Radiation-induced Thyroid Cancer Research Articles

Thyroid cancer incidence in Ukraine: trends with reference to the Chernobyl accident

For the first time, a comparative analysis of thyroid cancer incidence in Ukraine after the Chernobyl accident was done in a cohort that is almost as large as the general population. On the basis of thyroid doses from radioactive iodine in individuals aged 1-18 years at the time of accident, geographic regions of Ukraine with low and high average accumulated thyroid doses were established and designated "low-exposure" and "high-exposure" territories, respectively. A significant difference of thyroid cancer incidence rates as a function of time between the two territories was found. That is, the increase in the incidence was higher in high-exposure regions than in low-exposure regions. The incidence rates varied substantially among the different attained age-groups, especially in the youngest one (up to 19 years old). The analysis that was adjusted for screening and technological effects also indicated that in the high-exposure regions, thyroid cancer incidence rates at the age of diagnosis of 5-9, 10-14 and 15-19 years were significantly higher in those born in 1982-1986 compared to those born in 1987-1991, while in the low-exposure regions, no significant difference was observed. The observed probable excess of radiation-induced thyroid cancer cases in adults exposed to radioactive iodine from the Chernobyl accident, especially in females, may be due to the high power of the present study. However, it should be noted that our investigation was not essentially free from ecological biases.

Is ionizing radiation responsible for the increasing incidence of thyroid cancer?

The dose of exposure to ionizing radiation appears to correlate with increased risk of thyroid microcarcinoma. Can ionizing radiation be a factor contributing to the increasing incidence of thyroid cancer around the world?

2. Ionizing Radiation-induced Thyroid Cancer.

広島・長崎での原爆被爆者やチェルノブイリ原発事故後の疫学調査などより，外部被曝のみならず放射性ヨードによる内部被曝によるものと考えられる晩発性甲状腺癌が誘発される事が確認された．発癌リスクには線量依存性があり，被爆時の年齢と強い逆相関性が認められる．特に低年齢，5～10歳未満では顕著であり，この時期の被曝を避ける事がもっとも重要である．近年の分子生物学の進歩により，放射線誘発癌の分子メカニズムも次第に明らかになりつつある．

Radiation-induced thyroid cancer: The Chicago experience

IN 1901 KARL WILHELM ROENTGEN, a physics professor at Wurzburg, Germany, received the first Nobel Prize in physics for the discovery of x-rays in experiments, which began 6 years earlier in 1895. The invisible cathode rays generated were found to cause a fluorescence on a barium platinocyanide screen and, surprisingly, to outline the bones of his wife’s hand on this photographic film (Fig 1). By 1896, radiographs were being taken for clinical purposes and their diagnostic possibilities were quickly exploited. Bone films, chest x-rays, and even barium studies of the gastrointestinal tract were quickly tried. Roentgen found that prolonged exposure to x-rays produced burns and ulcerations of the skin, hair loss, and dermatitis. These effects were turned into therapy to burn off moles and to treat acne, hemangiomas, skin tuberculosis, and many other benign skin lesions. At about the same time (1891), Maria Sklodowska left Warsaw to study at the Sorbonne. She married fellow scientist Pierre Curie. Her work on uranium led to the discovery of polonium and radium, a substance 900 times more radioactive than uranium. Uranium, polonium, and radium released rays like x-rays that penetrated matter. Madame Curie and a colleague accidentally burned themselves when carrying vials of radium in their pockets. In 1901, Pierre Curie did so purposely by strapping some radium to his arm. By 1904, it was demonstrated that radium rays destroyed

The Usual Ultrasonographic Features of Thyroid Cancer Are Less Frequent in Small Tumors That Develop After a Long Latent Period After the Chernobyl Radiation Release Accident

