Comparative Histopathologic Analysis of "Radiogenic" and "Sporadic" Papillary Thyroid Carcinoma: Patients Born Before and After the Chernobyl Accident.

BACKGROUND: The issue of whether radiation-induced thyroid cancer is pathologically different from sporadic remains not fully answered. This study compared structural characteristics and invasive features of papillary thyroid carcinoma (PTC) in two age-matched groups: patients who were children (≤4 years old) at the time of the Chernobyl accident and who lived in three regions of Ukraine most contaminated by radioactive iodine 131I ("radiogenic" cancer), and those who lived in the same regions but who were born after 1987 and were not exposed to 131I ("sporadic" cancer). Further, the histopathologic features of PTC were analyzed in relation to age and individual 131I thyroid dose. METHODS: The study included 301 radiogenic and 194 sporadic PTCs. According to age at surgery, patients were subdivided into children (≤14 years old), adolescents (15-18 years old), and adults (19-28 years old). Statistical analyses included univariate tests and multivariable logistic regression within and across the age subgroups. Analyses of morphological features related to 131I doses were conducted among exposed patients on categorical and continuous scales controlling for sex and age. RESULTS: Among children, radiogenic PTC displayed a significantly higher frequency of tumors with a dominant solid growth pattern, intrathyroidal spread, extrathyroidal extension, lymphatic/vascular invasion, and distant metastases. Exposed adolescents more frequently displayed extrathyroidal extension, lymphatic/vascular invasion, and distant metastases. Exposed adults more frequently had intrathyroidal spread and extrathyroidal extension. The frequency of PTC with dominant papillary pattern and oxyphilic cell metaplasia was significantly lower in radiogenic compared to sporadic tumors for all age groups. Manifestations of tumor aggressiveness were most frequent in children compared to adolescents and adults regardless of etiology. CONCLUSIONS: Radiogenic PTC is less likely to demonstrate a dominant papillary growth pattern and more likely to display more aggressive tumor behavior than sporadic PTC. Histopathologic tumor aggressiveness declines with patient age in both radiogenic and sporadic cases.

Anaplastic lymphoma kinase (ALK) gene rearrangements in radiation-related human papillary thyroid carcinoma after the Chernobyl accident.

Childhood radiation exposure has been associated with increased papillary thyroid carcinoma (PTC) risk. The role of anaplastic lymphoma kinase (ALK) gene rearrangements in radiation-related PTC remains unclear, but STRN-ALK fusions have recently been detected in PTCs from radiation exposed persons after Chernobyl using targeted next-generation sequencing and RNA-seq. We investigated ALK and RET gene rearrangements as well as known driver point mutations in PTC tumours from 77 radiation-exposed patients (mean age at surgery 22.4 years) and PTC tumours from 19 non-exposed individuals after the Chernobyl accident. ALK rearrangements were detected by fluorescence in situ hybridisation (FISH) and confirmed with immunohistochemistry (IHC); point mutations in the BRAF and RAS genes were detected by DNA pyrosequencing. Among the 77 tumours from exposed persons, we identified 7 ALK rearrangements and none in the unexposed group. When combining ALK and RET rearrangements, we found 24 in the exposed (31.2%) compared to two (10.5%) in the unexposed group. Odds ratios increased significantly in a dose-dependent manner up to 6.2 (95%CI: 1.1, 34.7; p = 0.039) at Iodine-131 thyroid doses >500 mGy. In total, 27 cases carried point mutations of BRAF or RAS genes, yet logistic regression analysis failed to identify significant dose association. To our knowledge we are the first to describe ALK rearrangements in post-Chernobyl PTC samples using routine methods such as FISH and IHC. Our findings further support the hypothesis that gene rearrangements, but not oncogenic driver mutations, are associated with ionising radiation-related tumour risk. IHC may represent an effective method for ALK-screening in PTCs with known radiation aetiology, which is of clinical value since oncogenic ALK activation might represent a valuable target for small molecule inhibitors.

Histopathological features of papillary thyroid carcinomas detected during four screening examinations of a Ukrainian-American cohort.

