Clinical behavior of radiation-induced thyroid cancer: factors related to recurrence.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Acoustic neuromas following childhood radiation treatment for benign conditions of the head and neck.

Childhood radiation exposure has been associated with an increased risk for developing several neoplasms, particularly benign and malignant thyroid tumors, but little is known about the risk of developing acoustic neuromas. The aim of this study was to confirm whether there is a risk for acoustic neuromas and, if so, to determine its magnitude and duration. We investigated the time trend and dose-response relationships for acoustic neuroma incidence in a cohort of 3,112 individuals who were irradiated as children between 1939 and 1962. Most of the patients were treated to reduce the size of their tonsils and adenoids and received substantial radiation exposure to the cerebellopontine angle, the site of acoustic neuromas. Forty-three patients developed benign acoustic neuromas, forty of them surgically resected, far in excess of what might be expected from data derived from brain tumor registries. The mean dose (+/-SD) to the cerebellopontine angle was 4.6 +/- 1.9 Gy. The relative risk per Gy was 1.14 (95% confidence interval 1.0-1.3). The earliest case occurred 20.4 years after exposure and the latest 55 years after exposure (mean 38.3 +/- 10.1 years). Our study provides support for an association between acoustic neuromas and childhood radiation exposure. Although acoustic neuromas are usually benign and often asymptomatic, many cause significant morbidity. Following childhood radiation exposure, they appear after a long latency and continue to occur many decades afterward. Any symptoms of an acoustic neuroma in a patient with a history of radiation to the head and neck area should be investigated carefully, and the threshold for employing imaging should be lowered.

Factors related to the recurrence of thyroid nodules after surgery for benign radiation-related nodules.

OBJECTIVE: Benign thyroid nodules are increased by radiation exposure and recurrences are common. The goal of this study was to determine the factors related to recurrence of nodular disease and the efficacy of thyroid hormone therapy in reducing them. DESIGN, SETTING, AND SUBJECTS: The study population was drawn from a cohort of 4296 people 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 632 subjects who had benign nodules removed surgically. At the discretion of their physicians, 426 subjects were treated with thyroid hormone after surgery, 198 were not, and in 8 subjects, thyroid hormone treatment status was unknown. MAIN OUTCOMES: There were 129 (20.4%) subjects who developed new nodules during follow-up. Women had a greater risk of recurrent nodules than men (27.5% vs. 13.5%) and the rate of recurrence correlated inversely with the extent of surgery. The group who took thyroid hormone had a lower recurrence rate than the untreated group (14.2% vs. 34.2%). The risk of recurrence was reduced to 0.69 (0.47-1.01) in thyroid hormone-treated subjects, regardless of extent of surgery, and to 0.66 (0.46-0.97) when only the subjects with less than 75% of their thyroid removed were considered. CONCLUSION: Thyroid hormone therapy reduced recurrences in this irradiated cohort. It should be recommended to all patients with irradiated thyroids and previous thyroid surgery.

Low frequency of BRAF mutations in adult patients with papillary thyroid cancers following childhood radiation exposure.

Radiation exposure at a young age is the only environmental factor known to cause thyroid cancer, predominantly of the papillary type. We have previously reported a high percentage (86.7%) of RET-positive papillary thyroid cancers in a cohort of individuals exposed to external radiation of the head and neck area before the age of 16. Recently, we and others have reported that point mutations of the BRAF gene occur with high frequency among sporadic adult papillary thyroid carcinomas, but occur at a much lower frequency in the population exposed after the Chernobyl accident. We here report that there is a similar low frequency of BRAF mutations among our cohort of those exposed to external beam radiation as children who later developed papillary thyroid cancer as adults. Samples were analyzed by mutation allele-specific amplification (MASA) for the most common T1799A mutation in exon 15 that converts amino acid 600 from valine to glutamate. In 23 cases, only 1 sample was positive. These results are further evidence that BRAF mutations, while common in sporadic adult papillary thyroid cancers, are rare events in cancers seen in subjects exposed to radiation as children.

Ultrasound-detected thyroid nodules in radiation-exposed patients: changes over time.

The relationship between radiation exposure and thyroid cancer is well known, but whether all irradiated patients should have thyroid ultrasounds is unresolved. We have performed follow-up ultrasound examinations of patients in a cohort who were exposed to conventional external radiation during 1939-63 for benign conditions of the head and neck area prior to their 16th birthday. Of 54 subjects who had normal radionuclide scans in 1974-76 and were reexamined in 1996-97 by thyroid ultrasonography, 42 remained eligible and 34 agreed to participate in the present ultrasound study. After an additional 4-8 years of follow-up and using an ultrasound machine with increased resolution, we found 160 nodules (in 33 of these 34 subjects), compared with 96 nodules (in 29 of the 34 subjects) detected in the previous examination. Only four of the new nodules were > or =10 mm. Of the previously diagnosed large (> or =10 mm) nodules, four nodules in four subjects resolved; nine nodules in six subjects regressed to <10 mm; 14 nodules in 13 subjects remained at > or =10 mm. The four new large nodules appeared in four subjects, and six small nodules increased to > or =10 mm in six other subjects. The total volume of the thyroid nodules decreased in the 13 subjects on thyroid hormone (by 0.20 cm(3)) and increased in the 21 subjects who were not (by 0.34 cm(3), p < 0.05 by unpaired t-test). In summary, thyroid nodules are extremely common in irradiated subjects. Many new ones may be observed over time, but most are small and seen because of the increased resolution of ultrasound machines. Compared to patients on no medication, nodules in patients on thyroid hormone tended to regress. Since FNA of all thyroid nodules in irradiated patients is not feasible, ultrasound is useful in identifying those lesions that are growing.

Familial concordance of thyroid and other head and neck tumors in an irradiated cohort: analysis of contributing factors.

Relatively little is known about variations in susceptibility to the effects of radiation in the general population. We have been studying 4296 individuals exposed as children to head and neck radiation. The present study was designed to evaluate the pattern of thyroid, parathyroid, salivary, and neural tumors in irradiated siblings for evidence of heritable susceptibility factors. We also wanted to determine whether the characteristics of thyroid cancers were influenced by familial factors. The following criteria were met by 251 sibling pairs: both irradiated, both with follow-up (average, 44.3 +/- 9.4 yr; range, 9.4-59.5 yr), and both with organ-dose estimates. For each sibling pair we derived a quantitative score, taking into account the length of follow-up and known risk factors, for their concordance and used the sum of these scores to characterize the population. Whether we used thyroid cancer or all thyroid nodules as an end point, the degree of concordance did not exceed what could be explained by the length of follow-up and known risk factors. For thyroid cancer, neither the presenting characteristics nor their rates of recurrence were influenced by their concordance status. In summary, we were unable to identify familial factors that modify the strong effects of radiation exposure. There is no reason to alter the evaluation or treatment of thyroid cancer in an irradiated patient based on whether another member of the family has radiation-related tumors.