Lee Hyun, Kim Sue Youn, Park Ji Min, Jung Seung-Hyun, Mete Ozgur, Jung Chan Kwon
Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
Endocr Pathol. 2025 Mar 18;36(1):7. doi: 10.1007/s12022-025-09852-5.
NTRK fusions are rare but recurrent driver alterations in papillary thyroid carcinoma (PTC), with therapeutic significance due to the availability of targeted TRK inhibitors. Pan-TRK immunohistochemistry (IHC) provides a practical approach for the identification of NTRK fusions; however, its application and reliability in routine pathology require further exploration. This study is aimed at evaluating the diagnostic utility of pan-TRK IHC for detecting NTRK fusions in PTC, assessing its correlation with histopathologic features, and developing a diagnostic algorithm. We analyzed 107 BRAF p.V600E-negative PTC cases using pan-TRK IHC, correlating staining patterns with molecular data and histopathologic features. RNA-based targeted sequencing confirmed gene fusions. NTRK fusion-positive tumors were enriched in distinct histopathologic features, including BRAF-like PTC with predominant follicular architecture, clear cells, and secretory-like cells. Findings such as tumor cell stratification, glomeruloid structures, and papillae with subfollicle formation (microfollicles within papillary structures) were associated with both NTRK and RET fusion-positive PTCs. Correlation of pan-TRK IHC and molecular testing results identified non-specific reactivity or false positivity in 62% of pan-TRK IHC-positive PTCs, including cases with RET fusions, BRAF fusion, or no detectable fusion. However, pan-TRK IHC with high H-scores (≥ 110) was observed exclusively in cases with NTRK fusions. For cases with lower H-scores (< 110), integrating histopathologic features improved the identification of fusion-driven PTCs. While our series further supports the limitations of pan-TRK IHC, a diagnostic algorithm that combines pan-TRK IHC H-scores and histopathologic patterns improved the triaging of NTRK molecular testing of BRAF p.V600E-negative PTCs when a stepwise approach is undertaken. This study also demonstrated that TRK protein localization may vary with tumor progression and dedifferentiation.
神经营养酪氨酸激酶（NTRK）融合在甲状腺乳头状癌（PTC）中罕见但为复发性驱动改变，鉴于靶向TRK抑制剂的可用性而具有治疗意义。泛TRK免疫组织化学（IHC）为识别NTRK融合提供了一种实用方法；然而，其在常规病理学中的应用及可靠性仍需进一步探索。本研究旨在评估泛TRK IHC在检测PTC中NTRK融合的诊断效用，评估其与组织病理学特征的相关性，并制定一种诊断算法。我们使用泛TRK IHC分析了107例BRAF p.V600E阴性的PTC病例，将染色模式与分子数据及组织病理学特征相关联。基于RNA的靶向测序证实了基因融合。NTRK融合阳性肿瘤富含独特的组织病理学特征，包括具有主要滤泡结构、透明细胞和分泌样细胞的BRAF样PTC。肿瘤细胞分层、肾小球样结构以及伴有滤泡下形成（乳头状结构内的微滤泡）的乳头等表现与NTRK和RET融合阳性的PTC均相关。泛TRK IHC与分子检测结果的相关性表明，62%的泛TRK IHC阳性PTC存在非特异性反应或假阳性，包括伴有RET融合、BRAF融合或未检测到融合的病例。然而，高H评分（≥110）的泛TRK IHC仅在NTRK融合病例中观察到。对于H评分较低（<110）的病例，整合组织病理学特征可改善对融合驱动型PTC的识别。虽然我们的系列研究进一步支持了泛TRK IHC的局限性，但当采用逐步方法时，结合泛TRK IHC H评分和组织病理学模式的诊断算法改善了BRAF p.V600E阴性PTC的NTRK分子检测的分类。本研究还表明，TRK蛋白定位可能随肿瘤进展和去分化而变化。
