ImportanceMolecular testing is commonly used in the diagnosis of thyroid nodules with indeterminate cytology. The role of molecular testing in prognosticating oncologic outcomes in thyroid nodules with suspicious or malignant cytology is unclear.ObjectiveTo determine whether molecular profiling of Bethesda V (suspicious for thyroid cancer) and VI (thyroid cancer) nodules is associated with improved prognostication and whether it may inform initial treatment.Design, Setting, and ParticipantsThis retrospective cohort study included consecutive patients with Bethesda V or VI nodules who underwent surgery, with histopathology showing differentiated thyroid cancer, between May 1, 2016, and July 31, 2019 in the University of California, Los Angeles health system. Data were analyzed between April 2, 2021, and January 18, 2023.ExposuresMasked ThyroSeq, version 3 molecular analysis after completion of initial treatment and acquisition of follow-up data.Main Outcomes and MeasuresStructural disease persistence or recurrence, distant metastasis, and recurrence-free survival were assessed using ThyroSeq Cancer Risk Classifier (CRC) molecular risk groups (low, RAS-like; intermediate, BRAF-like; high, combination of BRAF/RAS plus TERT or other high-risk alterations) using Cox proportional hazards regression models.ResultsIn 105 patients with papillary thyroid cancer (median [IQR] follow-up, 3.8 [3.0-4.7] years), ThyroSeq identified genomic alterations in 100 (95%) samples (6 [6%] low risk, 88 [88%] intermediate risk, and 6 [6%] high risk; median [IQR] age, 44 [34-56] years; 68 [68%] female and 32 [32%] male). No patients with low-risk or negative results experienced recurrence. Of the 88 patients with intermediate risk, 6 (7%) experienced local recurrence, with 1 of them also developing distant metastasis. The 6 patients with high risk (all with BRAF V600E plus TERT mutation) underwent total thyroidectomy followed by radioactive iodine (RAI) ablation. Four patients with high risk (67%) experienced local recurrence, with 3 of them also developing distant metastasis. Thus, patients with high-risk alterations were more likely to experience persistence or recurrence and distant metastasis than patients with intermediate risk. In a multivariable analysis incorporating patient age, sex, cancer size, ThyroSeq molecular risk group, extrathyroidal extension, lymph node positivity, American Thyroid Association risk, and RAI ablation, only cancer size (hazard ratio, 1.36; 95% CI, 1.02-1.80) and ThyroSeq CRC molecular risk group (high vs intermediate and low: hazard ratio, 6.22; 95% CI, 1.04-37.36) were associated with structural recurrence.Conclusions and RelevanceAmong the 6% of patients with high-risk ThyroSeq CRC alterations in this cohort study, the majority experienced recurrence or distant metastasis despite initial treatment with total thyroidectomy and RAI ablation. In contrast, patients with low- and intermediate-risk alterations had a low recurrence rate. Preoperative knowledge of molecular alteration status at diagnosis may allow for deescalation of initial surgery and refining of the intensity of postoperative surveillance in patients presenting with Bethesda V and VI thyroid nodules.

Context Molecular testing has improved risk stratification and increased non-operative management for patients with indeterminate thyroid nodules, but data on the long-term outcomes of current molecular tests Afirma Gene Sequencing Classifier (GSC) and Thyroseq v3 are limited. Objective To determine the rate of delayed operation and the false-negative rate of the Afirma GSC and Thyroseq v3 in Bethesda III and IV thyroid nodules. Design Prospective follow-up of a single center randomized clinical trial comparing the performance of Afirma GSC and Thyroseq v3 in the diagnosis of indeterminate thyroid nodules. Setting University of California, Los Angeles Participants Consecutive participants who underwent thyroid biopsy in the UCLA health system with Bethesda III and IV cytology from August 2017 to November 2019. Main Outcomes and Measures False negative rate of molecular testing. Results Of 176 indeterminate nodules with negative or benign molecular test results, 14 (8%) nodules underwent immediate resection, with no malignancies found on surgical pathology. Non-operative management with active surveillance was pursued for 162 (92%) nodules with benign or negative test results. The median surveillance was 34 months (range 12-60 months), and 44 patients were lost to follow-up. Of 15 nodules resected during surveillance, one malignancy was found (overall false negative rate of 0.6%). This was a 2.7 cm minimally invasive Hurthle cell carcinoma that initially tested negative with Thyroseq v3 and underwent delayed resection due to sonographic growth during surveillance. Conclusions The majority of Bethesda III/IV thyroid nodules with negative or benign molecular test results are stable over 3 years of follow-up. These findings support the high sensitivity of current molecular tests and their role in ruling out malignancy in indeterminate thyroid nodules.

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