Department of Pathology; Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Division of Endocrinology, Department of Medicine; Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Thyroid. 2021 Aug;31(8):1253-1263. doi: 10.1089/thy.2020.0969. Epub 2021 Jun 22.
Molecular testing (MT) refines risk stratification for thyroid nodules that are indeterminate for cancer by fine needle aspiration (FNA) cytology. Criteria for selecting nodules for MT vary and remain largely untested, raising questions about the best strategy for maximizing the usefulness of MT while minimizing the harms of overtesting. We used a unique data set to examine the effects of repeat FNA cytology-based criteria for MT on management decisions and nodule outcomes. This was a study of adults (age 25-90 years; 281 women and 72 men) with cytologically indeterminate (Bethesda III/IV) thyroid nodules who underwent repeat FNA biopsy and Afirma Gene Expression Classifier (GEC) testing ( = 363 nodules from 353 patients) between June 2013 and October 2017 at a single institution, with follow-up data collected until December 2019. Subgroup analysis was performed based on classification of repeat FNA cytology. Outcomes of GEC testing, clinical/sonographic surveillance of unresected nodules, and histopathologic diagnoses of thyroidectomies were compared between three testing approaches: (i) Reflex (MT sent on the basis of the initial Bethesda III/IV FNA), (ii) SemiRestrictive (MT sent if repeat FNA is Bethesda I-IV), and (iii) Restrictive (MT sent only if repeat FNA is Bethesda III/IV) testing approaches. Restricting MT to nodules that remain Bethesda III/IV on repeat FNA would have missed 4 low-risk cancers and 3 noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) (collectively 2% of the test population) but would have avoided diagnostic surgery for 42 benign nodules (12% of the test population). The Restrictive testing strategy was more specific (delta 0.126 confidence interval [CI 0.093 to 0.159] and 0.129 [CI 0.097 to 0.161], respectively) but less sensitive (delta -0.339 [CI -0.424 to -0.253] and -0.340 [CI -0.425 to -0.255], respectively) than the Reflex and SemiRestrictive approaches for detecting NIFTP or cancer. Repeat FNA cytology can guide the selection of cytologically indeterminate thyroid nodules that warrant MT. The Restrictive model of performing Afirma GEC only on nodules with two separate biopsies showing Bethesda III/IV cytology would reduce the rate of diagnostic surgery for histologically benign nodules while missing only rare low-risk tumors. Given the low but nontrivial risks of thyroidectomy, the higher specificity of the Restrictive testing approach disproportionately outweighs the potential harms.
分子检测（MT）通过细针抽吸（FNA）细胞学来细化对癌症不确定的甲状腺结节的风险分层。选择进行 MT 的结节的标准各不相同，且在很大程度上未经检验，这引发了关于最大限度地提高 MT 有用性而最小化过度检测危害的最佳策略的问题。我们使用独特的数据集中，研究了基于重复 FNA 细胞学的 MT 标准对管理决策和结节结果的影响。这是一项对 25-90 岁（281 名女性和 72 名男性）细胞学不确定（Bethesda III/IV）甲状腺结节患者的研究，这些患者在 2013 年 6 月至 2017 年 10 月期间在一家机构接受了重复 FNA 活检和 Afirma 基因表达分类器（GEC）检测（来自 353 名患者的 363 个结节），并在 2019 年 12 月之前收集了随访数据。根据重复 FNA 细胞学的分类进行了亚组分析。比较了三种检测方法（Reflex、SemiRestrictive 和 Restrictive）的 GEC 检测结果、未切除结节的临床/超声监测和甲状腺切除术的组织病理学诊断：（i）Reflex（基于初始 Bethesda III/IV FNA 发送 MT）、（ii）SemiRestrictive（如果重复 FNA 是 Bethesda I-IV，则发送 MT）和（iii）Restrictive（仅在重复 FNA 是 Bethesda III/IV 时发送 MT）。将 MT 限制在重复 FNA 仍为 Bethesda III/IV 的结节上，将错过 4 例低风险癌症和 3 例具有乳头状核特征的非侵袭性滤泡性甲状腺肿瘤（NIFTP）（总测试人群的 2%），但将避免对 42 个良性结节进行诊断性手术（总测试人群的 12%）。限制性检测策略更具特异性（0.126 置信区间 [CI 0.093 至 0.159]和 0.129 [CI 0.097 至 0.161]，分别），但敏感性较低（0.339 [CI 0.424 至 0.253]和 0.340 [CI 0.425 至 0.255]，分别），与 Reflex 和 SemiRestrictive 方法相比，前者用于检测 NIFTP 或癌症。重复 FNA 细胞学可以指导选择需要 MT 的细胞学不确定的甲状腺结节。仅对两个单独的活检显示 Bethesda III/IV 细胞学的结节进行 Afirma GEC 的限制性模型将减少对组织学良性结节进行诊断性手术的比率，同时仅错过罕见的低风险肿瘤。鉴于甲状腺切除术的风险较低但并非微不足道，限制性检测方法的更高特异性不成比例地超过了潜在危害。
