Malpractice Trends Involving Active Surveillance Across Cancers.

OBJECTIVE: To characterize malpractice trends related to active surveillance (AS) as a treatment strategy across cancers. BACKGROUND: Active surveillance is increasingly considered a viable management strategy for low-risk cancers. Since a subset of AS cases will progress, metastasize, or exhibit cancer-related mortality, a significant barrier to implementation is the perceived risk of litigation from missing the window for cure. Data on malpractice trends across cancers are lacking. METHODS: Westlaw Edge and LexisNexis Advance databases were searched from 1990 to 2022 for malpractice cases involving active surveillance in conjunction with thyroid cancer, prostate cancer, kidney cancer, breast cancer, or lymphoma. Queries included unpublished cases, trial orders, jury verdicts, and administrative decisions. Data were compiled on legal allegations, procedures performed, and verdicts or settlements rendered. RESULTS: Five prostate cancer cases were identified that pertained to active surveillance. Two cases involved alleged deliberate indifference from AS as a management strategy but were ruled as following the appropriate standard of care. In contrast, 3 cases involved alleged physician negligence for not explicitly recommending AS as a treatment option after complications from surgery occurred. All cases showed documented informed consent for AS, leading to defense verdicts in favor of the physicians. No cases of AS-related malpractice were identified for other cancer types. CONCLUSIONS: To date, no evidence of successful malpractice litigation for active surveillance in cancer has been identified. Given the legal precedent detailed in the identified cases and increasing support across national guidelines, active surveillance represents a sound management option in appropriate low-risk cancers, with no increased risk of medicolegal exposure.

Expanded Parameters in Active Surveillance for Low-risk Papillary Thyroid Carcinoma: A Nonrandomized Controlled Trial.

Importance: Unlike for prostate cancer, active surveillance for thyroid cancer has not achieved wide adoption. The parameters by which this approach is feasible are also not well defined, nor is the effect of patient anxiety. Objective: To determine if expanded size/growth parameters for patients with low-risk thyroid cancer are viable, as well as to assess for cohort differences in anxiety. Design, Setting, and Participants: This prospective nonrandomized controlled trial was conducted at a US academic medical center from 2014 to 2021, with mean [SD] 37.1 [23.3]-month follow-up. Of 257 patients with 20-mm or smaller Bethesda 5 to 6 thyroid nodules, 222 (86.3%) enrolled and selected treatment with either active surveillance or immediate surgery. Delayed surgery was recommended for size growth larger than 5 mm or more than 100% volume growth. Patients completed the 18-item Thyroid Cancer Modified Anxiety Scale over time. Interventions: Active surveillance. Main Outcomes and Measures: Cumulative incidence and rate of size/volume growth. Results: Of the 222 patients enrolled, the median (IQR) age for the study population was 46.8 (36.6-58) years, and 76.1% were female. Overall, 112 patients (50.5%) underwent treatment with active surveillance. Median tumor size was 11.0 mm (IQR, 9-15), and larger tumors (10.1-20.0 mm) comprised 67 cases (59.8%). One hundred one (90.1%) continued to receive treatment with active surveillance, 46 (41.0%) had their tumors shrink, and 0 developed regional/distant metastases. Size growth of more than 5 mm was observed in 3.6% of cases, with cumulative incidence of 1.2% at 2 years and 10.8% at 5 years. Volumetric growth of more than 100% was observed in 7.1% of cases, with cumulative incidence of 2.2% at 2 years and 13.7% at 5 years. Of 110 patients who elected to undergo immediate surgery, 21 (19.1%) had equivocal-risk features discovered on final pathology. Disease severity for all such patients remained classified as stage I. Disease-specific and overall survival rates in both cohorts were 100%. On multivariable analysis, immediate surgery patients exhibited significantly higher baseline anxiety levels compared with active surveillance patients (estimated difference in anxiety scores between groups at baseline, 0.39; 95% CI, 0.22-0.55; P < .001). This difference endured over time, even after intervention (estimated difference at 4-year follow-up, 0.50; 95% CI, 0.21-0.79; P = .001). Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that a more permissive active surveillance strategy encompassing most diagnosed thyroid cancers appears viable. Equivocal-risk pathologic features exist in a subset of cases that can be safely treated, but suggest the need for more granular risk stratification. Surgery and surveillance cohorts possess oppositional levels of worry, elevating the importance of shared decision-making when patients face treatment equivalence. Trial Registration: ClinicalTrials.gov Identifier: NCT02609685.

