Zurnadzhy Liudmyla, Bogdanova Tetiana, Rogounovitch Tatiana I, Ito Masahiro, Tronko Mykola, Yamashita Shunichi, Mitsutake Norisato, Bolgov Michael, Chernyshov Serhii, Masiuk Sergii, Saenko Vladimir A
Laboratory of Morphology of Endocrine System, State Institution "VP Komisarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Sciences of Ukraine", Kyiv, Ukraine.
Department of Radiation Molecular Epidemiology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
Front Med (Lausanne). 2022 Apr 26;9:882727. doi: 10.3389/fmed.2022.882727. eCollection 2022.
With time after the Chernobyl accident, the number of papillary thyroid carcinomas (PTCs) driven by the BRAF oncoprotein is growing in patients exposed to radiation at a young age. Clinicopathological associations of BRAF in PTCs from patients with internal radiation history have not been sufficiently studied so far. This work analyzes the structural characteristics, proliferative activity, invasive features, clinical information, and dosimetric data in the BRAF-positive and BRAF-negative PTCs from the Ukrainian patients exposed to Chernobyl radiation and treated over 30 years after the accident. The study included 428 PTCs from patients aged 4-49 years at surgery who lived in the six northern regions of Ukraine most contaminated by I, were ≤18 years of age at the time of exposure, and were operated on from 1990 to 2017. Immunohistochemical staining for BRAF was performed with the VE1 antibody. The probability of causation (POC) of a tumor due to radiation was determined using an interactive online NIH/NCI software. BRAF was detected in 136/428 (31.8%) PTCs. In comparison with the BRAF-negative PTCs, the BRAF-positivity was associated with older patient age at the accident and at surgery, a longer period of latency, and lower POC. The BRAF-positive PTCs were characterized by smaller tumor size, higher Ki67 labeling index, more frequent oncocytic changes, multifocality, and dominant papillary growth pattern. Tumor invasive features were less frequent in the BRAF-positive PTCs and did not change with POC level. Despite a less aggressive tumor phenotype, BRAF was a risk factor for recurrence, namely radioiodine-refractory (RAI-R) recurrent metastases. Multivariate models of RAI-R included BRAF and/or histopathological parameters closely correlating with BRAF such as tumor size, multifocality, dominant papillary growth pattern, or oncocytic changes. Thus, the BRAF-positive PTCs from patients from a high-risk group for radiogenic thyroid cancer diagnosed in the 30 years after the Chernobyl accident did not display higher invasiveness regardless of POC level, but in view of the prognostic impact of this genetic alteration, knowledge of the BRAF status may be beneficial for middle-aged patients with radiogenic PTC considered for RAI therapy, and suggests more careful follow-up of patients with the BRAF-positive tumors.
随着切尔诺贝利事故后的时间推移，在年轻时遭受辐射的患者中，由BRAF癌蛋白驱动的甲状腺乳头状癌（PTC）数量不断增加。迄今为止，对于有内照射史患者的PTC中BRAF的临床病理相关性尚未进行充分研究。本研究分析了乌克兰切尔诺贝利辐射暴露患者在事故发生30多年后接受治疗的BRAF阳性和BRAF阴性PTC的结构特征、增殖活性、侵袭特征、临床信息和剂量学数据。该研究纳入了428例手术时年龄在4至49岁之间的PTC患者，这些患者居住在乌克兰北部受碘污染最严重的六个地区，暴露时年龄≤18岁，手术时间为1990年至2017年。使用VE1抗体对BRAF进行免疫组织化学染色。使用交互式在线NIH/NCI软件确定肿瘤因辐射导致的因果概率（POC）。在428例PTC中，有136例（31.8%）检测到BRAF。与BRAF阴性PTC相比，BRAF阳性与事故发生时和手术时患者年龄较大、潜伏期较长以及POC较低相关。BRAF阳性PTC的特征是肿瘤体积较小、Ki67标记指数较高、嗜酸性变更频繁、多灶性以及以乳头状生长模式为主。BRAF阳性PTC的肿瘤侵袭特征较少，且不随POC水平变化。尽管肿瘤表型侵袭性较小，但BRAF是复发的危险因素，即放射性碘难治性（RAI-R）复发转移。RAI-R的多变量模型包括BRAF和/或与BRAF密切相关的组织病理学参数，如肿瘤大小、多灶性、乳头状生长模式为主或嗜酸性变。因此，切尔诺贝利事故后30年内诊断出的放射性甲状腺癌高危组患者的BRAF阳性PTC，无论POC水平如何，均未表现出更高的侵袭性，但鉴于这种基因改变的预后影响，了解BRAF状态可能对考虑接受RAI治疗的放射性PTC中年患者有益，并建议对BRAF阳性肿瘤患者进行更密切的随访。
