Clinicopathological Implications of the BRAFV600E Mutation in Papillary Thyroid Carcinoma of Ukrainian Patients Exposed to the Chernobyl Radiation in Childhood: A Study for 30 Years After the Accident

Abstract

With time after the Chernobyl accident, the number of papillary thyroid carcinomas (PTCs) driven by the BRAFV600E oncoprotein is growing in patients exposed to radiation at a young age. Clinicopathological associations of BRAFV600E 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 BRAFV600E-positive and BRAFV600E-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 131I, were ≤18 years of age at the time of exposure, and were operated on from 1990 to 2017. Immunohistochemical staining for BRAFV600E 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. BRAFV600E was detected in 136/428 (31.8%) PTCs. In comparison with the BRAFV600E-negative PTCs, the BRAFV600E-positivity was associated with older patient age at the accident and at surgery, a longer period of latency, and lower POC. The BRAFV600E-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 BRAFV600E-positive PTCs and did not change with POC level. Despite a less aggressive tumor phenotype, BRAFV600E was a risk factor for recurrence, namely radioiodine-refractory (RAI-R) recurrent metastases. Multivariate models of RAI-R included BRAFV600E and/or histopathological parameters closely correlating with BRAFV600E such as tumor size, multifocality, dominant papillary growth pattern, or oncocytic changes. Thus, the BRAFV600E-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 BRAFV600E-positive tumors.

The relationship of the clinicopathological characteristics and treatment results of post-Chornobyl papillary thyroid microcarcinomas with the latency period and radiation exposure

“…As in our previous works ( 14 , 24 – 26 ), in addition to the usual clinicopathological features, we used an integrative variable, the “invasiveness score”, which is an unweighted arithmetic sum of each manifestation of multifocality, lymphatic/vascular invasion, any extrathyroidal extension (i.e., minimal to the adipose or connective tissue, or significant to the muscle), pN1 and M1 (distant metastases to the lung were usually detected on postoperative diagnostic imaging), either isolated or in combination with other(s) for each tumor. The invasiveness score determined in this way ranged from “0” (no sign of invasiveness) to “5” (all the above signs present); the actual highest individual invasiveness score observed in this study was “4”.…”

“…On the other hand, the longer latency period led to an increase in the frequency of the BRAF V600E mutation, oncocytic changes, and a decrease in the probability of excellent response to RIT (see Table 2 and Figure 2C, F ) . The increasing with longer latency period/older patient age frequency of the BRAF V600E mutation was described in our previous study of radiogenic PTCs, although no special analysis in the context of tumor size was performed in that work ( 26 ). A more frequent BRAF V600E mutation was also found in sporadic PTCs (including MPTCs) in older patients ( 33 – 35 ).…”

“…Immunohistochemical (IHC) staining for BRAF V600E and Ki67 was performed in 95 and 92 MPTCs, respectively, for which the additional paraffin sections with tumor tissue were available. IHC staining for BRAF V600E expression was performed as previously described ( 14 , 25 , 26 ): a mouse monoclonal antibody to BRAF (V600E mutated protein) (VE1) ab228461 (Abcam) at a 1:100 dilution and a Novolink Polymer Detection System (250T) (Leica RE7140-K) were used to detect the product of IHC reaction. A positive IHC reaction for BRAF V600E was consistent with the presence of the BRAF V600E mutation ( 27 ).…”

“…The probability of causation (POC) of a tumor by exposure to a known radiation dose of an individual of a given sex and age after a certain period of latency was determined using the US NIH/NCI Division of Cancer Epidemiology and Genetics’ Interactive RadioEpidemiological Program - Probability of Cancer Causation from Radiation Version 5.7.1 software ( 29 )( ). This software, as mentioned in our previous work ( 26 ), uses “Personal Information” such as gender, birth year, diagnosis year and a cancer model (here, the “Thyroid (193)”), and “Dose Exposure Information” such as exposure year (here, 1986), exposure rate (here, the acute), radiation type (here, the electrons E > 15keV as 90% of 131 I beta-decay has the energy of 606keV), organ dose (here, Constant) and parameter 1 (here, the thyroid dose in cSv; since radiation weighting factor for the beta-particles is 1, the equivalent doses were considered to be numerically equal to the absorbed doses) as input variables. The output are the values of the “Assigned Share (Probability of Causation)” that range from the 1 st to the 99 th percentile based on 10,000 random-seeded simulations, and the assigned share associated with the expected value of the excess relative risk (ERR).…”

Characteristics and immune checkpoint status of radioiodine-refractory recurrent papillary thyroid carcinomas from Ukrainian Chornobyl Tissue Bank donors

“…The probability of causation (POC) of a tumor by exposure to a known dose of radiation of a certain quality of a subject of a given sex and age after a definite period of latency was determined using the US NIH/NCI Division of Cancer Epidemiology and Genetics’ Interactive RadioEpidemiological Program - Probability of Cancer Causation from Radiation Version 5.7.1 software [ https://radiationcalculators.cancer.gov/irep , ( 37 )] as described in our previous works ( 38 , 39 ). In this study, the assigned share associated with the expected value of the excess relative risk was used as a POC estimate.…”