Predictive Impact of Metastatic Lymph Node Burden on Distant Metastasis Across Papillary Thyroid Cancer Variants.

Background: While numerous factors determine prognosis in papillary thyroid carcinoma (PTC), distant metastasis (M1) represents one of the most dire. Escalating nodal burden and aggressive histology may contribute to higher metastatic risk, but this relationship is poorly defined and challenging to anticipate. We evaluate the predictive impact of these histological features on predicting distant metastases at initial presentation. Methods: Univariate and multivariable logistic regression models of conventional and aggressive thyroid cancer variants (well-differentiated papillary thyroid carcinoma [WDPTC], diffuse sclerosing variant [DSV], tall cell variant [TCV], poorly differentiated thyroid cancer [PDTC], and anaplastic thyroid carcinoma [ATC]) identified via U.S. cancer registry data were constructed to determine associations between M1 status and quantitative nodal burden. Associations between metastatic lymph node (LN) number and M1 disease were modeled using univariate and multivariable logistic regression with interaction terms, as well as a linear continuous probability model. Results: Overall, M1 prevalence at disease presentation was 3.6% (n = 1717). When stratified by subtype, M1 prevalence varied significantly by histology (WDPTC [1.0%], DSV [2.3%], TCV [4.1%], PDTC [17.4%], ATC [38.4%] [p < 0.001]). For WDPTC, M1 prevalence escalated with metastatic LN number (0 LN+ [0.5%], 1-5 LN+ [2.0%], 6-10 LN+ [3.4%], >10 LN+ [5.5%] [p < 0.001]) and LN ratio (p < 0.001). A statistically significant interaction was observed between histology and increasing nodal burden for M1 risk. On multivariable analysis, each successive metastatic LN conferred increased M1 risk for WDPTC (odds ratio [OR] 1.06 [1.05-1.08], p < 0.001) and TCVs (OR 1.04 [1.02-1.07], p < 0.001). In contrast, other aggressive variants had a higher baseline M1 risk, but this did not vary based on the number of positive LN (DSV, OR 1.02 [0.95-1.10], p = 0.52; PDTC, OR 1.00 [0.98-1.02], p = 0.66; ATC, 1.00 [0.98-1.02], p = 0.97). Conclusions: Progressive nodal burden independently escalates the risk of distant metastasis in WDPTC and TCVs of PTC. Conversely, aggressive variants such as PDTC and ATC have substantial M1 risk at baseline and appear to be minimally affected by metastatic nodal burden. Consideration of these factors after surgery may help tailor clinical decision-making for treatment and surveillance. Further studies are warranted to calibrate the ideal management approach for these higher risk patient groups.

Incidental parathyroidectomy in thyroidectomy and central neck dissection.

BACKGROUND: Although higher thyroidectomy volume has been linked with lower complication rates, its association with incidental parathyroidectomy remains less studied. The volume relationship is even less clear for central neck dissection, where individual parathyroid glands are at greater risk. METHODS: Patients undergoing thyroidectomy with or without central neck dissection were evaluated for incidental parathyroidectomy, hypoparathyroidism, and hypocalcemia. Univariate and multivariable analyses were performed using binary logistic regression. RESULTS: Overall, 1,114 thyroidectomies and 396 concurrent central neck dissections were performed across 7 surgeons. Incidental parathyroidectomy occurred in 22.4% of surgeries (range, 16.9%-43.6%), affecting 7.1% of parathyroids at risk (range, 5.8%-14.5%). When stratified by surgeon, lower incidental parathyroidectomy rates were associated with higher thyroidectomy volumes (R2 = 0.77, P = .008) and higher central neck dissection volumes (R2 = 0.93, P < .001). On multivariable analysis, low-volume surgeon (odds ratio 2.94, 95% confidence interval 2.06-4.19, P < .001), extrathyroidal extension (odds ratio 3.13, 95% confidence interval 1.24-7.87, P = .016), prophylactic central neck dissection (odds ratio 2.68, 95% confidence interval 1.65-4.35, P <.001), and therapeutic central neck dissection (odds ratio 4.44, 95% confidence interval 1.98-9.96, P < .001) were the most significant factors associated with incidental parathyroidectomy. In addition, incidental parathyroidectomy was associated with a higher likelihood of temporary hypoparathyroidism (odds ratio 2.79, 95% confidence interval 1.45-5.38, P = .002) and permanent hypoparathyroidism (odds ratio 4.62, 95% confidence interval 1.41-5.96, P = .025), but not permanent hypocalcemia (odds ratio 1.27, 95% confidence interval 0.48-3.35, P = .63). Higher lymph node yield in central neck dissection was not associated with higher incidental parathyroidectomy rates (odds ratio 1.13, 95% confidence interval 0.85-8.81, P = .82). CONCLUSION: Higher surgical volume conferred a lower rate of incidental parathyroidectomy. Nonetheless, greater lymph node yield in central neck dissections did not result in greater parathyroid-related morbidity. Such findings support the value of leveraging surgical volume to both optimize oncologic resection and minimize complication rates.

