Chernobyl-related cancers vs. controls from other countries: a comment

There has been no convincing evidence of cause-effect relationships between radiation exposures from the Chernobyl accident (CA) and the incidence increase of cancers in residents of contaminated territories except for thyroid cancer (TC) in people exposed at a young age [1]; therefore, pediatric TC is predominantly discussed here below. Since 2009 we have defended the hypothesis [2–7] that the registered increase in the TC incidence after CA was largely caused by the screening, improved medical surveillance and registration of unexposed patients as exposed. The “successive waves of tumors in those exposed to high levels of fallout as children, each with different molecular, morphological, and clinical findings” [8] after CA were largely determined by changing intensity of the screening, improving accuracy of diagnostics and registration, exhaustion by the screening of the pool of neglected cancers [2–7]. TC had been under-diagnosed and under-reported before CA. The incidence of TC among people younger than 15 years in the “five most northerly regions” of Ukraine was 0.1 and in Belarus — 0.3 cases/million/year from 1981 through 1985 [9]. Worldwide, the incidence of TC in children was estimated at 0.5–1.2 and in adolescents — 4.4–11 cases/million/year [10]. The figures tend to be higher in more developed countries [10,11] obviously due to better diagnostics. Many experts argue that the gradual increase in TC incidence worldwide is caused by technological advancements in diagnostics. At the same time, the long-term mortality from differentiated TCs declined or stabilized almost everywhere [10]. Only 5 children were diagnosed with TC in Belarus in the period 1978–1985, the detection rate of pediatric TC prior to CA being much lower than that in other developed countries [11]. This indicates that there were undiagnosed cases in the population. Some neglected advanced cancers, detected by the screening, self-reported in conditions of increased public awareness after CA, or brought from other areas and registered as Chernobyl victims, were misinterpreted as rapidly growing radiogenic malignancies [2–7]. Many people strived for the registration as Chernobyl victims to gain access to health care provisions [12]. Cases from non-contaminated areas must have been averagely more advanced as there was no extensive screening there. The proposed increase in the “aggressivity” of cancers after the radioactive contamination in the Chernobyl area [13] apparently resulted from detection by the screening of old neglected malignancies, interpreted as radiogenic tumors with the “rapid onset and aggressive development” [13].

International comparisons are informative in this connection. Differences in the average histological grade of malignancies may reflect the diagnostic quality and averagely earlier or later tumor detection in a given country. This hypothesis has been supported by comparisons of renal cancer (RC) specimens from Ukraine with random cases from Colombia and Spain. RCs from Ukraine were averagely less differentiated than the overseas counterparts [14–20]. The differences can be attributed to a more efficient and early cancer diagnostics in Spain and Colombia [21]. The proposed increase in the “aggressivity” of RC and TC after the radioactive contamination in the Chernobyl area apparently resulted from detection by the screening of old neglected cases, interpreted as radiogenic tumors with the “rapid onset and aggressive development” [13]. The screening detected not only small nodules but also advanced tumors, neglected because of the incomplete coverage of the population by medical checkups. This is confirmed by the fact that the “first wave” TCs (found during ~10 years following CA) were on average larger and higher-grade than those diagnosed later [22].

Some molecular-genetic markers of RC from Ukraine vs. those from Spain and Colombia need a re-interpretation. The marker VEGF was found more frequently in clear-cell renal cell carcinoma from Ukraine [20]. The “level of serum VEGF has been shown to be closely related to tumor stage and grade of renal cell carcinoma, and the expression of VEGF to be significantly associated with tumor stage” [20]. Other studies also reported associations between VEGF and microvascular density, stage and grade of RC. The same considerations probably apply to other markers, where differences between the Spanish and Ukrainian RCs were found, in particular, NF-kappa-B, its p50 and p65 subunits [17]. The >10 % cell positivity for p50 was found in 25 from 59 (42.4 %) of specimens from Ukrainian vs. 4 from 19 (21.1 %) of Spanish patients; the >50 % p65 positivity was found, correspondingly, in 18 from 59 (30.1 %) vs. 1 from 19 (5.3 %) of the specimens (p<0.05) [17]. In accordance with the concept presented here, NF-kappa-B activation has been discussed in the literature as a marker and promoter of the neoplastic progression.

The analogy with RET/PTC3 chromosomal rearrangements in papillary thyroid carcinoma (PTC) is further helpful. According to our hypothesis, the frequency of RET/PTC3 positivity in PTC specimens correlates with the average tumor grade and hence with the disease duration [4,6]. This is not surprising as mutations generally tend to accumulate with the neoplastic progression. For example, mutations were found in TCs from Russia more frequently than in those from the United States [23,24], which indicates earlier diagnostics in the latter country. An association was found between RET/PTC3 and aggressive phenotype, advanced stage and larger size of PTC [25]. With the time passing after CA, the prevalence of RET/PTC3 in Chernobyl-related TCs declined [8,26,27] while advanced neglected tumors were sorted out by the screening. The cohort of post-Chernobyl pediatric PTCs, with RET/PTC3 as a prevailing RET rearrangement type, was supposed to be worldwide exceptional [28]. In fact, this cohort is exceptional not worldwide but for industrialized high-income countries where cancer is diagnosed relatively early. Similarly to Chernobyl, RET/PTC3 was the most prevalent RET rearrangement in the studies from India [29,30]. Asian populations generally demonstrated a higher positivity rate for RET/PTC3 than Western populations (26.50 % vs. 17.05 %) [31] with the exception of such highly developed country as Japan (discussed below). Along the same lines, RET/PTC3 are rare in France [32], which suggests an averagely early tumor detection.

