Malignancies after Chernobyl Accident: What Is True and What Is Untrue

Thyroid cancer (TC) in children and adolescents is the only type of malignancy, significant increase of which in consequence of the Chernobyl accident (CA) is generally regarded to be proven [1]. Early reports of a TC increase after the CA were doubted as radioiodine was thought to have low or absent carcinogenicity in humans [2]. High incidence and the short latent period were deemed unusual; the number of TC in children and adolescents exposed to radiation has been higher than expected on the basis of previous knowledge [1,3]. There was uncertainty about accuracy of the diagnoses [4]. The accident gives an example of considerable difference in diagnostic quality before and after the event. Introduction of ultrasound and fine needle aspiration (FNA), coupled with superficial location of the thyroid gland, resulted in detection of large numbers of thyroid nodules, while “radiation phobia” [5], suboptimal quality of specimens and insufficient experience with pediatric material [6] contributed to occasional overdiagnosis of malignancy. Availability of children at schools and kindergartens for the mass screening explains for the TC incidence increase predominantly in this age group and also for differences compared to the Fukushima accident in Japan [2], where screening intensity has probably been less dependent on the age. The Fukushima Prefecture program was set up to screen everyone under the age of 19 at the time of the accident. After CA the risk was greatest in those who were infants at the time of the accident, falling rapidly with increasing age. None of the Fukushima TC cases had been infants at the time of the accident, the majority being adolescents [2].

The registered incidence of pediatric TC in the former Soviet Union (SU) before the accident was low compared to other developed nations, which had obviously been caused by differences in diagnostic quality and coverage of the population by medical examinations [7]. Accordingly, there was a pool of undiagnosed TC prior to the accident. The percentage of more advanced cancers was negatively associated with the time between the accident and surgery [8-10] probably due to the gradual exhaustion by the screening of the pool of advanced cancers. Morphologically, TC in patients from contaminated territories were more aggressive than usual [11-14]. Correlations between radiation doses to the thyroid, tumor invasiveness and “aggressive solid-follicular” pattern were reported [9,10]. However, the time factor was not discussed by Bogdanova et al. [9]: the cases with higher doses were probably diagnosed averagely earlier, when the pool of neglected cancers was still untapped. Accordingly, a weak negative correlation (Spearman's r =-0.12, P=0.15) between the “latency” (time from exposure to surgery) and thyroid dose was found by Zablotska et al. [10]. Note that it is incorrect to speak about latency if a cause-effect relationship has not been proven [15]. The incidence increase of TC after the accident was additionally favored by iodine deficiency in the contaminated territories with a corresponding increase of goiter and thyroid nodules [16-18], found by the screening, providing more opportunities for false-positivity.

There have been several factors to predisposing the over-diagnosis of TC. Equipment of histopathological laboratories was outdated in the 1990s; excessive thickness of histological sections hindered reliable assessment of morphological criteria. Gross dissection of surgical specimens was often made with blunt autopsy knives, without rinsing instruments and the board for cutting, often without access to water [19], which can result in tissue deformation and contamination of the cut surface by cells mimicking malignancy criteria. It can explain for the high frequency of the “ingrowths of tumor cells into blood vessels” in post-Chernobyl pediatric TC: 45 % of cases [20]. Celloidin embedding was still broadly in use, where all nuclei appear somewhat cleared or “ground-glass-like” compared to paraffin-embedded specimens, which can be misinterpreted as a sign of papillary TC. Pathologists in Russia, who had worked with thyroid tumors from contaminated areas, pointed out low quality of histological specimens interfering with evaluation of nuclei [21].

False-positive diagnosis of TC was not excluded after cytological and histological examinations. One of the mechanisms has been as follows. If a thyroid nodule is found by ultrasonic screening, FNA is normally performed. Thyroid FNA cytology has a certain percentage of inconclusive results [22], which must have been relatively high in the former SU, one of the causes being shortage of modern literature [23]. Data about sensitivity of the FNA in detecting of post-Chernobyl childhood TC were reported: “In a definite or presumptive form, diagnosis of carcinoma was established in 161 from 238 cases”, while papillary carcinoma was diagnosed correctly by FNA in 69.5 % and follicular subtype of papillary TC-only in 36.5 % of cases [24]. After receiving a cytological report in a presumptive form (suspicious for malignancy), a hemithyroidectomy, subtotal or total thyroidectomy has been performed [20,25]. After 1991, the total thyroidectomy predominated; hemithyroidectomy was applied only for TC 20]. The prevalent opinion was that surgical treatment of radiogenic TC must be “more radical” than usual, while subtotal thyroidectomy was regarded “oncologically not justified” [26]. The surgical specimen is normally sent for pathological examination. The thickness of histological slides and quality of staining were generally suboptimal during the 1990s. After in toto removal of a supposed cancer, pathologists sometimes confirmed malignancy also in cases with equivocal histology. Data about verification by expert commissions of post-Chernobyl pediatric TC in Russia confirmed false-positivity: “As a result of histopathological verification, diagnosis of TC was confirmed in 79.1% of cases (federal level of verification-354 cases) and 77.9% (international level-280 cases)” [24]. Falsepositive cases, not covered by verifications, have remained undisclosed, the more so as archives of histological specimens have been in disarray also in some central institutions, slides often “taken by relatives for external consultations” etc. thus becoming unavailable for checkups.

