The Effect Modification of Ultrasound Risk Classification on Molecular Testing in Predicting the Risk of Malignancy in Cytologically Indeterminate Thyroid Nodules.

Background: Thyroid nodules with indeterminate cytology are increasingly subjected to molecular testing. We evaluated the diagnostic performances of Afirma Genomic Sequencing Classifier (GSC) and ThyroSeq v3 in thyroid nodules with high versus low/intermediate suspicion ultrasound classification. Methods: In this prospective cohort study, we analyzed all Bethesda III and IV thyroid nodules that underwent fine-needle aspiration biopsies in the University of California Los Angeles Health System from July 2017 to April 2020. All patients underwent molecular testing with Afirma GSC or ThyroSeq v3 as part of an institutional randomized trial (NCT02681328). Nodules were categorized according to the American Thyroid Association (ATA) ultrasound risk classification. The benign call rate and the positive predictive value of molecular testing were compared between ATA high suspicion versus all other categories. Results: A total of 343 patients with 375 indeterminate thyroid nodules were included. The malignancy rate in ATA high suspicion nodules was not significantly increased by a suspicious Afirma GSC result (77.8% for all ATA high suspicion nodules vs. 87.5% for nodules with ATA high suspicion and suspicious Afirma GSC results, positive likelihood ratio [LR] = 2.0, 95% confidence interval [CI 0.5-8.0], p = 1.0) or by a positive ThyroSeq v3 result (80.0% vs. 80.0%, positive LR = 1.0 [CI 1.0-1.0], p = 1.0). The rate of malignancy in ATA low/intermediate suspicion nodules increased from 21.0% to 56.3% with a suspicious Afirma GSC result (positive LR = 4.8 [CI 3.4-6.9], p < 0.0001) and decreased to 3.8% with a benign Afirma GSC result (negative LR = 0.1 [CI 0.07-0.3], p < 0.0001). Similarly, the rate of malignancy in ATA low/intermediate suspicion nodules increased from 24.3% to 66.7% with a positive ThyroSeq v3 result (positive LR = 6.2 [CI 4.0-9.7], p < 0.0001) and decreased to 2.1% with a negative ThyroSeq v3 result (negative LR = 0.07 [CI 0.02-0.3], p < 0.0001). Conclusions: Afirma GSC and ThyroSeq v3 performed well in ruling out malignancy in sonographically low/intermediate suspicion thyroid nodules but has limited diagnostic value in sonographically high suspicion nodules. Molecular testing can prognosticate more aggressive thyroid cancers, which can inform treatment decisions.

Patient-Centered Decision-making for Postoperative Narcotic-Free Endocrine Surgery: A Randomized Clinical Trial.

Importance: Historically, opioid pain medications have been overprescribed following thyroid and parathyroid surgery. Many narcotic prescriptions are incompletely consumed, creating waste and opportunities for abuse. Objective: To determine whether limiting opioid prescriptions after outpatient thyroid and parathyroid surgery to patients who opt in to narcotic treatment reduces opioid consumption without increasing postoperative pain compared with usual care (routine narcotic prescriptions). Design, Setting, and Participants: A randomized clinical trial of Postoperative Opt-In Narcotic Treatment (POINT) or routine narcotic prescription (control) was conducted at a single tertiary referral center from June 1 to December 30, 2020. A total of 180 adults undergoing ambulatory cervical endocrine surgery, excluding patients currently receiving opioids, were assessed for eligibility. POINT patients received perioperative pain management counseling and were prescribed opioids only on patient request. Patients reported pain scores (0-10) and medication use through 7 daily postoperative surveys. Logistic regression was used to determine factors associated with opioid consumption. Interventions: Patients in the POINT group were able to opt in or out of receiving prescriptions for opioid pain medication on discharge. Control patients received routine opioid prescriptions on discharge. Main Outcomes and Measures: Daily peak pain score through postoperative day 7 was the primary outcome. Noninferiority was defined as a difference less than 2 on an 11-point numeric rating scale from 0 to 10. Analysis was conducted on the evaluable population. Results: Of the 180 patients assessed for eligibility, the final study cohort comprised 102 patients: 48 randomized to POINT and 54 to control. Of these, 79 patients (77.5%) were women and median age was 52 (interquartile range, 43-62) years. A total of 550 opioid tablets were prescribed to the control group, and 230 tablets were prescribed to the POINT group, in which 23 patients (47.9%) opted in for an opioid prescription. None who opted out subsequently required rescue opioids. In the first postoperative week, 17 POINT patients (35.4% of survey responders in the POINT group) reported consuming opioids compared with 27 (50.0%) control patients (P = .16). Median peak outpatient pain scores were 6 (interquartile range, 4-8) in the control group vs 6 (interquartile range, 5-7) in the POINT group (P = .71). In multivariate analysis, patients with a history of narcotic use were 7.5 times more likely to opt in (95% CI, 1.61-50.11; P = .02) and 4.8 times more likely to consume opioids (95% CI, 1.04-1.52; P = .01). Higher body mass index (odds ratio, 1.11; 95% CI, 1.01-1.23; P = .03) and highest inpatient postoperative pain score (odds ratio, 1.24; 95% CI, 1.04-1.52; P = .02) were also associated with opioid consumption. Conclusions and Relevance: In this trial, an opt-in strategy for postoperative narcotics reduced opioid prescription without increasing pain after cervical endocrine surgery. Trial Registration: ClinicalTrials.gov Identifier: NCT04710069.