The Chernobyl accident resulted in an unprecedented number of radiation-induced thyroid cancers in young individuals as detected by national and international screening programs. The vast majority of thyroid malignancies were papillary carcinomas that, despite being similar by histopathology, displayed large variability in clinical course. The correlations between ultrasound (US) and clinicopathological features in young patients with radiation-induced thyroid cancer, however, have not been well studied. Because of the importance of US for deciding which subjects should have fine-needle aspiration biopsy, we assessed the US features of papillary thyroid carcinoma in patients exposed to Chernobyl fallouts. We performed a retrospective multivariate logistic regression analysis of US features, clinicopathological data, and the latency period between radiation exposure and the diagnosis of cancer in 94 patients who were 10.6-34.3 years old (16.5 +/- 6.2, mean +/- standard deviation) at the time of diagnosis and 0.1-18.0 years old (5.6 +/- 4.2) at the time of the Chernobyl accident. Nodules greater than 10 mm were associated with the higher frequency of irregular margins (p = 0.001), longer period of latency (p = 0.016), and bilateral lymph node involvement (p = 0.025). Irregular tumor margins correlated with the shorter period of latency (p = 0.009) and unilateral nodal disease (p = 0.010). Hypoechoic nodules were observed more frequently in female patients (p = 0.012), in the absence of halo (p = 0.003) or calcifications (p = 0.005). Hypoechogenicity also correlated with the shorter latency (p = 0.015) and younger age of patients (p = 0.048). Irregular nodule margins, a usual sign of malignancy, are less useful in detecting thyroid cancers in radiation-exposed patients with tumors less than 10 mm. Thyroid cancers that are detected after longer latent periods display less of the US features characteristic of a malignant process, while benign US features are observed more frequently. Therefore, we recommend fine-needle aspiration biopsy to ensure early diagnosis of thyroid cancer for patients with a history of radiation exposure, even if their nodules are less than 10 mm.

Clinical Behavior of Radiation-Induced Thyroid Cancer: Factors Related to Recurrence

Whether thyroid cancer is more aggressive in radiation-exposed patients is not resolved. The frequency of aggressive features in post-Chernobyl patients suggests this may be the case. Our aim was to address this question by re-examining the pattern of risk factors for recurrence of thyroid cancers found in a cohort exposed to external radiation. The study population was drawn from a cohort of 4296 people, followed since 1974, who were treated before the age of 16 with conventional external radiation for benign conditions of the head and neck between 1939 and the early 1960s. The study group consisted of 390 patients who had surgically verified thyroid cancer. Potential risk factors for recurrence were evaluated by proportional hazards analysis. Fifty patients had recurrences an average of 8.7 years after diagnosis while the other 340 patients were followed for an average of 19.7 years. The sooner after radiation exposure the cancer occurred, the more likely it was to recur (hazard ratio, 0.96/year; 95% confidence interval [CI] 0.91-0.99). Taking into account the effect of the onset of screening in 1974, the features predictive of recurrence were younger age at the initial diagnosis (hazard ratio, 0.95/year; 95% CI, 0.91-0.99) and the size of the thyroid cancer (hazard ratio, 1.2/cm; 95% CI, 1.0-1.6). Although not based on a direct comparison, we conclude that thyroid cancers following external radiation exposure are not, on average, more aggressive than other thyroid cancers. The similarity of risk factors for recurrence suggests that they should be treated and followed in the same way as non-radiation-induced thyroid cancers.

Dr. Joseph Edward (“Ed”) Rall 1920–2008

Dr. Joseph Edward (“Ed”) Rall 1920–2008

Sixty years of follow-up of Hiroshima and Nagasaki survivors: Current progress in molecular epidemiology studies

