Multifocal papillary thyroid carcinomas (PTCs) are common and the majority of the tumors harbor mutual BRAF p.V600E mutation. This study aimed to investigate a contemporary series of multifocal PTCs with discordant molecular drivers. Consecutive thyroidectomies diagnosed with multifocal PTCs ≥0.5 cm between 2019 and 2023 were reviewed. Immunohistochemistry (IHC) for BRAF VE1 was performed for all tumors. Cases with discordant BRAF IHC results or morphologic discrepancy were identified, and BRAF IHC-negative tumors were subjected to RAS Q61R IHC and/or targeted RNA next-generation sequencing. A total of 770 patients with a main PTC ≥0.5 cm were identified; 255 (33.1%) had multifocal disease, and 142 (18.4%) had at least another PTC ≥0.5 cm. Among them, 13 cases (9.2%, 13/142) had discordant molecular drivers. Twelve cases had one or more BRAF-positive PTCs accompanied by a BRAF-negative PTC (3 with CCDC6::RET fusion, 1 with NCOA4::RET fusion, 1 with ACBD5::RET fusion, 2 with ETV6::NTRK3 fusion, 1 with TG::FGFR1 fusion, 1 with LMTK2::BRAF fusion, 1 with AGK::BRAF fusion and RAS p.Q61R mutation, 1 with RAS p.Q61R mutation, and 1 without detectable molecular drivers). The last case had tumors with discordant fusion drivers (VIM::NTRK3 and TNS1::BRAF). Most cases showed tumors that were morphologically distinct (92.3%, 12/13) and occurred in the contralateral lobes (76.9%, 10/13). Notably, we identified 4 cases (30.8%) that presented as collision tumors and 6 cases (46.2%) that showed lymph node metastases, including 2 with simultaneous involvement by tumors with discordant molecular drivers, as novel findings. In summary, a subset (9.2%) of multifocal PTCs had discordant molecular drivers and 84.6% of them were a combination of BRAF-positive and kinase gene fusion-associated PTCs, most with distinct morphologies. Almost half of the cases had nodal metastasis and a third of them showed simultaneous involvement by tumors with discordant molecular drivers. The results highlight the clinical importance of identifying such cases, given the potentially different treatments.

中文翻译：

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分子驱动因素不一致的多灶性甲状腺状癌：强调形态学和碰撞肿瘤。


多灶性甲状腺状癌 （PTC） 很常见，大多数肿瘤都带有相互的 BRAF p.V600E 突变。本研究旨在研究一系列具有不一致分子驱动因素的当代多焦点 PTC。回顾了 2019 年至 2023 年间诊断为 ≥0.5 cm 多灶性 PTC 的连续甲状腺切除术。对所有肿瘤进行 BRAF VE1 免疫组化 （IHC）。确定了 BRAF IHC 结果不一致或形态学差异的病例，并对 BRAF IHC 阴性肿瘤进行 RAS Q61R IHC 和/或靶向 RNA 下一代测序。共确定了 770 例主要 PTC ≥0.5 cm 的患者;255 例 （33.1%） 患有多灶性疾病，142 例 （18.4%） 至少患有另一种 PTC ≥0.5 cm。其中 13 例 （9.2%，13/142） 存在不一致的分子驱动因素。12 例有一个或多个 BRAF 阳性 PTC 伴有 BRAF 阴性 PTC（3 例 CCDC6：：RET 融合，1 例 NCOA4：：RET 融合，1 例 ACBD5：：RET 融合，2 例 ETV6：：NTRK3 融合，1 例 TG：：FGFR1 融合，1 例 LMTK2：：BRAF 融合，1 例 AGK：：BRAF 融合和 RAS p.Q61R 突变，1 例 RAS p.Q61R 突变， 和 1 个没有可检测的分子驱动因素）。最后一例肿瘤融合驱动因子不一致 （VIM：：NTRK3 和 TNS1：：BRAF）。大多数病例显示肿瘤形态不同 （92.3%，12/13） 并发生在对侧叶 （76.9%，10/13）。值得注意的是，我们确定了 4 例 （30.8%） 表现为碰撞肿瘤和 6 例 （46.2%） 显示淋巴结转移，其中 2 例同时由分子驱动不一致的肿瘤参与，作为新发现。总之，一部分 （9.2%） 多焦点 PTC 具有不一致的分子驱动因素和 84.其中 6% 是 BRAF 阳性和激酶基因融合相关 PTC 的组合，大多数具有不同的形态。几乎一半的病例有淋巴结转移，其中三分之一的病例显示肿瘤同时参与，分子驱动因素不一致。鉴于可能不同的治疗方法，结果强调了识别此类病例的临床重要性。