Longitudinal Assessment of Quality of Life Following Molecular Testing for Indeterminate Thyroid Nodules.

BACKGROUND: Molecular testing can refine the risk of malignancy in cytologically indeterminate thyroid nodules and can reduce the need for diagnostic thyroidectomy. However, quality of life (QOL) in patients mananged with molecular testing is not well studied. OBJECTIVE: We aimed to assess the QOL of patients undergoing surveillance after a benign molecular test result, or thyroidectomy after a suspicious molecular test result. METHODS: This prospective longitudinal follow-up of the Effectiveness of Molecular Testing Techniques for Diagnosis of Indeterminate Thyroid Nodules randomized trial utilized the Thyroid-Related Patient-Reported Outcome, 39-item version (ThyPro-39) to assess the QOL of patients with indeterminate cytology on thyroid fine needle aspiration (FNA) biopsy. All patients underwent molecular testing at the time of initial FNA. A mixed-effect model was used to determine changes in QOL over time. RESULTS: Of 252 eligible patients, 174 completed the assessment (69% response rate). Molecular test results included 72% (n = 124) benign and 28% (n = 50) suspicious. ThyPro-39 scores of benign molecular test patients were unchanged from baseline (following initial FNA and molecular test results) to 18 months of ultrasound surveillance. Baseline symptoms of goiter, anxiety, and depression were more severe for patients with suspicious compared with benign molecular test results. At a median of 8 months after thyroidectomy, suspicious molecular test patients reported improved symptoms of goiter, anxiety, and depression. CONCLUSION: A benign molecular test provides sustained QOL throughout ultrasound surveillance, without worsening anxiety or depression relating to the risk of malignancy. Definitive surgery results in improvement of QOL in patients with suspicious molecular tests.

Systems-Level Opportunities in the Management of Primary Hyperparathyroidism: An Informatics-based Assessment.

CONTEXT: Primary hyperparathyroidism (PHPT), a leading cause of hypercalcemia and secondary osteoporosis, is underdiagnosed. OBJECTIVE: This work aims to establish a foundation for an electronic medical record-based intervention that would prompt serum parathyroid hormone (PTH) assessment in patients with persistent hypercalcemia and identify care gaps in their management. METHODS: A retrospective cohort study was conducted in a tertiary academic health system of outpatients with persistent hypercalcemia, who were categorized as having classic or normohormonal PHPT. Main outcome measures included the frequencies of serum PTH measurement in patients with persistent hypercalcemia, and their subsequent workup with bone mineral density (BMD) assessment, and ultimately, medical therapy or parathyroidectomy. RESULTS: Among 3151 patients with persistent hypercalcemia, 1526 (48%) had PTH measured, of whom 1377 (90%) were confirmed to have classic (49%) or normohormonal (41%) PHPT. PTH was measured in 65% of hypercalcemic patients with osteopenia or osteoporosis (P < .001). At median 2-year follow-up, bone density was assessed in 275 (20%) patients with either variant of PHPT (P = .003). Of women aged 50 years or older with classic PHPT, 95 (19%) underwent BMD assessment. Of patients with classic or normohormonal PHPT, 919 patients (67%) met consensus criteria for surgical intervention, though only 143 (15%) underwent parathyroidectomy. CONCLUSION: Within a large academic health system, more than half of patients with confirmed hypercalcemia were not assessed for PHPT, including many patients with preexisting bone disease. Care gaps in BMD assessment and medical or surgical therapy represent missed opportunities to avoid skeletal and other complications of PHPT.