This article provides an overview of the on-going molecular epidemiology studies among atomic-bomb survivors conducted at the Radiation Effects Research Foundation in Japan. The focus is on: (a) inter-individual variations in sensitivity to radiation-induced somatic mutations (glycophorin A (GPA) mutations) and their potential relevance to differences in susceptibility to radiation-related cancers and (b) the role of specific mutations/rearrangements in radiation-induced thyroid and colorectal cancers. The glycophorin A mutant fractions showed large differences between the survivors at each of the estimated bone marrow doses. Of note is the finding at doses>or=1 Gy; that the slope of the mutant fraction was significantly higher in the 'cancer group' than in the 'non-cancer group'. This study provided the basis for validating the use of gammaH2AX and reticulocyte micronucleus assays for evaluating radiosensitivity differences and genetic instability, respectively, in our studies in the coming years. Preliminary results from our molecular oncology studies on adult-onset papillary thyroid cancer provide evidence for the induction of RET/PTC rearrangements and BRAF point mutation (both known to be early stage events in adult-onset papillary thyroid cancer) but with a difference: cases associated with the rearrangements were more frequent at high doses, and developed sooner than those with BRAF mutation. In the case of colorectal cancer, the results suggest that radiation exposure might influence microsatellite instability (MSI) status through MSI-related epigenetic and genetic alterations-processes that might occur in the early stage of colorectal carcinogenesis.

A Radiation-Induced Gene Signature Distinguishes Post-Chernobyl from Sporadic Papillary Thyroid Cancers

We investigated selected gene targets to differentiate radiation-induced papillary thyroid cancers (PTCs) from other etiologies. Total RNA was isolated from 11 post-Chernobyl PTCs and 41 sporadic PTCs characterized by a more aggressive tumor type and lacking a radiation exposure history. RNA from 10 tumor samples from both groups was pooled and hybridized separately on a whole genome microarray for screening. Then 92 selected gene targets were examined quantitatively on each tumor sample using an RTQ-PCR-based low-density array (LDA). Screening for more than fivefold differences in gene expression between the groups by microarray detected 646 up-regulated and 677 down-regulated genes. Categorization of these genes revealed a significant (P < 0.0006) over-representation of the number of up-regulated genes coding for oxidoreductases, G-proteins and growth factors, while the number of genes coding for immunoglobulin appeared to be significantly down-regulated. With the LDA, seven genes (SFRP1, MMP1, ESM1, KRTAP2-1, COL13A1, BAALC and PAGE1) made a complete differentiation between the groups possible. Gene expression patterns known to be associated with a more aggressive tumor type in older patients appeared to be more pronounced in post-Chernobyl PTC, thus underlining the known aggressiveness of radiation-induced PTC. Seven genes were found that completely distinguished post-Chernobyl (PTC) from sporadic PTC.

Childhood thyroid cancer in Belarus, Russia, and Ukraine after Chernobyl and at present

Thyroid cancer in children is usually rare, but in the individuals exposed to radiation risk of disease increases considerably. After the Chernobyl accident in 1986, an over 10-fold maximal elevation in the incidence of thyroid cancer was registered about a decade later, cumulatively resulting in more than a thousand of newly diagnosed cases in children who lived in the territories of Belarus, Russia, and Ukraine affected by radioactive fallouts. Experience from the epidemic substantially promoted knowledge in clinical pediatric oncology, pathology and basic sciences. This article overviews epidemiology, clinical features, results of treatment and follow-up of childhood patients with radiation-induced Chernobyl thyroid cancer in comparison to sporadic cases diagnosed at present. In addition, we discuss general issues of pathology and molecular findings in childhood thyroid carcinomas.

RET oncogene amplification in thyroid cancer: correlations with radiation-associated and high-grade malignancy

A radiation etiology is well known in thyroid carcinogenesis. RET oncogene rearrangement is the most common oncogenic alteration in Chernobyl-related papillary thyroid cancer (PTC). To find the characteristic alteration associated with RET rearrangements in radiation-induced thyroid cancers, we analyzed the RET oncogene by fluorescence in situ hybridization. The fluorescence in situ hybridization technique has the possibility of detecting RET rearrangements at a single-cell level regardless of the specific fusion partner involved and directly reveals RET copy number on a per-cell basis. Our study demonstrated RET amplification in all 3 cases of radiation-associated thyroid cancers but not in sporadic well-differentiated PTC (n = 11). Furthermore, RET amplification was observed in all 6 cases of sporadic anaplastic thyroid cancers (ATCs). The frequency of RET amplification-positive cells was higher in ATC (7.2%-24.1%) than in PTC (1.5%-2.7%). The highest frequency of RET amplification-positive cells was observed among ATC cases with a strong p53 immunoreactivity. In conclusion, we found RET amplification, which is a rare oncogenic aberration, in thyroid cancer. This report is the first one to suggest the presence of RET amplification in PTC and ATC. RET amplification was correlated with radiation-associated, high-grade malignant potency, and p53 accumulation, suggesting genomic instability. RET amplification might be induced by a high level of genomic instability in connection with progression of thyroid carcinogenesis and, subsequently, be associated with radiation-induced and/or high-grade malignant cases.