BACKGROUND: There are limited data on the histopathology of papillary thyroid carcinomas (PTCs) diagnosed in irradiated populations. We evaluated the associations between iodine-131 dose and the histopathological characteristics of post-Chernobyl PTCs, the changes in these characteristics over time, and their associations with selected somatic mutations. METHODS: This study included 115 PTCs diagnosed in a Ukrainian-American cohort (n=13,243) during prescreening and four successive thyroid screenings. Of these PTCs, 65 were subjected to somatic mutation profiling. All individuals were <18 years at the time of the Chernobyl accident and had direct thyroid radioactivity measurements. Statistical analyses included multivariate linear and logistic regression. RESULTS: We identified a borderline significant linear-quadratic association (P=0.063) between iodine-131 dose and overall tumour invasiveness (presence of extrathyroidal extension, lymphatic/vascular invasion, and regional or distant metastases). Irrespective of dose, tumours with chromosomal rearrangements were more likely to have lymphatic/vascular invasion than tumours without chromosomal rearrangements (P=0.020) or tumours with BRAF or RAS point mutations (P=0.008). Controlling for age, there were significant time trends in decreasing tumour size (P<0.001), the extent of lymphatic/vascular invasion (P=0.005), and overall invasiveness (P=0.026). CONCLUSIONS: We determined that the invasive properties of PTCs that develop in iodine-131-exposed children may be associated with radiation dose. In addition, based on a subset of cases, tumours with chromosomal rearrangements appear to have a more invasive phenotype. The increase in small, less invasive PTCs over time is a consequence of repeated screening examinations.

The need for changes in ICRP policy: some examples based on the Chernobyl experience in Ukraine.

Current ICRP policy in radiological protection (ICRP Publication 60) is based on the independent restriction of exposure and sources for practice and intervention. Such subdivision of exposure and sources leads to a number of problems and contradictions in different applications. In a recent memorandum of the ICRP, published in the Journal of Radiological Protection in 2001, and ICRP Publications 81 and 82, the directions for settling some of these problems are indicated. This paper shows that in Ukraine, after the Chernobyl accident, a number of problems and contradictions occurred as the result of strictly separated limitation of the sources and exposure. These are demonstrated through four 'radiological paradoxes': (1) resettlement of inhabitants from territories radioactively contaminated after the Chernobyl accident to 'clean' ones, but with anomalous high levels of radon exposure in houses; (2) necessity of summation of the Chernobyl accidental doses and doses caused by normally operating nuclear power plant (NPP) to meet the requirements of Ukrainian law, which is based on the principle of 'social equity' of different sources of exposure; (3) the necessity to answer the question of primary importance: when will the Chernobyl accident finally end and when can exposure from contaminated territories be considered as exposure from old contamination? (4) the start of decommissioning of the Chernobyl NPP and transformation of the 'Object Shelter' (located inside the exclusion zone) are now slowed down because of the absence of a definite ideology for dose limitation of workers involved, who are exposed to several types of source simultaneously. The authors believe that the concept of controllable dose as presented by Professor Roger H Clarke on behalf of the ICRP can resolve such paradoxes. The changes to ICRP policy need to be made carefully in order to provide an orderly transition.

Chernobyl accident: retrospective and prospective estimates of external dose of the population of Ukraine.

Following the Chernobyl accident many activities were conducted in Ukraine in order to define the radiological impact. Considered here are gamma spectrometric analyses of soil-depth-profile samples taken in the years 1988-1999, gamma spectrometric measurements of radionuclide concentration in soil samples taken in 1986, and measurements of external gamma-exposure rate in air. These data are analyzed in this paper to derive a "reference" radionuclide composition and an attenuation function for the time-dependent rate of external gamma exposure that changes due to the migration of radiocesium into the soil column. An attenuation function for cesium is derived that consists of two exponential functions with half lives of 1.5 and 50 y. The dependencies of attenuation on direction and distance from the Chernobyl Nuclear Power Plant are also demonstrated. On the basis of these analyses the average individual and collective external gamma doses for the population of Ukraine are derived for 1986, 1986-2000, and 1986-2055. For the 1.4 million persons living in rural areas with 137Cs contamination of >37 kBq m(-2), the collective effective dose from external exposure is estimated to be 7,500 person-Sv by the end of 2000. A critical group of 22,500 persons who received individual doses of >20 mSv is identified for consideration of increased social and medical attention.