Prognostic Impact of Histologic Grade for Papillary Thyroid Carcinoma.

BACKGROUND: While numerous factors affect prognosis in papillary thyroid carcinoma (PTC), the comparative impact of histologic grade has not been well described. Moreover, indications for external beam radiation therapy (EBRT) remain imprecise. We evaluate clinicopathologic characteristics and outcomes for PTC stratified by grade. METHODS: We profiled histologic grade for PTC (well differentiated, moderately differentiated, poorly differentiated) via hospital (National Cancer Database) and population-based (Surveillance, Epidemiology, and End Results) registries. Cox regression was used to adjust for clinicopathologic covariates. Statistical interactions between subtypes and the effect of EBRT on survival were assessed. RESULTS: Collectively, worsening clinicopathologic factors (age, tumor size, extrathyroidal extension, nodal spread, M1 disease) and outcomes (disease-free survival, overall survival) correlated with less differentiated state, across all histologic grades (p < 0.001). Multivariable analysis showed escalating hazard with loss of differentiation relative to well-differentiated PTC (moderately differentiated hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.04-1.41, p = 0.02; poorly differentiated HR 2.62, 95% CI 2.23-3.08, p < 0.001). Correspondingly, greater survival benefit was associated with EBRT for poorly differentiated cases (HR 0.36, 95% CI 0.18-0.72, p = 0.004). This finding was upheld after landmark analysis to address potential immortal time bias (HR 0.37, 95% CI 0.17-0.80, p = 0.01). CONCLUSIONS: Worsening histologic grade in PTC is independently associated with parallel escalation in mortality risk, on a scale approximating or surpassing established thyroid cancer risk factors. On preliminary analysis, EBRT was associated with improved survival in the most aggressive or least differentiated subvariants. Further investigation is warranted to examine the efficacy of EBRT for select poorly differentiated thyroid carcinomas.

Incidence and Mortality Risk Spectrum Across Aggressive Variants of Papillary Thyroid Carcinoma.

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 Participants: This 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.

Papillary thyroid microcarcinoma: optimal management versus overtreatment.

PURPOSE OF REVIEW: The treatment of small, low-risk papillary thyroid carcinoma has undergone a paradigm shift, with many tumors now initially treated with active surveillance rather than upfront surgery. Further studies on patients enrolled in active surveillance have refined our knowledge of the clinical behavior of papillary thyroid microcarcinomas. RECENT FINDINGS: This article summarizes the major conclusions of landmark trials that launched active surveillance as a viable treatment option for selected patients. We discuss patient factors such as age and tumor size, the assessment of candidates for active surveillance, barriers to acceptance of active surveillance, quality of life issues, and economic considerations. SUMMARY: Active Surveillance is a viable first-line treatment option for select papillary microcarcinomas.

Mortality Risk of Nonoperative Papillary Thyroid Carcinoma: A Corollary for Active Surveillance.

