Introduction: Hyperfunctioning papillary thyroid carcinoma (PTC) is rare and consequently, little information on its molecular etiology is available. Although BRAF V600E (BRAF c.1799T#x3e;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 #x3c;0.8 IU/L (reference value: #x3c;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#x3e;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.
Eur Thyroid J

中文翻译：

---

功能亢进的乳头状甲状腺癌与BRAF突变：第一例报告和文献复习。

简介：机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＃x3e; A，p.V600E）在PTC中是显着的癌基因，但在功能亢进的PTC中尚未报道其突变。病例介绍：超声检查发现一名48岁男性甲状腺右叶有一个26毫米结节。甲状腺功能测试表明他是甲状腺功能亢进症，TSH水平为0.01 mIU / L（参考范围：0.05–5.00），游离甲状腺素水平为23.2 pmol / L（参考范围：11.6–21.9）。TSHR自身抗体为＃x3c; 0.8 IU / L（参考值：＃x3c; 2.0 IU / L）。该^99米Tc甲状腺闪烁图显示，结节对示踪剂的摄取集中在圆形的右侧，而其余腺体的摄取减少。该患者接受全甲状腺切除术是因为细针穿刺细胞学检查显示为恶性肿瘤。组织病理学诊断为常规PTC。BRAF（第15外显子），TSHR（第1-10外显子），GNAS（第7-10外显子），EZH1（第16外显子），KRAS，NRAS，HRAS（第12、13和61号密码子）和TERT启动子的后续突变分析（C250T和C228T）在肿瘤组织样品中鉴定了BRAF V600E中的杂合点突变。此外，我们确定了TSHR肿瘤和周围正常甲状腺组织中的D727E多态性（TSHR c.2181C＃x3e; G，p.D727E）。讨论与结论：我们首次报道了一个具有BRAF V600E突变的功能亢进PTC病例。我们的文献搜索产生了16例甲状腺功能亢进癌，其中进行了突变分析。我们在其中13例病例中发现了TSHR突变。一个病例显示出TSHR和KRAS突变的组合。另一例显示带有PAX8 / PPARG的TSHR突变重排。这些发现表明，癌基因的伴随激活（除了TSHR-环状AMP级联的组成性激活）与甲状腺功能亢进结节中的恶性表型有关。
甲状腺素