Age and Sex
A major risk factor is a young age at the time of irradiation. The risk of thyroid cancer after external irradiation in children less than 5 years of age is two times higher than in children treated between 5 and 9 years and five times higher than in children treated between 10 and 14 years. From the Lifespan Study of atomic bomb survivors in Hiroshima and Nagasaki, it is known that little risk is carried for exposures after the age of 20 and almost none after the age of 40. The excess risk of thyroid cancer was 9.5, 3.0, 0.3, and 0.2 in the age categories 0– 9, 10– 19, 20– 39, and over 40 years, respectively, at the time of bombing. The excess risk was not significant for subjects exposed above the age of 15– 20 years. This increased risk of very young children to develop thyroid cancer after radiation exposure can be explained, at least in part, by the higher proliferative activity of thyroid cells during intrauterine development and childhood. The high susceptibility of young children to radiation has been confirmed in the thyroid cancer studies after the Chernobyl nuclear reactor accident, supporting the concept that the radiation effect is maximal during periods of rapid cell proliferation, as in the case of the developing thyroid of very young children. Data on irradiation in adults are scarce, but estimates of the ERR/ Gy are largely below those of individuals exposed during childhood, and it is likely the risk is negligible.
Gender does not seem to influence the risk of developing radiation- induced thyroid cancer. Although females are 2– 3 times more likely to develop both benign and malignant thyroid nodules after irradiation, this finding reflects the higher natural incidence of thyroid nodules and cancer in the female general population. Very recently a new study on the association between radiation dose and thyroid cancer incidence among Japanese survivors who were adults at the time of the atomic bombings of Hiroshima and Nagasaki has shown that the exposure to ionizing radiation in adults was positively associated with thyroid cancer among women atomic bomb survivors. However, this association was lower than that observed in those who were exposed during childhood.
Fractionation and Dose Rate
External radiation therapy for benign and malignant diseases is given at a high dose rate. Lower dose rates or fractionation of the dose may theoretically allow radiation- induced DNA lesions to be repaired, thus decreasing the carcinogenic effects of radiation. In the pooled analysis of seven studies, fractionation of the dose was associated with a 30% reduction of the ERR/ Gy. However, in a recent update of thyroid cancer after radiation therapy for malignant disorders in childhood, no reduction in ERR/ Gy was observed with fractionation.
The importance of the dose rate is suggested by several observations. In children treated for skin angioma of the neck, a dose– effect relationship was observed after external radiation at a high dose rate, but no such relation was found after brachytherapy at a low dose rate. The incidence of thyroid nodules is similar in two regions of China where natural radiation is different (i.e. 140 mGy and 50 mGy/ lifetime, respectively). In contrast, an increased RR (1.7) of thyroid cancer was found among 27 000 medical diagnostic radiographers in China, who probably received more than 1 Gy to the thyroid during their working life. No such increase was observed in similar workers in industrialized countries.
Genetic Predisposition
Several clinical observations suggest that genetic predisposition, such as defects in the DNA repair mechanisms, may affect the risk of developing radiation- induced thyroid cancer. Patients who experience one radiation- related cancer are more likely to develop a second radiation- related cancer. Sibling pairs, exposed to radiation, develop thyroid tumours more often than would be expected by chance. The risk of thyroid cancer in patients treated with radiotherapy during childhood for a cancer (other than neuroblastoma) is 3– 10 times higher than in children treated for benign conditions. Those treated for neuroblastoma have a fivefold risk of thyroid cancer with respect to patients treated for other cancers, suggesting a common predisposition for neuroblastoma and thyroid cancer.
The search for the gene(s) predisposing to radiation- induced thyroid cancer is currently in progress in pedigrees showing recurrence of thyroid cancer. No linkage has been found as yet with genes known to be involved in thyroid tumorigenesis, such as ras, p53, BRaf, or RET/ PTC. A distinct genome- wide gene expression pro filing has been reported in post- Chernobyl papillary thyroid cancer when compared with that occurring naturally, suggesting a greater susceptibility to thyroid cell radiation damage.