Background: Active surveillance is established as an alternative to surgery for papillary thyroid microcarcinomas, but inclusion criteria and mortality risk for pursuing a nonsurgical approach have not been clearly defined. To gauge the feasibility of expanding active surveillance thresholds, we investigated the effects of increasing size and age on disease-specific survival (DSS) in a large nonoperative thyroid cancer cohort, compared against a matched group of surgical patients. Methods: Papillary thyroid carcinoma patients staged T1-4N0M0 were identified in the Surveillance, Epidemiology, and End Results (SEER) database between 1975 and 2015, stratified by nonsurgical and surgical management. Propensity score matching was performed to adjust for imbalances in covariates. Multivariable models were constructed using restricted cubic splines to model nonlinear relationships of age and tumor size with DSS. Results: Overall, 1453 nonoperative patients and 54,718 surgical patients met the inclusion criteria. Collectively, increasing age and size after certain thresholds independently led to greater differences in DSS between nonsurgical and surgical patients. For younger ages (14-55 years), surgical approach compared with nonsurgical approach was not associated with any difference in the 10-year DSS among 0-4 cm cancers (99.8% vs. 100%, p = 0.470), 4.1-6 cm cancers (98.8% vs. 100%, p = 0.599), or >6 cm cancers (97.3% vs. 100%, p = 0.718). Older patients with larger tumors (>75 years, >6 cm) demonstrated the greatest difference in DSS (48.1% vs. 91.3%, p < 0.001). Similar results were found when applying propensity score matching. For age, restricted cubic spline plots showed minimal relative survival hazard in nonoperative cases beginning after age 60 years, with a change point illustrating acceleration in relative hazard beyond age 72 years. For size, relative survival hazard was observed after 2.0 cm and increased slowly with nodule growth up to an inflection point of 4.5 cm. Beyond this, mortality risk escalated with each additional year without plateau. Conclusions: Increasing age and size lead to progressively greater mortality risk without surgery, but only beyond certain thresholds. We define escalating gradients at which a nonsurgical approach may be deemed appropriate, and beyond which survival benefits from surgery become apparent. Such findings reconcile controversial observations regarding age and size in active surveillance and further reshape evolving treatment paradigms in thyroid cancer.

Interinstitutional variation in predictive value of the ThyroSeq v2 genomic classifier for cytologically indeterminate thyroid nodules.

BACKGROUND: The ThyroSeq v2 next-generation sequencing assay estimates the probability of malignancy in indeterminate thyroid nodules. Its diagnostic accuracy in different practice settings and patient populations is not well understood. METHODS: We analyzed 273 Bethesda III/IV indeterminate thyroid nodules evaluated with ThyroSeq at 4 institutions: 2 comprehensive cancer centers (n = 98 and 102), a multicenter health care system (n = 60), and an academic medical center (n = 13). The positive and negative predictive values of ThyroSeq and distribution of final pathologic diagnoses were analyzed and compared with values predicted by Bayes theorem. RESULTS: Across 4 institutions, the positive predictive value was 35% (22%-43%) and negative predictive value was 93% (88%-100%). Predictive values correlated closely with Bayes theorem estimates (r2 = 0.84), although positive predictive values were lower than expected. RAS mutations were the most common 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%, noninvasive follicular thyroid neoplasm with papillary-like nuclear features 5%-46%). CONCLUSION: In a multi-institutional analysis, ThyroSeq positive predictive values were variable and lower than expected. This is attributable to differences in the prevalence of malignancy and variability in pathologist interpretations of noninvasive tumors. It is important that clinicians understand ThyroSeq performance in their practice setting when evaluating these results.

Parallels Between Low-Risk Prostate Cancer and Thyroid Cancer: A Review.

IMPORTANCE: Across many countries, a rapid escalation of the incidence of thyroid cancer has been observed, a surge that nonetheless underestimates the true extent of the disease. Most thyroid cancers now diagnosed comprise small, low-risk cancers that are incidentally found and are unlikely to cause harm. In many ways, prostate cancer similarly harbors a well-behaved subclinical reservoir, a long natural history, and superlative outcomes that have made active surveillance the de facto guideline recommendation for low-risk disease. This review highlights the parallels and differences between prostate cancer and thyroid cancer regarding screening, diagnosis, risk stratification, and considerations for active surveillance. OBSERVATIONS: Prostate cancer and thyroid cancer have undergone recalibrated, de-escalatory shifts to counter changing epidemiologic landscapes. The US Preventive Services Task Force has issued cautionary recommendations on screening via prostate-specific antigen testing or neck ultrasonography, while the thresholds to performing biopsy have increased. Comparable changes to cancer terminology and staging have also helped alleviate patient anxiety and minimize pressure for overtreatment. Long-term, randomized prospective clinical trials for prostate cancer have established active surveillance as a first-line treatment approach for properly stratified low-risk patients, while observational trials for thyroid cancer have also made strides in defining risk and eligibility for surgery. Caveats requiring deeper investigation include aggressive disease in older patients, underestimation of the extent of the disease, and patient-physician bias in shared decision making. For prostate cancer, survival may not improve and function will likely worsen after intervention; for thyroid cancer, patients are younger, surgery is safer, and the bar for surveillance will likely be higher. CONCLUSIONS AND RELEVANCE: Despite similarities in biological indolence between low-risk prostate and thyroid malignant neoplasms, key distinctions in life expectancy and treatment sequelae may ultimately confer somewhat disparate management paradigms for the 2 diseases. Nevertheless, the experience forged by prostate cancer trials serves as a model for thyroid cancer management, potentially reshaping the perception of active surveillance into a credible, valuable treatment modality.

