Markers of Radiogenic Cancer vs. Tumor Progression: an Overview of Chernobyl Studies

Abstract

Differences in the histological grade of malignancies may reflect diagnostic quality, that is, averagely earlier or later tumor detection in a given country. Studies of Chernobyl-related renal-cell carcinoma with a control from Spain and Colombia are discussed here in comparison with thyroid cancer research. It is concluded that suppositions about averagely higher grade and enhanced aggressiveness of malignancies from the areas previously contaminated by the Chernobyl fallout are unfounded and can lead to overtreatment. Results of many studies of Chernobyl-related malignancies are valuable; but conclusions should be reassessed taking into account that some cases, classified as aggressive radiogenic cancers, were in fact late-stage neglected malignancies. Associations of various markers with the tumor progression can become a field for the future research and re-interpretation of data obtained in studies comparing malignancies from different countries. Some markers may reflect efficiency of healthcare services. Citation: Citation: Jargin SV. Markers of Radiogenic Cancer vs. Tumor Progression: an Overview of Chernobyl Studies. J Cancer Sci. 2021;8(1): 7 J Cancer Sci 8(1): 7 (2021) Page 02 ISSN: 2377-9292 but the statistical significance vanished if only doses <200 mSv were considered [19,20]. Doses <100 mGy at low rates may induce adaptive response against neoplastic transformation [21]. Annual average doses from natural radiation should be specified in papers where cohorts from different geographical regions are compared; otherwise doses among controls may turn out to be not significantly different from those in the “exposed” cohort e.g. in patients from Spain vs. those from Kiev [6,8]. The average annual individual dose from the background radiation in Spain is ~5 mSv [22,23]. According to an estimate, the mean whole-body individual dose to inhabitants of Kiev from all sources was ≤10 mSv in 1986, decreasing thereafter [24]. No dose estimates were given in the articles [4-10]; it is only written with a self-reference: “This observation also supports the prevailing suspicion [9] that in Ukraine the radiation contamination levels were similar within and beyond the officially-established 80-km extent of radiation contamination around Chernobyl [25]” [10]. The source [25], a Ministry report, has been unavailable. Radiation Effects vs. Late Detection The Chernobyl accident (CA) provides an example of considerable difference in diagnostic quality before and after the accident. There has been no convincing evidence of cause-effect relationships between radiation exposures from CA and the incidence increase of cancers in residents of contaminated territories other than TC in people exposed at a young age [18]. TC and probably also other cancers were underreported before CA. Mechanisms of the registered TC incidence increase included the screening and improved medical surveillance after CA [18]. According to the UNSCEAR, “the background rate of thyroid cancer among children under the age 10 was approximately two to four cases per million per year” [26]. The UNSCEAR 2008 Report compared the enhanced TC incidence rates 4 years after the accident and later not with the pre-accident level but with the years 1986-1990 (Annex D, pp. 60-61), when the incidence had increased up to 4.1 cases per million per year in people exposed at the age of <10 years and up to 5.4 in those exposed at <18 years [18]. The period 1986-1990 was chosen for comparison because “since 1986 and not earlier, specific data on thyroid cancer incidence have been specifically collected by local oncologists” (UNSCEAR Secretariat, e-mail communication of 22 October 2013). According to another source, the incidence of TC among people younger than 15 years in the North of Ukraine (overlapping with the contaminated area) was 0.1 and in Belarus 0.3 cases/million/year from 1981 through 1985 [27]; more details are in [28]. Only 5 children were diagnosed with thyroid malignancies in Belarus during the period 1978-1985, the detection rate of pediatric TC prior to CA being lower than that in other developed parts of the world [29]. This indicates that there were undiagnosed cases in the population. The underreporting tendency is known also for renal malignancies [30]. Some neglected 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 [1]. Many people wanted to be recognized as Chernobyl victims to gain access to health care provisions and compensations [31]. Cases from non-contaminated areas must have been averagely more advanced as there was no extensive screening there. Renal cell carcinoma (RCC) By analogy with TC, the registered incidence rise of RCC in Ukraine following CA [4,7,9,10] was probably caused by improved