Clinicopathological Implications of the BRAF(V600E) Mutation in Papillary Thyroid Carcinoma of Ukrainian Patients Exposed to the Chernobyl Radiation in Childhood: A Study for 30 Years After the Accident

With time after the Chernobyl accident, the number of papillary thyroid carcinomas (PTCs) driven by the BRAF(V600E) oncoprotein is growing in patients exposed to radiation at a young age. Clinicopathological associations of BRAF(V600E) 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(V600E)-positive and BRAF(V600E)-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-131, were <= 18 years of age at the time of exposure, and were operated on from 1990 to 2017. Immunohistochemical staining for BRAF(V600E) 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(V600E) was detected in 136/428 (31.8%) PTCs. In comparison with the BRAF(V600E)-negative PTCs, the BRAF(V600E)-positivity was associated with older patient age at the accident and at surgery, a longer period of latency, and lower POC. The BRAF(V600E)-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(V600E)-positive PTCs and did not change with POC level. Despite a less aggressive tumor phenotype, BRAF(V600E) was a risk factor for recurrence, namely radioiodine-refractory (RAI-R) recurrent metastases. Multivariate models of RAI-R included BRAF(V600E) and/or histopathological parameters closely correlating with BRAF(V600E) such as tumor size, multifocality, dominant papillary growth pattern, or oncocytic changes. Thus, the BRAF(V600E)-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(V600E)-positive tumors.