Some diagnostic criteria of TC remained largely unknown, being not mentioned by Russian-language literature used at that time [27,28]. One of the most significant diagnostic criteria of papillary TC-ground-glass or cleared nuclei - was mistranslated as “watch-glass nuclei” and presented by the most authoritative Russian-language handbook of tumor pathology [28] as a feature not only of papillary, but also of follicular TC. Nuclear features, typical for papillary carcinoma, are not visible in the illustrations of this handbook [28]. In the authoritative Atlas of tumor histopathology [29], the following is stated about thyroid nodules: “In severe dysplasia there appear cell groups with clearly visible atypia. Therefore, 3rd grade dysplasia is considered as an obligate pre-cancer, which histologically is hardly distinguishable from carcinoma in situ”. Accordingly, diagnostic formulations such as “follicular thyroid carcinoma without invasion” or “follicular carcinoma in situ ”, suggestive of false-positivity, could be encountered [29]. Note that nuclear atypia is generally not regarded as a malignancy criterion of thyroid nodules; and the concepts of carcinoma in situ and dysplasia are not applied to them [30]. Several images from [28,29], potentially misleading for practice, have been reproduced by Jargin et al. [31]. Admittedly, a recent atlas on thyroid pathology [32] is devoid of the imperfections described above. Cases of false-positive diagnosis, caused by misinterpretation of nuclear atypia as a malignancy criterion of thyroid nodules, are known from practice.

A few words should be said about parathyroid glands. The risk of primary hyperparathyroidism in a cohort of Chernobyl cleanup workers was reported to be considerably higher than among the controls from Germany [33], which is in line with a report from Abomb survivors [34]. However, serum calcium tests, probably much more frequent in the West, potentially conductive to detection and treatment of hyperparathyroidism [35], could have contributed to a lower prevalence of this condition among the controls [33]. On the other hand, the risk of postsurgical hyperparathyroidism (6% of operated pediatric TC cases [25]; 10.5% of those undergoing completion total thyroidectomy [36]), recurrent nerve palsy etc. [20,37], are among reasons why false-positive diagnosis should be precluded. The following treatment was recommended to the children with radiogenic TC: “Total thyroidectomy combined with neck dissections followed by radioiodine ablation” [38]; “Careful and complete removal of the lymph nodes is of great clinical relevance” [39]. External radiotherapy (40 Gy) was applied as well [18]. Total thyroidectomy has been seen by some experts to be indicated regardless of tumor size and histopathology [40]; whereas technical difficulties of parathyroid glands preservation were pointed out [20].

Chromosomal rearrangements in the Chernobyl-related TC, providing further evidence in favor of the late diagnostics rather than radiogenic nature of tumors, have been discussed previously [12]. Remarkable data were reported about thyroid adenoma. The RET rearrangements were found in 57.1% of the adenomas in patients from non-contaminated areas of Ukraine but in 0% of thyroid adenomas from France [41]. This discrepancy was explained in the same article: at a re-examination, in 8 from 14 adenomas from Ukraine, but in no one from France, were found groups of cells with “limited nuclear features of papillary cancers” [41], which is indicative of uncertainty of the histopathological diagnostics.

Diagnostic uncertainty is an apparent explanation for the fact that in different groups of males with benign prostatic hyperplasia (BPH) and females with chronic cystitis, from contaminated areas and Kiev, severe urothelial dysplasia and carcinoma in situ (CIS) were found by bladder biopsy as frequently as in 56-92% of all randomly selected cases; while the random selection mode was repeatedly pointed out [42-46]. Such a high prevalence of severe dysplasia and CIS in randomly selected BPH cases is obviously unrealistic and indicative of false-positivity. Radiation doses resulting from activity concentration of 137Cs in urine (6.47 Bq/l in the most exposed group [43,44]) were discussed previously [47]: the doses were obviously too low to cause any increase in bladder malignancy.

