Abstract Introduction: The diagnostic utility of molecular profiling for the evaluation of indeterminate pediatric thyroid nodules is unclear. We aimed to assess pediatric cases with indeterminate thyroid fine-needle aspiration (FNA) alongside clinicopathologic features and mutational analysis. Methods: A retrospective review of 126 patients with indeterminate cytology who underwent FNA between January 2010 and December 2021 at the Children’s Hospital of Philadelphia was performed. Indeterminate cases defined by The Bethesda System for Reporting Thyroid Cytopathology (AUS/FLUS or TBSRTC III; FN/SFN or TBSRTC IV; SM or TBSRTC V) were correlated to clinicopathologic and genetic characteristics. Results: Of the 114 surgical cases, 48% were malignant, with the majority of malignant cases diagnosed as follicular variant of papillary thyroid carcinoma (28/55). Risk of malignancy increased with TBSRTC category: 23% for AUS/FLUS, 51% for FN/SFN, and 100% for SM nodules. There were significant differences in surgical approach (p < 0.01), performance of lymph node dissection (p < 0.01), histological diagnosis (p < 0.01), primary tumor focality/laterality (p = 0.04), and lymphatic invasion (p = 0.02) based on TBSRTC classification, with resultant differences in post-surgical risk stratification per American Thyroid Association (ATA) pediatric guidelines (p = 0.01). Approximately 89% (49/55) of cases were classified as ATA low-risk, and 5 of 6 patients with ATA intermediate- or high-risk disease had SM cytology. Somatic molecular testing was performed in 40% (51/126) of tumors; 77% (27/35) of malignant cases and 38% (6/16) of benign cases harbored driver alteration(s). Of the driver-positive malignant cases, 52% (14/27) were associated with low-risk (DICER1, PTEN, RAS, and TSHR mutations), 33% (9/27) were associated with high-risk (BRAF mutations and ALK, NTRK, and RET fusions), and 15% (4/27) had unreported risk for invasive disease (APC, BLM, and PPM1D mutations and TG-FGFR1 fusion). Incidence of high-risk drivers increased with TBSRTC category. Approximately 23% (8/35) of patients harboring thyroid malignancy did not have an identifiable driver alteration. Conclusions: Molecular analysis is useful to discriminate benign and malignant thyroid nodules with indeterminate cytology. Patients with driver genetic alteration(s) and indeterminate cytology should consider surgical management secondary to the high incidence (82%; 27/33) of thyroid malignancy in these patients.


中文翻译：

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儿科不确定性甲状腺细针穿刺：探索分子谱分析的临床病理特征和效用

摘要 介绍：分子谱分析在评估不确定的小儿甲状腺结节中的诊断效用尚不清楚。我们旨在评估甲状腺细针穿刺 (FNA) 不确定的儿科病例以及临床病理特征和突变分析。方法：对 2010 年 1 月至 2021 年 12 月期间在费城儿童医院接受 FNA 的 126 例细胞学不确定的患者进行回顾性分析。贝塞斯达甲状腺细胞病理学报告系统（AUS/FLUS 或 TBSRTC III；FN/SFN 或 TBSRTC IV；SM 或 TBSRTC V）定义的不确定病例与临床病理学和遗传特征相关。结果：114例手术中，48%为恶性，大多数恶性病例被诊断为甲状腺乳头状癌的滤泡型变异 (28/55)。TBSRTC 类别的恶性肿瘤风险增加：AUS/FLUS 为 23%，FN/SFN 为 51%，SM 结节为 100%。在手术方法 (p < 0.01)、淋巴结清扫术 (p < 0.01)、组织学诊断 (p < 0.01)、原发肿瘤局灶性/偏侧性 (p = 0.04) 和淋巴管浸润 (p = 0.02) 方面存在显着差异) 基于 TBSRTC 分类，根据美国甲状腺协会 (ATA) 儿科指南在术后风险分层中产生差异 (p = 0.01)。大约 89% (49/55) 的病例被归类为 ATA 低危，6 例 ATA 中危或高危患者中有 5 例细胞学检查结果为 SM。40% (51/126) 的肿瘤进行了体细胞分子检测；77% (27/35) 的恶性病例和 38% (6/16) 的良性病例存在驱动程序改变。在驱动程序阳性的恶性病例中，52% (14/27) 与低风险（DICER1、PTEN、RAS 和 TSHR 突变）相关，33%（9/27）与高风险（BRAF 突变和ALK、NTRK 和 RET 融合），15% (4/27) 有未报告的侵袭性疾病风险（APC、BLM 和 PPM1D 突变和 TG-FGFR1 融合）。随着 TBSRTC 类别的增加，高风险驾驶员的发生率增加。大约 23% (8/35) 的患有甲状腺恶性肿瘤的患者没有可识别的驱动改变。结论：分子分析有助于鉴别细胞学不确定的甲状腺结节的良恶性。