Background: Bethesda III and IV thyroid nodules, which fall under the category of indeterminate cytology, pose challenges in clinical decision-making due to their ambiguous risk of malignancy. Molecular testing has been increasingly employed to aid risk stratification and optimize the extent of surgical intervention.Methods: A retrospective review of 410 patients with Bethesda III and IV thyroid nodules who underwent thyroid surgery at McGill University teaching hospitals between January 2016 and April 2022. Patients were grouped based on whether or not they underwent preoperative molecular testing. Data were collected on demographic variables, histopathologic diagnosis, mutation profiles, and surgical outcomes. The primary outcome was to assess for concordance between surgical intervention and final pathology in both groups, with a focus on identifying optimal versus suboptimal management. Optimal management is defined as surgery appropriate to the aggressiveness of disease, meaning a hemi-thyroidectomy for a non-aggressive malignancy, total thyroidectomy for an aggressive malignancy, and no surgery for a benign nodule. Furthermore, suboptimal management includes unnecessary surgery or incorrect surgery for the level of aggressivity of the nodule.Results: Among the 410 patients, 203 underwent molecular testing, while 207 did not. Of those who underwent molecular testing, 117 had Bethesda III nodules and 86 had Bethesda IV nodules. In the non-tested group, 129 and 78 patients had Bethesda III and IV nodules, respectively. Optimal surgical intervention was achieved in 67.5% of patients who underwent molecular testing, compared with 25.1% in those who did not (p< 0.001). Subgroup analysis revealed that 61.5% of Bethesda III nodules with molecular testing received optimal care versus 21.0% of those without testing. In the Bethesda IV cohort, optimal surgery was achieved in 75.6% with testing versus 32.1% without. Among the suboptimally managed patients, 70.1% (155/221) were from the group that did not undergo molecular testing. In addition, molecular testing identified aggressive mutations such asBRAF V600EandTERTpromoter mutations more frequently in Bethesda III nodules, whileRAS-like mutations, associated with indolent behavior, predominated in Bethesda IV nodules.Conclusions: In this study, molecular testing significantly improved risk stratification and the likelihood of optimal surgical management in patients with Bethesda III and IV thyroid nodules. Incorporating molecular diagnostics into the standard preoperative workflow may enhance patient care, reduce unnecessary surgeries, and optimize the extent of surgery. Future studies should evaluate the cost-effectiveness and broader implementation of molecular testing in diverse healthcare settings.
背景：Bethesda III类和IV类甲状腺结节属于细胞学不确定类别，因其恶性风险不明确给临床决策带来挑战。分子检测已越来越多地用于辅助风险分层并优化手术干预范围。 方法：回顾性分析2016年1月至2022年4月期间在麦吉尔大学教学医院接受甲状腺手术的410例Bethesda III类和IV类甲状腺结节患者。根据是否接受术前分子检测将患者分组。收集人口统计学变量、组织病理学诊断、突变谱和手术结果数据。主要结局是评估两组患者手术干预与最终病理结果的一致性，重点关注最佳与次优管理的识别。最佳管理定义为与疾病侵袭性相匹配的手术，即对非侵袭性恶性肿瘤行甲状腺半切除术，对侵袭性恶性肿瘤行全甲状腺切除术，良性结节不手术。次优管理包括不必要的手术或与结节侵袭程度不符的手术。 结果：在410例患者中，203例接受了分子检测，207例未接受。在接受分子检测的患者中，117例为Bethesda III类结节，86例为Bethesda IV类结节。在未检测组中，分别有129例和78例患者为Bethesda III类和IV类结节。接受分子检测的患者中，67.5%实现了最佳手术干预，而未检测组仅为25.1%（p<0.001）。亚组分析显示，接受分子检测的Bethesda III类结节中61.5%获得最佳治疗，而未检测组仅为21.0%。在Bethesda IV类队列中，接受检测组最佳手术率为75.6%，未检测组为32.1%。在次优管理的患者中，70.1%（155/221）来自未接受分子检测组。此外，分子检测更频繁地在Bethesda III类结节中识别出侵袭性突变（如BRAF V600E和TERT启动子突变），而与惰性行为相关的RAS样突变在Bethesda IV类结节中占主导。 结论：本研究显示，分子检测显著改善了Bethesda III类和IV类甲状腺结节患者的风险分层，并提高了最佳手术管理的可能性。将分子诊断纳入标准术前工作流程可提升患者护理质量，减少不必要手术，并优化手术范围。未来研究应评估分子检测在不同医疗环境中的成本效益和更广泛实施。
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