It should be stressed that overdiagnosis of premalignant and malignant bladder lesions entails overtreatment and overmanipulation including cystoscopies and repeated biopsies [42-46], which could have been conductive to a transmission of infection such as viral hepatitis [48,49]. It seems to be probable that the so-called “irradiation cystitis” [44,50], characterized not only by urothelial dysplasia and CIS but also by “reactive epithelial proliferation associated with hemorrhage, fibrin deposits, fibrinoid vascular changes, and multinuclear stromal cells” [50], was at least in part caused by repeated cystoscopies, biopsies, electrocoagulation etc. Accordingly, it can be assumed that some of molecular markers, especially those associated with tissue damage, inflammation and cell proliferation (TGF-β1, NF-κB, p38 mitogen-activated protein kinases, growth factors, etc.), as well as the “marked activation of angiogenesis in urinary bladder lamina propria” [44], reflected chronic inflammation and increased cellular proliferation unrelated to ionizing radiation. In this regard, the images from Romanenko et al. [44,46] reproduced by Jargin [51,52] should be commented: All the slides are too thick for reliable diagnostics, nuclei are weakly stained. Insufficient quality of specimens could have been caused also by fixation- and processing-related factors, tissue damage due to electrocoagulation etc. Some images from Romanenk et al. [44] and Romanenko et al. [46], published with the interval of 9 years, are identical. The same is true for the earlier articles Romanenko et al. [53,54]. It seems to be probable that overdiagnosis of dysplastic and neoplastic bladder lesions had taken place also earlier: in both papers, Jargin [53,54] used the same image of bladder leukoplakia with invasion according to the caption. However, invasive growth is not clearly recognizable. Histological images of bladder and thyroid lesions, potentially conductive to overdiagnosis of malignancy, can be seen in broadly used editions on tumor histopathology [28,29] were reproduced in Jargin [31,51].

Poorly substantiated statements can be found in the literature with regard to other supposedly radiation-related conditions. For example, the statement: “During the 25-year period subsequent to the Chernobyl accident, the morbidity of malignant renal tumors in Ukraine has increased from 4.7 to 10.7 per 100,000 of the total population” [55] was supported by a reference to a report by the Ministry of Health of Ukraine. However, the incidence increase of renal cell carcinoma (RCC) due to the Chernobyl fallout has never been proven scientifically; some increase could have been caused by improved diagnostics [56]. Furthermore, the following was pointed out: “The strong significant differences between the Ukrainian and Spanish groups were found in tumoral nuclear grade” [57] and “Our data showed in the majority of Ukrainian patients a radiation sclerosing proliferative atypical nephropathy in association with an increase in the incidences of tubular epithelial nuclear atypia and carcinoma in situ ” [58]. It was reported that in 73 % of RCC patients from contaminated territories and 72 % of patients from noncontaminated areas of Ukraine, the tumor displayed a relatively high level of microvessel density: the average density in both Ukrainian groups combined was 1.65 times higher than in a control group from Spain [55]. Radiation exposure was put in connection with tumor dedifferentiation [55]. An association of microvessel density with the grade of RCC had been also reported previously [59,60]. However, the difference in the histological grade can be explained by the averagely earlier detection of malignancies in Spain compared to Ukraine. The higher microvessel density in RCC from Ukraine, as well as the higher grade and “aggressiveness” of cancers after the Chernobyl accident in general [11], were apparently caused by detection after the CA of old neglected tumors accumulated in the population, misinterpreted as radiogenic cancers [7,56,61]. It can be confirmed by the following citation: “The tumors were randomly selected (successive cases) from the laboratories of Kiev and Valencia... (tumors were) clearly more aggressive in the Ukrainian population in comparison with the Valencian cases” [62]. This phenomenon has an obvious explanation: on average earlier diagnostics of malignancies in Valencia!

The above and previously published [6,7,12,47] arguments question in principle the cause-effect relationship between ionizing radiation and cancer incidence increase after the CA. With regard to pediatric TC, existence of radiogenic cases cannot be excluded, but the registered incidence increase was largely caused by factors other than radiation. A concluding point is that results of some Chernobyl-related molecular-genetic and other studies should be re-evaluated, considering that many tumors detected during the first decade after the CA due to the screening and improved diagnostics, or brought from non-contaminated areas and registered as Chernobyl victims, were advanced neglected cancers.

Last presented at the Conference Preconditioning in Biology and Medicine Mechanisms and Translational Research April 21-22, 2015, University of Massachusetts Amherst.

The author declares that they have no competing interests.