Is ionizing radiation responsible for the increasing incidence of thyroid cancer

The incidence of thyroid cancer has been rising at a high pace in the United States and many other countries. Based on the data from the National cancer Institute’s Surveillance, Epidemiology and End Results (SEER) dataset, the incidence has nearly doubled in the U.S. during the last decade and almost tripled since the early 1970’s.1, 2 Thyroid cancer is two to three times more common among women, and in this gender group it is now the fastest growing cancer type and the 6th most common. The reasons for such a steep increase in thyroid cancer incidence are not well understood. The highest rate of increase is for small and localized thyroid cancers, which led many to suggest that the increase is due to better cancer detection by ultrasonography and other imaging techniques. Indeed, the use of thyroid ultrasound has become progressively more widespread since the 1980’s and it can detect thyroid nodules as small as 0.2 cm in size.3 Under ultrasound guidance, even very small nodules can be biopsied using fine needle aspiration (FNA) and examined cytologically. This is likely to result in the increased detection of small thyroid cancer nodules, which are common in the general population. Indeed, in autopsy series, small foci of papillary carcinoma are found in 5-10% of thyroids in patients with no known thyroid disease in many regions of North America, Europe, and South America, and even with higher frequency in Japan and Finland 4-7. These small cancers rarely progress to a clinically relevant disease and are believed to represent an incidental finding. Improved detection undoubtedly has contributed to the growing incidence of thyroid cancer. However, it most likely is not the sole reason and other etiologic factors probably have played a role. One of the potential culprits is ionizing radiation, which is a major known risk factor for thyroid cancer and particularly for papillary carcinoma, the most common thyroid cancer type. Both external radiation (X-ray and γ-radiation) and internal exposure to radioiodines through inhalation or ingestion carry an increased cancer risk. The well documented examples include medical therapeutic external beam radiation and accidental exposure to γ-radiation and radioiodines as a result of nuclear weapon explosions or nuclear reactor accidents.8 The most recent reminder for the association between radiation exposure and thyroid cancer risk comes from the Chernobyl nuclear power accident in 1986. To date, it resulted in the development of thyroid cancer in more than 4,000 individuals who were children or adolescents at the time of the accident and received substantial doses of radiation to the thyroid. However, much larger populations in various countries were exposed to nuclear fallout as a result of the accident. It appears that this has not resulted in the detectable increase in thyroid cancer incidence. However, accurate dose reconstruction and detection of small variations in the cancer rate in these populations would be difficult. Similarly, no increase in cancer risk due to diagnostic X-ray procedures and occupational radiation exposure has been established.9 Despite this, in light of the increasing volume of radiation-based medical diagnostic procedures and levels of environmental contamination by radioactive materials, the contribution of low-dose radiation remains a possibility, particularly in individuals with genetic predisposition to radiation-associated carcinogenesis. The growing incidence of thyroid cancer over the last decades is entirely due to papillary carcinoma, whereas the incidence of other thyroid cancer types remains unchanged or is decreasing.1, 3, 10 About half of the increase is due to tumors that are 1 cm or less in size, which are designated by the World Health Organization classification of endocrine tumors as papillary microcarcinomas.11 Therefore, better understanding of the biology and etiologic factors responsible for the development of papillary microcarcinomas is particularly important for unraveling the reasons behind the general increase in thyroid cancer incidence. In the current issue of the Journal, Hayashi and colleagues report the results of their study aimed to explore the association between papillary microcarcinoma and radiation exposure received by atomic bomb survivors in Japan in 1945. The study was based primarily on the autopsy data and employed strict selection criteria to minimize the potential confounding factors. Specifically, only tumors of 1 cm or less in patients with no prior cancer history and no other tumors found in the thyroid were included in the analysis. The study finds a statistically significant radiation-dose response for the prevalence of these tumors, with an excess odds ratio (EOR) per Gray of radiation of 0.57. The excess risk was limited to women, and among them the EOR was 2.4 per Gray. These data raise the possibility