1. Radiation-related Thyroid Cancer (TC): Re-evaluation of Chernobyl Consequences Sergei V. Jargin Peoples’ friendship university of Russia Moscow

2. There is a consensus that Chernobyl accident has induced thyroid cancer (TC) increase in children and adolescents. A hypothesis is discussed in this presentation that the increase of TC was caused predominantly by screening, overdiagnosis, and registration of non-irradiated persons as Chernobyl victims. Older neglected tumors found by the screening shortly after the accident or brought from non-contaminated areas were misclassified as aggressive radiation-induced cancers: Jargin SV. Validity of thyroid cancer incidence data following the chernobyl accident. Health Physics 2011;101:754-7.

3. Epidemiologic studies, demonstrating correlations between the radiation doze and the risk of TC, constitute the main body of evidence in support of the cause-effect relationship between exposure and TC after the Chernobyl accident. However, such studies are not free from biases: children with higher doses were probably on average more frequently examined; attitude to questionnaires was not the same in healthy individuals and those operated for TC (recall bias), etc.

4. Appearance of advanced TC shortly after the accident can be explained by detection of old undiagnosed cancers, and by the fact that the patients from non-contaminated areas were registered as Chernobyl victims. Some of such cases were classified as radiogenic cancers developing after a short latency. Accordingly, some features of supposedly radiogenic TC must characterize, on average, a later stage of the tumor progression. The following tables illustrate that there had been a pool of undiagnosed TC in the population, detected by screening after the accident.

5. Thyroid cancer incidence in childhood in different countries before Chernobyl from: Stsjazhko VA et al. BMJ. 1995,310:801; IARC Publication No 144, 1999. Country (region)Period Crude incidence rate per million Belarus1981-850.3 Bulgaria1980-890.7 Canada1982-911.6 Costa Rica1984-920.7 Czech Republic1980-891.1 Norway1980-891.4 Ukraine (northern regions) 1981-850.1

6. Incidence of TC in Children in Ukraine according to the TNM Number of patients (%). From: Tronko MD et al. Cancer 1999,86:149-56 TNM1981-19851986-19901991-19951996-1996Total T1004 (2.7)1 (1.6)5 (2.0) T23 (100)9 (31.0)49 (32.4)18 (28.6)79 (32.4) T306 (20.7)27 (18.2)6 (9.5)39 (16.0) T4014 (48.3)69 (46.3)38 (60.3)121 (49.6) N109 (31.0)45 (20.2)22 (34.9)77 (31.5) N21(33.3)9 (31.0)45 (30.2)22 (34.9)77 (31.5)

7. Proposed markers of the Chernobyl-related radiogenic cancer Chromosomal rearrangements of the tyrosine kinase proto-oncogenes RET, the RET/PTC3 in particular, found in high proportion in papillary TC of patients exposed to radiation during childhood and adolescence, were discussed as possible markers of radiogenic cancer. Over time after the Chernobyl accident, percentage of tumors with RET rearrangements declined, while among RET- positive tumors the percentage with RET/PTC1 increased and RET/PTC3 decreased. Therefore, these markers can be associated not with radiation but with disease duration/tumor progression and patients’ age..

8. The RET/PTC3 rearrangements were most frequent in the “first wave” TC after the Chernobyl accident. Old neglected cancers must have been overrepresented among the early cases, when the pool of undiagnosed tumors was still untapped, equipment of histopathological laboratories not modernized, and post-Chernobyl radiophobia was at its apogee. The first wave TC were on average “older” than those detected later; accordingly, the earlier tumors were generally larger in size than the later ones: Williams ED et al. Thyroid carcinoma after Chernobyl latent period, morphology and aggressiveness. British Journal of Cancer. 2004;90(11):2219–2224.

9. False-positivity: one of the mechanisms If a thyroid nodule is found by screening, a fine-needle aspiration is usually performed. Aspiration cytology of the thyroid is accompanied by some percentage of uncertain conclusions (“grey zone”), when histological verification is indicated. Hemithyroidectomy or subtotal thyroidectomy was usually performed in such cases; the surgical specimen was sent to a pathologist, who could be sometimes prone, in conditions of old laboratory equipment and shortage of modern literature, to confirm malignancy even in case of some uncertainty. The fact of overdiagnosis was admitted in some Russian-language publications; exact figures are unknown.

10. Conclusion The post-Chernobyl incidence increase of TC was largely caused by detection by mass screening of old neglected cancers plus cases brought from non-contaminated areas, registered as Chernobyl victims, and some percentage of overdiagnosis. Therefore, proposed markers and other features of Chernobyl-related TC are probably associated not with ionizing radiation but with longer disease duration and tumor progression because of the on average later detection of malignancies in the former Soviet Union.

11. Thyroid doses to some children could have been high enough to induce cancer; but the latent period (4 years or less after the exposure) was unexpectedly short. The possibility of radiogenic TC after the accident cannot be excluded, but their quantity has been exaggerated. Radiation doses received by Chernobyl victims are inexactly known and on average low for carcinigenesis. Chernobyl data will hardly provide any reliable information on the dose- effect relationships. Dose-effect relationships and markers of radiogenic cancer should be verified in experiments with exactly known doses and dose rates. Jargin SV. Thyroid cancer after Chernobyl. Dose Response 2011;9:471.