International Collaborative Projects on Chernobyl and Radiation Induced Thyroid Cancer

International Collaborative Projects on Chernobyl and Radiation Induced Thyroid Cancer

Polymorphic ATM gene variants in radiation-induced and sporadic papillary thyroid cancer in children

Polymorphic ATM gene variants in radiation-induced and sporadic papillary thyroid cancer in children

Radiation-induced thyroid cancer: What we have learned from Chernobyl

An increased incidence of thyroid cancer in the exposed children remains the most well-documented long-term effect of radioactive contamination after the Chernobyl nuclear accident in April, 1986. Multiple studies on approx 4000 children and adolescents with thyroid cancer have provided important new information about the epidemiological, clinical, pathological, and molecular aspects of radiation-induced carcinogenesis in the thyroid gland. They revealed that environmental exposure to 131I during childhood carries an increased risk of thyroid cancer and the risk is radiation dose dependent. The youngest children are most sensitive to radiation-induced carcinogenesis, and the minimal latent period for thyroid cancer development after exposure is as short as 4 yr. The vast majority of these cancers are papillary carcinomas, many of which have characteristic solid or solid-follicular microscopic appearance. On the molecular level, post-Chernobyl tumors are characterized by frequent occurrence of chromosomal rearrangements, such as RET/PTC, whereas point mutations of BRAF and other genes are much less common in this population.

Risk of Thyroid Cancer after Childhood Exposure to Ionizing Radiation for Tinea Capitis 1

The thyroid gland is known to be sensitive to the carcinogenic effect of ionizing radiation, especially in children. The role of potential modifiers of the risk and latency period effects needs further investigation. We examined the effect of low doses of ionizing radiation (4.5-49.5 cGy) on the risk of developing thyroid cancer after long latent periods of up to 54 yr after childhood exposure. The study population included 10,834 individuals irradiated against tinea capitis in the 1950s and two matched nonirradiated groups (general population and siblings) for comparison. Cancer statistics and vital status data were obtained from national registries, updated to December 2002. Excess relative and absolute risks [excess relative risk per gray (ERR/Gy), excess absolute risk (EAR)] were estimated using Poisson regression for survival analysis. Within the study period, 159 cases of thyroid cancer were diagnosed. Total ERR/Gy and excess absolute risk per gray per 10(4) person-years for developing thyroid cancer reached 20.2 (95% confidence interval 11.8-32.3) and 9.9 (95% confidence interval 5.7-14.7), respectively. The risk was positively associated with dose and negatively associated with age at exposure. ERR/Gy was significantly elevated 10-19 yr after exposure, peaking at 20-30 yr, and decreasing dramatically (although still significantly elevated) 40 yr after exposure. Our findings agree with patterns of risk modification seen in most studies of radiation-induced thyroid cancer, although risk per unit dose seems higher. Our data show that 40 yr after irradiation, ERR decreases dramatically, although remaining significantly elevated. The hypothesis of different genetic susceptibility of the Jewish population deserves further exploration.