that the incidence of thyroid microcarcinoma may in fact be related to radiation exposure. However, this possibility is far from being fully established. Although correlation between radiation dose and papillary microcarcinoma found by Hayashi and colleagues represents the most direct evidence for such an association, other and more circumstantial indicators are less definitive or were not searched for in this study. Several associations are typically found in the studies of radiation-induced thyroid cancer. Those include the inverse correlation between cancer risk and age at exposure as well as characteristic histopathologic features and molecular alterations in radiation-induced cancer.12 In the study by Hayashi and colleagues, no association with age at exposure was found. However, the study cohort was comprised of a relatively small number of individuals who were irradiated at young age. The study also provides a quite detailed histopathologic analysis of these microcarcinomas and finds that most tumors had a classic papillary growth pattern with significant fibrosis, well-developed nuclear features of papillary carcinoma, and psammoma bodies seen in a proportion of cases. These features constitute a common presentation of papillary microcarcinoma in the general presentation.13 Unfortunately, the study did not report the extent of the solid growth pattern in these tumors. Solid architecture, exclusively or admixed with other architectural patterns, was commonly seen in post-Chernobyl papillary carcinomas in children,14 but it is rare in thyroid tumors with no history of radiation exposure. Twenty-eight percent of microcarcinomas in the study by Hayashi and colleagues were multiple, and no correlation between radiation dose and number of tumors was seen. The frequency of multifocality was overall similar to the general population, where 20-40% of microcarcinomas are miltifocal.15 With respect to molecular alterations, the vast majority of thyroid papillary carcinomas carry genetic alterations in the effectors of the mitogen-activated protein kinase (MAPK) signaling cascade. Activation of this cascade appears to be crucial for thyroid cancer development. The effected genes that signal along MAPK pathway are RET, NTRK1, RAS, and BRAF. Remarkably, the mechanisms of these gene activation is quite different in tumors associated with radiation exposure as compared to those from the general population. The dominant mutation mechanism in radiation-induced tumors is chromosomal rearrangement, such as those leading to the formation of RET/PTC, TRK and BRAF/AKAP9 fusion oncogenes.16 A very different mutation mechanism, i.e. point mutation, is the most prevalent in sporadic tumors, which typically carry point mutations of BRAF and RAS genes. Of particular interest is the RET/PTC rearrangement, which is found in up to 80% of radiation-induced papillary carcinomas.17, 18 Correlation between radiation exposure and high frequency of RET/PTC in papillary carcinomas has been seen after accidental radiation exposure from Chernobyl, in patients treated by external beam radiation, and more recently in atomic bomb survivors in Japan. In the study reported by Hamatani et al, the presence of RET/PTC rearrangement had direct correlation with increasing radiation dose, whereas BRAF point mutation had strong inverse correlation with the dose.19 The molecular status of papillary microcarcinomas has not been analyzed by Hayashi and colleagues. It would be of significant interest to identify the molecular profiles of papillary microcarcinomas reported in this series of cases. This information could provide additional evidence for the association between this subtype of papillary carcinoma and radiation exposure. Similarly, it is of substantial interest to determine if the genetic makeup of papillary carcinomas has changed during the last several decades in the U.S. and other countries that have witnessed the increased incidence of thyroid cancer. It would be of particular interest to follow the trends in the prevalence of RET/PTC and BRAF. The increased RET/PTC frequency would point to the increasing role of exposure to ionizing radiation and other similar DNA-damaging agents, whereas rising BRAF incidence would be more consistent with the chemical carcinogenesis and possible dietary iodine fluctuation. In summary, the results of the study reported by Hayashi and colleagues provide evidence suggesting that the growing incidence of small thyroid tumors may be related in part to increasing exposure of humans to ionizing radiation. This possibility needs further testing in other populations, as well as incorporation of additional scientific tools, such as genetic markers. The importance of finding a definitive answer on this question is high. It could not only help to understand the current trend in thyroid cancer incidence, but would stimulate the development of measures to slow down and possibly reverse this trend in the future.