Prognostic Value of Preoperative Molecular Testing and Implications for Initial Surgical Management in Thyroid Nodules Harboring Suspected (Bethesda V) or Known (Bethesda VI) Papillary Thyroid Cancer

Importance: Molecular 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. Objective: To 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 Participants: This 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. Exposures: Masked ThyroSeq, version 3 molecular analysis after completion of initial treatment and acquisition of follow-up data. Main Outcomes and Measures: Structural 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. Results: In 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 Relevance: Among 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.