The comparison between the former Soviet Union (SU) and Japan is not straightforward because screening activities after the Chernobyl and Fukushima Daiichi accidents have been confounding factors. Obviously, CA had a greater impact on the diagnostic practices in the former SU than the Fukushima accident in Japan. The registered TC incidence in Belarus in people ≤18 years old has remained at an enhanced level — several times higher than in Western countries [27], although the radiation factor has no longer been active and no country-wide screening was performed [27], which indicates that other mechanisms e. g. enhanced vigilance and over-diagnosis have contributed to the high detection rate. In accordance with the concept discussed here, the frequency of RET/PTC3 in Japan is relatively low [31,33]. Japanese pediatric TCs have been different from those in Belarus and Ukraine, showing less frequently the de-differentiated solid and solid-trabecular patterns [34,35]. Unlike Chernobyl, most TCs after the Fukushima accident were of the classical papillary type i. e. having a comparatively high differentiation grade [36,37]. International comparisons of the TC grade may be more informative than those of the stage because large nodules with uncertain malignant potential can be classified as high-stage cancers if there is a propensity to histo- and cytological over-diagnosis in conditions of hypervigilance, insufficient quality of specimens and disagreements between panel members [2,6,38,39]. The hypervigilance can be illustrated by the following citation: “Practically all nodular thyroid lesions, independently of their size, were regarded at that time in children as potentially malignant tumors, requiring an urgent surgical operation” [40]. Potential mechanisms of the over-diagnosis have been discussed previously [2,6].

The misclassification of advanced cases as aggressive radiogenic cancers has given rise to the concept that radiogenic TCs are more aggressive than sporadic ones [13,41]. This had consequences for the practice: the surgical treatment of radiogenic TC was recommended to be more radical [42]. In the 1990s, the thyroid surgery in some institutions of the former SU adopted more radical methods; details and references are in [7,43]. Reasonable considerations about TC over-diagnosis and overtreatment can be found in the recent review: “After the Chernobyl and Fukushima nuclear accidents, thyroid cancer screening was implemented mainly for children, leading to case over-diagnosis;” “The existence of a natural reservoir of latent thyroid carcinomas, together with advancements in diagnostic practices leading to case over-diagnosis explain, at least partially, the rise in TC incidence in many countries;” “Total thyroidectomy, as performed after the Chernobyl accident, implies patients must live the rest of their lives with thyroid hormone supplementation. Additional treatment using radioactive iodine-131 therapy in some cases may result in potentially short- or long-term adverse effects” [44]. Preceding publications expressing the same concept [2–6,43] have not been cited in [44]. Obfuscation of the over-diagnosis and overtreatment of post-Chernobyl TCs and other lesions is recognizable in the literature from the former SU. Certain authors know our publications on this topic [2–7,43,45] but do not cite them in spite of personal communications. In the earlier report with participation of Prof. E. Dillwyn Williams (2008) it was stated that “The exposed and unexposed tumors from the same geographical area are essentially identical morphologically and in their degree of aggressiveness… childhood PTCs from Japan were much more highly differentiated (p<0.001), showed more papillary differentiation (p<0.001) and were less invasive (p<0.01) than ‘Chernobyl’ tumors” [34]. Later on, in unsupervised publications by the co-authors, the accents were changed, e.g.: “Childhood Japanese PTCs differed from Ukrainian PTCs by more pronounced invasive properties… higher morphological aggressiveness of PTC in young Japanese patients” [35]. In last paper by the same researchers it was acknowledged that Ukrainian “radiogenic” or “radiation-related” PTCs “had a solid-trabecular growth pattern and displayed morphological features of aggressive biological behavior” [41] without any satisfactory proof that (a considerable part of) tumors in the studied residents of Kiev, Chernigov and Zhitomir provinces [41] were caused or influenced by radiation. What was indeed different about inhabitants of these regions were the screening with detection of neglected cases and some over-diagnosis, radiophobia with increased self-reporting, as well as registration of some unexposed people as Chernobyl victims [6,7,12]. The cases coming from non-contaminated areas must have been averagely more advanced as there was no mass screening there. We intended to comment on the article [41] by a letter to the editor but it was possible only against payment (fig. 1), which is an obstacle for a scientific discussion. Therefore this commentary is published here.

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Fig. 1. The message that a “fee is need for the processing the article and for it to undergo peer review” for a letter to the editor commenting on [41], signed by Electron Kebebew

In conclusion, international differences in the histological grade of malignancies may reflect diagnostic quality, that is, averagely earlier or later tumour detection in a given country. Associations of various markers with the tumor progression (disease duration, tumor grade and stage) is a potential field for the future research and re-interpretation of the data already obtained in studies comparing malignancies from different regions. Some markers may characterize an averagely later or earlier cancer detection in a given country and hence the efficiency of healthcare services.

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