A retrospective analysis of the performance of the RosettaGX® Reveal™ thyroid miRNA and the Afirma Gene Expression Classifiers in a cohort of cytologically indeterminate thyroid nodules.

BACKGROUND: Molecular tests are increasingly used to triage cytologically indeterminate thyroid nodules for surgery and/or follow-up. We retrospectively compared the performance of the Afirma Gene Expression Classifier (AGEC) with that of the more recently developed RosettaGX® Reveal™ miRNA Classifier (Reveal) in a cohort of Bethesda III-V thyroid FNAs with surgical follow-up. DESIGN: Eighty-one samples (54 Bethesda III, 26 Bethesda IV, 1 Bethesda V) with available AGEC (74 AGEC-SUSP and 7 AGEC-BENIGN) and surgical pathology results were studied from three academic centers. Reveal was performed in a blinded fashion. RESULTS: The final diagnoses were benign/NIFTP (n = 63) and malignant (n = 18). The overall "correct" rate was 64.2% for Reveal and 28.4% for AGEC (P = 1.4e-6). The specificity of Reveal was 60.3%, compared with 9.5% for AGEC (P = 2.1e-9). Among the 18 malignant cases, 77.8% and 94.4% were correctly classified as suspicious by Reveal and AGEC, respectively (P = 0.2). In the FLUS and the FN group, the specificity of AGEC was lower than the specificity of Reveal. Whether the 7 NIFTP in our study were considered benign or malignant, specificity and PPV of Reveal were higher than those of AGEC. Reveal also outperformed AGEC in correctly classifying the 26 benign Hürthle lesions studied (P = 7.6e-5). CONCLUSION: Reveal outperformed AGEC in this cohort, whether NIFTP is considered benign or malignant, and in Hürthle lesions. Reveal has the potential to reduce the number of unnecessary resections in patients with indeterminate thyroid cytology. Based on our findings and the practical advantages offered by Reveal methodology, large prospective studies are warranted. Diagn. Cytopathol.

Evolving management considerations in active surveillance for micropapillary thyroid carcinoma.

PURPOSE OF REVIEW: To summarize developments on active surveillance for micropapillary thyroid cancers, with a focus on strategies for optimal risk stratification and caveats that currently limit adoption. RECENT FINDINGS: Observational trials encompassing thousands of active surveillance patients worldwide have increasingly demonstrated the viability of active surveillance for small, low-risk thyroid cancers. Collectively, these data have established that with proper patient selection and strict monitoring, more than 85% of such cases remain indolent no meaningful clinical growth over at least 10 years. Moreover, to date no cases of symptomatic progression or distant metastasis have been reported, and that delayed treatment when needed has not led to unresectable disease or higher risk of complications. Deeper investigation to better predict clinical progression is necessary to improve patient selection, given concerns regarding patient anxiety, age eligibility, and underestimation of true disease extent. SUMMARY: Compelling data from ongoing trials support active surveillance as a first-line management option for micropapillary thyroid carcinomas. Proper risk stratification and strict monitoring protocols will be necessary to sustain the excellent results achieved to date. Broad adoption of active surveillance will require further education, collaboration, and equipoise between physicians and patients to optimize such individualized treatment plans.

Impact of Afirma gene expression classifier on cytopathology diagnosis and rate of thyroidectomy.

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.