Sholl Lynette M, Zheng Mei, Nardi Valentina, Hornick Jason L
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
Histopathology. 2021 Aug;79(2):260-264. doi: 10.1111/his.14351. Epub 2021 Apr 7.
Tropomyosin receptor kinase (TRK)-targeted therapies represent an important therapeutic option for patients with advanced solid tumours harbouring neurotrophin receptor kinase (NTRK) gene fusions. However, NTRK fusions are rare in common adult carcinomas, and systematic approaches to screening for these alterations are lacking. Pan-TRK immunohistochemistry (IHC) has been proposed as one method to screen for NTRK fusion-positive tumours. Reflexive testing strategies have been endorsed for several IHC-based biomarkers, and thus offer a convenient and low-cost entry point to incorporate pan-TRK screening.
In this study, 447 consecutive cases of adult solid tumours undergoing mismatch repair (MMR), human epidermal growth factor receptor 2 (HER2) and/or programmed cell death ligand 1 (PD-L1) testing were prospectively stained with pan-TRK IHC. Four cases (0.9%) were pan-TRK positive, including three (1.3% of 223) colonic adenocarcinomas, two of which were MMR-deficient and one (1.4% of 71) was gastroesophageal carcinoma. None of 108 non-small cell lung carcinomas showed pan-TRK expression. NTRK gene fusion was confirmed by DNA sequencing in one MMR-deficient colonic adenocarcinoma. In one MMR-deficient tumour, an alternative mitogen-activated protein kinase (MAPK) driver was identified. In the oesophageal (squamous cell) carcinoma, RNA sequencing identified relative NTRK2 transcript overexpression in the absence of a fusion. In one MMR-proficient colonic adenocarcinoma, no MAPK drivers were identified; therefore, a falsely negative sequencing result was favored. None of the patients met clinical criteria for TRK-targeted therapy.
The clinical impact of pan-TRK IHC 'piggybacking' on existing reflexive testing strategies in surgical pathology appears negligible. Carcinomas may rarely show high-level pan-TRK expression in the absence of an underlying NTRK fusion event.
靶向原肌球蛋白受体激酶（TRK）的疗法是患有神经营养因子受体激酶（NTRK）基因融合的晚期实体瘤患者的重要治疗选择。然而，NTRK融合在常见成人癌中很少见，且缺乏系统的方法来筛查这些改变。泛TRK免疫组织化学（IHC）已被提议作为筛查NTRK融合阳性肿瘤的一种方法。反射性检测策略已被认可用于几种基于IHC的生物标志物，因此为纳入泛TRK筛查提供了一个方便且低成本的切入点。
在本研究中，对447例连续接受错配修复（MMR）、人表皮生长因子受体2（HER2）和/或程序性细胞死亡配体1（PD-L1）检测的成人实体瘤病例进行前瞻性泛TRK IHC染色。4例（0.9%）为泛TRK阳性，包括3例（223例中的1.3%）结肠腺癌，其中2例为MMR缺陷型，1例（71例中的1.4%）为胃食管癌。108例非小细胞肺癌均未显示泛TRK表达。通过DNA测序在1例MMR缺陷型结肠腺癌中证实了NTRK基因融合。在1例MMR缺陷型肿瘤中，鉴定出一种替代的丝裂原活化蛋白激酶（MAPK）驱动因子。在食管（鳞状细胞）癌中，RNA测序发现在无融合的情况下相对NTRK2转录本过表达。在1例MMR proficient结肠腺癌中，未鉴定出MAPK驱动因子；因此，倾向于假阴性测序结果。所有患者均不符合TRK靶向治疗的临床标准。
在外科病理学中，泛TRK IHC“搭便车”于现有反射性检测策略的临床影响似乎微不足道。在没有潜在NTRK融合事件的情况下，癌很少显示高水平的泛TRK表达。