Molecular cytogenetic characterization of chromosome 9-derived material in a human thyroid cancer cell line

The incidence of papillary thyroid carcinoma (PTC) increases significantly after exposure of the head and neck region to ionizing radiation, yet we know neither the steps involved in malignant transformation of thyroid epithelium nor the specific carcinogenic mode of action of radiation. Such increased tumor frequency became most evident in children after the 1986 nuclear accident in Chernobyl, Ukraine. In the eight years following the accident, the average incidence of childhood PTCs (chPTC) increased 70-fold in Belarus, 200-fold in Gomel, 10-fold in the Ukraine and 50-fold in Tschnigov, Kiev, Rovno, Shitomyr and Tscherkassy compared to the rate of about 1 tumor incidence per 106 children per year prior to 1986 (Likhtarev et al., 1995; Sobolev et al., 1997; Jacob et al., 1998). To study the etiology of radiation-induced thyroid cancer, we formed an international consortium to investigate chromosomal changes and altered gene expression in cases of post-Chernobyl chPTC. Our approach is based on karyotyping of primary cultures established from chPTC specimens, establishment of cell lines and studies of genotype-phenotype relationships through high resolution chromosome analysis, DNA/cDNA micro-array studies, and mouse xenografts that test for tumorigenicity. Here, we report the application of fluorescence in situ hybridization (FISH)-based techniques for the molecular cytogenetic characterization of a highly tumorigenic chPTC cell line, S48TK, and its subclones. Using chromosome 9 rearrangements as an example, we describe a new approach termed ‘BAC-FISH’ to rapidly delineate chromosomal breakpoints, an important step towards a better understanding of the formation of translocations and their functional consequences.

Proliferative Activity of Human Thyroid Cells in Various Age Groups and Its Correlation with the Risk of Thyroid Cancer after Radiation Exposure

The thyroid gland is vulnerable to the carcinogenic effects of ionizing radiation, and there is a well-documented inverse correlation between thyroid cancer and age at exposure, particularly for ages less than 20 yr. One of the factors responsible for this phenomenon may be more rapid cell proliferation in children. The objective of this study was to determine the proliferative rate of normal human thyroid cells in different age groups. We used immunohistochemical analysis to determine the Ki-67 proliferative index in 117 thyroid glands obtained at autopsy, including 25 fetal thyroids (11-40 wk gestation), 55 childhood thyroids (0-19 yr), and 37 adult thyroids (20-60 yr). The rate of Ki-67 labeling in the three groups was 7.4 +/- 6.10, 0.23 +/- 0.15, and 0.08 +/- 0.04% respectively, demonstrating an overall trend for diminishing proliferative activity of thyroid cells with increasing age. However, a lack of correlation was noted between the slopes of cancer risk calculated from previous studies of irradiated populations and proliferative rate in the pediatric age intervals of 0-4 and 5-9 yr, suggesting that other factors are likely to be responsible for the particularly high sensitivity to radiation-induced thyroid cancer among the youngest children. Our findings of a general decrease in proliferative activity of thyroid cells with age may explain, at least in part, the higher risks of radiation-related thyroid cancer in children compared with adults. However, the variation in the rate of cell proliferation is unlikely to be responsible entirely for this phenomenon and other factors may also be involved.

CHERNOBYL BEYOND 20 YEARS: WHAT IS RADIATION-INDUCED THYROID CANCER?

Along with a summary of clinical data on Chernobyl thyroid cancer, presented will be the scope of current understanding of the molecular mechanisms of radiation-induced thyroid cancer in children and adolescents with a focus on the discussion of how to further assist the long-term follow-up of the operated patients with thyroid cancer and to outline the approaches to the identification of the groups at high risk of the disease. Special attention should be paid to a high risk group of individuals who had been exposed to radioactive iodines after the Chernobyl accident and whose age is from 20 to 30 year-old in 2006.

1241 POSTER Risk estimation of radiation-induced thyroid cancer in children undergoing prophylactic cranial irradiation with photons 6 MV — A monte garlo study

1241 POSTER Risk estimation of radiation-induced thyroid cancer in children undergoing prophylactic cranial irradiation with photons 6 MV — A monte garlo study

Radiation-induced Thyroid Cancer—What's New?

Radiation-induced Thyroid Cancer—What's New?