Outcomes of Indeterminate Thyroid Nodules Managed Nonoperatively after Molecular Testing.

CONTEXT: Molecular testing to refine the diagnosis of cytologically indeterminate thyroid nodules has become increasingly popular, but data on long-term durability of test results and the rate of delayed operation are limited. OBJECTIVE: Determine the delayed rate of surgical resection in indeterminate nodules with benign/negative molecular testing and the risk of false-negative molecular test results. DESIGN: Prospective follow-up of the Gene Expression Classifier vs Targeted Next-Generation Sequencing in the Management of Indeterminate Thyroid Nodules randomized controlled trial comparing the diagnostic test performance of Afirma Gene Expression Classifier and ThyroSeq v2. SETTING: University of California, Los Angeles. PARTICIPANTS: Patients who underwent thyroid biopsy with indeterminate (Bethesda III/IV) cytology (April 2016 to July 2017). INTERVENTION: Ultrasound surveillance. MAIN OUTCOME MEASURE: False-negative rate of molecular testing. RESULTS: Of 95 indeterminate nodules with negative/benign molecular test results, 12 nodules underwent immediate resection (11 benign nodules, 1 noninvasive follicular thyroid neoplasm nodule with papillary-like nuclear features). Nonoperative management was pursued for 83 (87.4%) nodules. The median surveillance was 26.7 months. Ten nodules were resected during surveillance and malignancy was identified in 4 nodules (overall false-negative rate of 5.8%). In the 4 malignant nodules that underwent delayed operation, surgery was prompted by sonographic changes during surveillance. CONCLUSIONS: The majority of indeterminate nodules with negative molecular testing have a stable clinical course over 3 years of follow-up, but our finding of a 6% false-negative rate highlights the importance of continuing sonographic surveillance. Long-term studies are needed to determine the optimal length of follow-up.

Effectiveness of Molecular Testing Techniques for Diagnosis of Indeterminate Thyroid Nodules: A Randomized Clinical Trial.

IMPORTANCE: Approximately 20% of thyroid nodules display indeterminate cytology. Molecular testing can refine the risk of malignancy and reduce the need for diagnostic hemithyroidectomy. OBJECTIVE: To compare the diagnostic performance between an RNA test (Afirma genomic sequencing classifier) and DNA-RNA test (ThyroSeq v3 multigene genomic classifier). DESIGN, SETTING, AND PARTICIPANTS: This parallel randomized clinical trial of monthly block randomization included patients in the UCLA Health system who underwent thyroid biopsy from August 2017 to January 2020 with indeterminate cytology (Bethesda System for Reporting Thyroid Cytopathology category III or IV). INTERVENTIONS: Molecular testing with the RNA test or DNA-RNA test. MAIN OUTCOMES AND MEASURES: Diagnostic test performance of the RNA test compared with the DNA-RNA test. The secondary outcome was comparison of test performance with prior versions of the molecular tests. RESULTS: Of 2368 patients, 397 were eligible for inclusion based on indeterminate cytology, and 346 (median [interquartile range] age, 55 [44-67] years; 266 [76.9%] women) were randomized to 1 of the 2 tests. In the total cohort assessed for eligibility, 3140 thyroid nodules were assessed, and 427 (13.6%) nodules were cytologically indeterminate. The prevalence of malignancy was 20% among indeterminate nodules. The benign call rate was 53% (95% CI, 47%-61%) for the RNA test and 61% (95% CI, 53%-68%) for the DNA-RNA test. The specificities of the RNA test and DNA-RNA test were 80% (95% CI, 72%-86%) and 85% (95% CI, 77%-91%), respectively (P = .33); the positive predictive values (PPV) of the RNA test and DNA-RNA test were 53% (95% CI, 40%-67%) and 63% (95% CI, 48%-77%), respectively (P = .33). The RNA test exhibited a higher PPV compared with the prior test version (Afirma gene expression classifier) (54% [95% CI, 40%-67%] vs 38% [95% CI, 27%-48%]; P = .01). The DNA-RNA test had no statistically significant difference in PPV compared with its prior version (ThyroSeq v2 next-generation sequencing) (63% [95% CI, 48%-77%] vs 58% [95% CI, 43%-73%]; P = .75). Diagnostic thyroidectomy was avoided in 87 (51%) patients tested with the RNA test and 83 (49%) patients tested with the DNA-RNA test. Surveillance ultrasonography was available for 90 nodules, of which 85 (94%) remained stable over a median of 12 months follow-up. CONCLUSIONS AND RELEVANCE: Both the RNA test and DNA-RNA test displayed high specificity and allowed 49% of patients with indeterminate nodules to avoid diagnostic surgery. Although previous trials demonstrated that the prior version of the DNA-RNA test was more specific than the prior version of the RNA test, the current molecular test techniques have no statistically significant difference in performance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02681328.

