including 415 DSV, 3339 TCV, 362 insular, and 1331 PDTC cases), as well as 35 812 WDPTC and 2249 anaplastic cases. Over the study period, a substantial increase in aggressive variant incidence was observed (APC, 9.1 [95% CI, 7.33-10.89]; P < .001), surpassing the relative increases observed in WDPTC (APC, 5.1 [95% CI, 3.98-6.12]; P < .001) and anaplastic cases (APC, 1.9 [95% CI, 0.75-3.05]; P = .003; parallelism P < .007). Survival varied markedly based on histologic subtype, with a wide spectrum of mortality risk noted; 10-year overall survival was 85.4% (95% CI, 84.6%-86.3%) in WDPTC, 79.2% (95% CI, 73.6%-85.3%) in DSV, 71.9% (95% CI, 68.4%-75.6%) in TCV, 45.1% (95% CI, 40.2%-50.6%) in PDTC, 27.9% (95% CI, 20.0%-38.9%) in the insular variant, and 8.9% (95% CI, 7.5%-10.6%) in anaplastic cases (P < .001). These differences largely persisted even after adjusting for inherent differences in baseline characteristics by multivariable Cox regression and propensity-score matching.CONCLUSIONS AND RELEVANCE An upsurge in aggressive PTC incidence was observed at a rate beyond that seen in WDPTC or anaplastic thyroid carcinoma. Moreover, long-term survival outcomes for aggressive PTC subgroups exhibit heterogeneous clinical behavior and a wide range of mortality risk, suggesting that treatment should be tailored to specific histologic subtypes. Given increasing prevalence and disparate outcomes, further investigation to identify optimal therapeutic strategies is needed in these diverse, understudied populations.

BACKGROUND The Afirma gene expression classifier (GEC) assesses malignancy risk in patients with indeterminate thyroid nodules. Afirma putatively reduces costs by classifying certain nodules as benign and thereby avoiding unnecessary surgery. Prior studies have evaluated its impact exclusively on GEC‐tested nodules. The objective of the current study was to analyze the effect of Afirma on 1) cytopathology diagnosis, 2) the rate of surgery, and 3) the rate of malignancy on all indeterminate nodules at a high‐volume thyroid center. METHODS A retrospective cohort analysis of indeterminate (Bethesda III/IV) thyroid nodules from 2012 through 2014 was performed. Cases were evaluated from January 2012 to July 2013 (pre‐Afirma), and from July 2013 to December 2014 (post‐Afirma). RESULTS Of 4292 fine‐needle aspirations (FNAs) performed, 13.2% were classified as indeterminate. The GEC was used in 45.3% of post‐Afirma cases, with the GEC‐Benign call rate at 37.1%. In comparing pre‐Afirma and post‐Afirma cohorts, a significant increase in Bethesda III (10.7% vs 13.4%; P<.005) and Bethesda IV (1.8% vs 2.9%; P<.01) rates were observed. Conversely, the incidence of Bethesda II was found to be significantly decreased (74.6% vs 68.8%; P<.001). The rate of surgery did not change significantly between pre‐Afirma and post‐Afirma cohorts (37.7% vs 45.1%; P = .11), nor did the malignancy rate (25.3% vs 36.0%; P = .12). CONCLUSIONS The incidence of indeterminate FNA diagnoses significantly increased after Afirma became routinely available, whereas the incidence of benign diagnoses significantly decreased. These data suggest that Afirma may shift FNA interpretation toward Bethesda III/IV, in which molecular testing is used. Moreover, the institutional rates of surgery and malignancy did not appear to change, raising uncertainty regarding the benefits of molecular assay risk stratification. Afirma may produce unintended collateral effects, increasing the number of indeterminate FNA diagnoses while not affecting the institutional thyroidectomy rate or malignancy yield. Cancer Cytopathol 2016;124:722–8. © 2016 American Cancer Society.