Hyperfunctioning Papillary Thyroid Carcinoma with a BRAF Mutation: The First Case Report and a Literature Review
Hyperfunctioning Papillary Thyroid Carcinoma with a BRAF Mutation: The First Case Report and a Literature Review
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伴有 BRAF 突变的功能亢进性甲状腺乳头状癌：首例病例报告及文献综述
DOI：
10.1159/000513552
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发表时间：
2021
影响因子：
4.7
通讯作者：
Sasaki S
中科院分区：
文献类型：
--
作者：
Shinkai S;Ohba K;Kakudo K;Iwaki T;Mimura Y;Matsushita A;Kuroda G;Sakai Y;Nishino N;Umemura K;Suda T;Sasaki S
功能亢进性甲状腺乳头状癌（PTC）是一种罕见的疾病，因此，有关其分子病因的信息很少。虽然BRAF V600 E（BRAF C. 1799 T> A，p.V600E）是PTC的主要癌基因，其突变在功能亢进的PTC中未见报道。病例介绍一位48岁的男性，超声检查发现甲状腺右叶有一个26 mm的结节，甲状腺功能检查显示甲状腺功能亢进，TSH水平为0.01 mIU/L（参考范围：0.05-5.00）和游离甲状腺素水平为23.2 pmol/L（参考范围：11.6-21.9）。TSHR自身抗体< 0.8 IU/L（参考值：< 2.0 IU/L）。99 mTc甲状腺显像显示结节右侧圆形示踪剂摄取灶，其余腺体摄取减少。病人接受甲状腺全切除术，因为细针穿刺细胞学显示恶性肿瘤。组织病理学诊断为常规PTC。随后对BRAF（外显子15）、TSHR（外显子1-10）、GNAS（外显子7-10）、EZH 1（外显子16）、KRAS、NRAS、HRAS（密码子12、13和61）和TERT启动子（C250 T和C228 T）的突变分析鉴定了肿瘤组织样本中BRAF V600 E中的杂合点突变。此外，我们确定了TSHR D 727 E多态性（TSHR c. 2181 C> G，p.D727E）在肿瘤和周围正常甲状腺组织中表达。讨论和结论我们首次报道一例BRAF V600 E突变的功能亢进性PTC。我们的文献检索得到了16例功能亢进性甲状腺癌，其中进行了突变分析。我们在其中13例中发现了TSHR突变。1例病例显示TSHR和KRAS突变的组合;另1例病例显示TSHR突变伴PAX 8/PPARG重排。这些结果表明，癌基因的伴随激活（除了组成性激活的TSH-环AMP级联反应）与恶性表型在功能亢进的甲状腺结节。
IntroductionHyperfunctioning papillary thyroid carcinoma (PTC) is rare and consequently, little information on its molecular etiology is available. Although BRAF V600E (BRAF c. 1799T> A, p. V600E) is a prominent oncogene in PTC, its mutation has not yet been reported in hyperfunctioning PTC.Case PresentationUltrasonography detected a 26-mm nodule in the right lobe of the thyroid gland of a 48-year-old man. Thyroid function tests indicated that he was hyperthyroid with a TSH level of 0.01 mIU/L (reference range: 0.05–5.00) and a free thyroxine level of 23.2 pmol/L (reference range: 11.6–21.9). TSHR autoantibodies were< 0.8 IU/L (reference value:< 2.0 IU/L). The99mTc thyroid scintigram revealed a round, right-sided focus of tracer uptake by the nodule with a decreased uptake in the remainder of the gland. The patient underwent total thyroidectomy because fine-needle aspiration cytology revealed a malignancy. The histopathological diagnosis was conventional PTC. Subsequent mutational analysis of BRAF (exon 15), TSHR (exons 1–10), GNAS (exons 7–10), EZH1 (exon 16), KRAS, NRAS, HRAS (codons 12, 13, and 61), and TERT promoter (C250T and C228T) identified a heterozygous point mutation in BRAF V600E in a tumor tissue sample. In addition, we identified a TSHR D727E polymorphism (TSHR c. 2181C> G, p. D727E) in both the tumor and the surrounding normal thyroid tissue.Discussion and ConclusionsWe report a case of hyperfunctioning PTC with a BRAF V600E mutation for the first time. Our literature search yielded 16 cases of hyperfunctioning thyroid carcinoma in which a mutational analysis was conducted. We identified TSHR mutations in 13 of these cases. One case revealed a combination of TSHR and KRAS mutations; the other case revealed a TSHR mutation with a PAX8/PPARG rearrangement. These findings suggest that the concomitant activation of oncogenes (in addition to constitutive activation of the TSHR-cyclic AMP cascade) are associated with the malignant phenotype in hyperfunctioning thyroid nodules.