Measuring patient perceptions of surgeon communication performance in the treatment of thyroid nodules and thyroid cancer using the communication assessment tool.

BACKGROUND: Thyroid surgeons are offering their patients less aggressive diagnostic and therapeutic management strategies for thyroid nodules and low-risk thyroid cancer in an effort to decrease overdiagnosis and overtreatment of indolent disease. Explaining the rationale for less aggressive management plans requires physicians to be effective communicators. We aimed to assess the communication skills of thyroid surgeons with the Makoul Communication Assessment Tool and to identify risk factors for poor communication. METHODS: New adult patients with thyroid nodules or thyroid cancer presenting to a single tertiary-referral endocrine surgery clinic were enrolled from July 2018 through December 2019. Patients were administered the Communication Assessment Tool immediately after their clinical encounter. Outlier communication scores were identified, and clinical characteristics were compared between outlier and nonoutlier groups. RESULTS: A total of 107 patients completed the Communication Assessment Tool. Mean (standard deviation) total and top box scores were 67 (6) and 86% (29%), respectively. Twenty-five patients (23%) were in the low-outlier group, defined by a total score below 67.5/70 or top box score below 82.25%. Other race and non-Hispanic patients (versus white race) were more likely low outliers (odds ratio 3.58, P = .048). The lowest scoring Communication Assessment Tool item overall was "the doctor encouraged me to ask questions" (78.5% top box). CONCLUSION: We found communication to be perceived as excellent in the majority of patients; however, an opportunity for improvement was identified in 29% of participants. Significant differences in race and ethnicity between low outlier and nonoutlier communication score patients were observed, which warrants additional investigation. These findings support the utility of the Communication Assessment Tool in studying the effectiveness of communication improvement initiatives.

Rising Incidence and Incidence-Based Mortality of Thyroid Cancer in California, 2000-2017.

CONTEXT: The increased incidence of thyroid cancer globally over the past several decades is principally attributed to small, indolent papillary thyroid cancers. A possible concomitant increase in thyroid cancer-specific mortality remains debated. OBJECTIVE: The changes in thyroid cancer incidence and incidence-based mortality were assessed using a large population-based cohort over an 18-year period. DESIGN & PATIENTS: A retrospective analysis of all thyroid cancers reported in the California Cancer Registry was performed (2000-2017). Age-adjusted incidence and incidence-based mortality rates were analyzed using a log-linear model to estimate annual percent change. RESULTS: We identified 69 684 individuals (76% female, median age 50 years) diagnosed with thyroid cancer. The incidence of thyroid cancer increased across all histological subtypes (papillary, follicular, medullary, and anaplastic) and all tumor sizes. The incidence increased from 6.43 to 11.13 per 100 000 person-years (average increase 4% per year; P < 0.001) over the study period. Thyroid cancer-specific mortality rates increased on average by 1.7% per year (P < 0.001). The increased mortality rates were greater in men (2.7% per year, P < 0.001) and patients with larger tumors (2-4 cm) (3.4% per year, P < 0.05). CONCLUSIONS: Data from this statewide registry demonstrate that the incidence of thyroid cancer is increasing, and that this phenomenon is not restricted to small papillary thyroid cancers. Rising incidence in thyroid cancers of all sizes with concurrent increase of incidence-based mortality in men and those with larger tumors suggest a true increase in clinically significant disease.

Who Benefits from Treatment of Primary Hyperparathyroidism?

Parathyroidectomy (PTx) is the only definitive treatment for primary hyperparathyroidism (PHPT), but is commonly underutilized. Most patients are medically observed, whereas approximately 30% of patients are treated operatively. PTx is a low-risk surgical procedure and the most cost-effective treatment option. An international consensus statement was published in 1990 to guide clinicians in the management of patients with PHPT, particularly those with asymptomatic disease. Most patients with PHPT and low perioperative risk benefit from surgical treatment, regardless of whether they meet consensus criteria, due to fracture risk reduction, health-related quality-of-life improvements, and prevention or mitigation of disease progression.