diagnostics [12]. As mentioned above, RCCs from Ukraine tended to be less differentiated than those from Spain. RCCs from Ukraine showed sarcomatoid i.e. poorly differentiated pattern more frequently: 62 from 236 (26.3 %) of Ukrainian vs. 11 from 112 (9.8 %) of Spanish cases (p<0.001) [1]; the significant difference was confirmed by the subsequent study [7]. Apparently, the difference was caused by the more efficient and early cancer diagnostics in Spain. In this connection, the following citations should be commented: “The dramatic increase of aggressivity and proliferative activity” was found in RCC from Ukraine, while “the majority of the high grade tumors occurred in the Ukrainian (rather than in the Spanish) groups” [4]. These differences can be attributed to a more efficient and early cancer diagnostics in Western Europe and, conversely, detection by the screening of advanced cases in Ukraine. The misinterpretation of such cases as aggressive radiogenic cancers has been conductive to an overtreatment (discussed below). Some molecular-genetic characteristics of RCC from Ukraine vs. those from Spain and Colombia need a re-interpretation e.g. the absence of significant differences in the expression of ubiquitin [8]. Considering that RCCs from Ukraine were averagely more advanced than Spanish cases, these data indicate that ubiquitin is not associated with the progression of RCC. In contrast, VEGF was found more frequently in clear-cell RCC from Ukraine than in the specimens from Spain and Colombia [10]. The statement that “in RCC the level of serum VEGF has been shown to be closely related to tumor stage and grade of RCC, and the expression of VEGF to be significantly associated with tumor stage” [10] was confirmed by the reference [11]. Other studies also reported associations between VEGF expression and microvascular density, nuclear grade, tumor size, stage, and prognosis of RCC [32-35]. The study under discussion also “demonstrated a close relationship between VEGF expression and the stage of clear-cell RCC” [10]. The same considerations probably pertain to other markers, where substantial differences were found between the Spanish and Ukrainian RCCs, in particular, the transcriptional nuclear factor kappa B (NF-kappa-B), its p50 and especially p65 subunits [7]. 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) [7]. NF-kappa-B activation is discussed in the literature as a potential biomarker and promoter of the cancer progression [36-41]. Papillary thyroid carcinoma (PTC) For interpretation of the above data, the analogy with RET/PTC3 chromosomal rearrangements in PTC is helpful. The RET/PTC3 fusions apparently correlate with the progression of PTC and hence with the disease duration [42]. An association was found between the RET/PTC3 expression and aggressive phenotype, advanced stage and larger size of PTC [43]. With the time passing after CA, the prevalence of RET/PTC3 declined [44,45] while advanced neglected TCs were sorted out by the screening. The cohort of post-Chernobyl pediatric PTC, with RET/PTC3 being the most prevalent RET rearrangement Citation: Citation: Jargin SV. Markers of Radiogenic Cancer vs. Tumor Progression: an Overview of Chernobyl Studies. J Cancer Sci. 2021;8(1): 7 J Cancer Sci 8(1): 7 (2021) Page 03 ISSN: 2377-9292 type, was supposed to be worldwide exceptional [46]. In fact, the cohort has been unique not globally but for industrialized highincome countries where cancer is diagnosed relatively early. Similarly to Chernobyl, RET/PTC3 was the most prevalent RET rearrangement in the studies from India [47,48]. Asian populations generally demonstrated a higher positive rate for RET/PTC3 compared to Western populations (26.50% vs. 17.05%) [49]. Of note, in Japan the frequency of RET/PTC3 is relatively low [49,50]. Pediatric TC in Japan has been different from that after CA, showing less frequently the poorly differentiated solid and solid-trabecular patterns [51,52]. International comparisons of TC size and stage may be less meaningful than those of differentiation grade because large nodules with uncertain malignant potential can be classified as high-stage cancers if there is a propensity to histological over-diagnosis, while screening activities may be a confounding factor. Unlike Chernobyl, most TCs after the Fukushima accident were of the classical papillary i.e. higher differentiated type [53,54], which suggests the averagely earlier tumor detection in such developed country as Japan. Along the same lines, RET/PTC3 are rare in France [55]. Mutations were found in TC from Russia more frequently compared to the United States [56,57], which indicates earlier diagnostics in the latter country. Another recent example is the study making a comparison between 359 PTCs from patients who underwent radiation exposure from CA and the contro