INTRODUCTION Hyperfunctioning 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 PRESENTATION Ultrasonography 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). The 99mTc 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 CONCLUSIONS We 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.

中文翻译：

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具有 BRAF 突变的功能亢进性甲状腺乳头状癌：首例报告和文献回顾。

引言 功能亢进的甲状腺乳头状癌 (PTC) 很少见，因此，关于其分子病因学的信息很少。尽管 BRAF V600E (BRAF c.1799T>A, p.V600E) 是 PTC 中的一个重要癌基因，但尚未报道其突变在功能亢进的 PTC 中。病例介绍 超声检查在一名 48 岁男性的甲状腺右叶发现一个 26 毫米的结节。甲状腺功能检查提示他甲状腺功能亢进，TSH 水平 0.01 mIU/L（参考范围：0.05-5.00），游离甲状腺素水平 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）。99mTc 甲状腺闪烁图显示结节摄取示踪剂的圆形右侧病灶，腺体其余部分的摄取减少。由于细针抽吸细胞学显示为恶性肿瘤，该患者接受了甲状腺全切除术。组织病理学诊断为常规PTC。BRAF（外显子 15）、TSHR（外显子 1-10）、GNAS（外显子 7-10）、EZH1（外显子 16）、KRAS、NRAS、HRAS（密码子 12、13 和 61）和 TERT 启动子的后续突变分析（C250T 和 C228T）在肿瘤组织样本中鉴定了 BRAF V600E 中的杂合点突变。此外，我们在肿瘤和周围正常甲状腺组织中均发现了 TSHR D727E 多态性（TSHR c.2181C>G，p.D727E）。讨论与结论 我们首次报告了一例带有 BRAF V600E 突变的功能亢进的 PTC。我们的文献检索产生了 16 例功能亢进的甲状腺癌，其中进行了突变分析。我们在其中 13 个病例中发现了 TSHR 突变。一个病例显示 TSHR 和 KRAS 突变的组合；另一个病例揭示了具有 PAX8/PPARG 重排的 TSHR 突变。这些发现表明，癌基因的伴随激活（除了 TSHR-环 AMP 级联的组成性激活）与功能亢进的甲状腺结节的恶性表型有关。