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 PARTICIPANTSThis 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.
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.
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.
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 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 (GEC) 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 nodules benign, 1 nodule noninvasive follicular thyroid neoplasm 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 5% false-negative rate highlights the importance of continuing sonographic surveillance. Long-term studies are needed to determine the optimal length of follow-up.
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