RET expression in papillary thyroid cancer from patients irradiated in childhood for benign conditions.

Both external and internal exposure to radiation have been linked to the development of papillary thyroid cancer. Rearrangement of the gene for RET tyrosine kinase and subsequent expression of this protein has also been found to occur in many papillary thyroid cancers, and with increased frequency in radiation-related cancers following the Chernobyl accident. However, little has been reported on the frequency of RET rearrangements in cancers after exposure to external radiation. We here report on RET protein immunoreactivity in paraffin-embedded thyroid samples from 30 patients with papillary thyroid cancer who received radiation treatment during childhood for benign conditions at Michael Reese Hospital in Chicago, and in 34 patients identified from the tumor registry as having papillary thyroid cancer with no history of therapeutic radiation. The subjects were characterized by sex, age at surgery, and the following attributes of tumor pathology: size, number of lobes involved, number of foci, lymph node metastases, and soft tissue invasion. Representative tissue samples were reacted with an antibody against the RET tyrosine kinase domain whose expression has been shown to correlate highly with RET/PTC rearrangements. A greater percentage of cancers positive for RET immunoreactivity was found in the radiation-exposed group (86.7% vs. 52.9%, P = 0.006). Although the mean age at surgery of the exposed group was lower than the control group, there was no correlation of positive RET immunoreactivity with the age at surgery. No characteristics of the tumors were associated with positive RET immunoreactivity. In summary, the greater incidence of RET-immunopositives in the irradiated group indicates that the expression of RET immunoreactivity is strongly associated with radiation exposure, but the prognostic significance of this is not yet clear.

Behavior of small thyroid cancers found by screening radiation-exposed individuals.

Thyroid cancers detected by screening irradiated individuals are often small and of uncertain clinical significance. We retrospectively analyzed the effect of screening in a cohort of 4296 individuals exposed to radiation as children in the 1940s and 1950s and followed by us from 1974 until the present. We compared the thyroid cancers diagnosed before 1974 (122 cases, routine care) with the cancers found in subjects screened by us after 1974 (172 cases, screened), using cancer recurrence as the end point. Screening included a thyroid scan or, more recently, thyroid ultrasound. As expected, many of the cancers found by screening were very small (52% were <10 mm), but the range of tumor sizes overlapped those found by routine care. The recurrence rate was significantly lower in the cases found by screening, but when the comparison was limited to cancers 10 mm or larger, no difference in the recurrence rates was seen. This would suggest that the lower recurrence rate observed for small thyroid cancers detected at screening was due to earlier diagnosis rather than more effective treatment. By univariate analysis, four factors were associated with an increased risk of recurrence of small (<10 mm) thyroid cancers: short latency (i.e. a shorter time interval between the radiation exposure and the first thyroid surgery), lymph node metastases present at diagnosis, multifocal cancers, and higher radiation dose. In a multivariate analysis combining the four risk factors, only short latency was significant. As thyroid cancers that escape detection by routine means should be diagnosed at screening, and both large and small thyroid cancers have the potential to recur, screening may be of value, but only if groups with a sufficiently high prevalence of thyroid cancer can be identified to offset the adverse effects of unnecessary treatment due to false positive results.

Fine-needle aspiration of thyroid nodules in radiation-exposed patients.

External radiation used to treat benign conditions in the head and neck area results in an increased risk of thyroid cancer in exposed individuals. Fine-needle aspiration (FNA) biopsy is the standard procedure used to evaluate suspicious thyroid nodules. Its accuracy has been extensively studied, but little is known about FNA in irradiated patients. We analyzed the FNA experience of 136 irradiated subjects. Fifty-two had surgery enabling a comparison of the histologic diagnosis with the FNA results. In these 52 patients with a total of 53 FNAs, 20 were reported as benign, 14 as follicular neoplasms, 6 as papillary cancer, and 13 as inadequate samples. Seven malignant nodules were aspirated; 4 were reported as papillary cancer, 1 was reported as benign and 2 had inadequate specimens. An additional 11 patients had thyroid cancer in foci that were not subjected to FNA. For the nodules that were aspirated, and considering an FNA report of follicular neoplasm as a false-positive when a follicular adenoma or a colloid nodule was found at surgery, the calculated sensitivity was 80%, specificity 54%, positive predictive value 20%, and negative predictive value 95%. Of the 14 follicular neoplasm FNA diagnoses, 10 were colloid nodules (71%), and 4 only were follicular adenomas. We conclude that the sensitivity of FNA in irradiated patients is similar to what is reported for the general population. However, smaller malignant nodules are common and are not diagnosed by the FNA. Also, the FNA diagnosis of follicular neoplasm is often inaccurate and inadequate aspirations are frequent in this patient group.

Salivary gland tumors after childhood radiation treatment for benign conditions of the head and neck: dose-response relationships.

We have investigated the dose-response relationships for the incidence of salivary gland tumors in a cohort of 2945 individuals who were irradiated as children between 1939-1962. Most of the patients were treated to reduce the size of their tonsils and adenoids. The mean dose to the salivary glands (+/-SD) was 4.2 +/- 1.7 Gy. Eighty-nine patients developed 91 salivary gland neoplasms; 22 had single malignancies, 64 had single benign neoplasms, 2 developed two separate benign neoplasms, and 1 developed a single neoplasm but did not have surgery. The majority (81 of 89) of the patients developed neoplasms in the parotid glands. Mucoepidermoid carcinomas were the most common malignancy and mixed (pleomorphic) adenomas were the most common benign neoplasm. For all salivary gland tumors, the excess relative risk per gray (ERR/Gy) was 0.82; however, the 95% confidence interval was wide (0.04, upper bound indeterminate). The trend was determined principally by benign tumors, as there was no dose-response relationship for salivary gland cancer, although there were too few cases to draw definitive conclusions. Overall, our study provides support for an association between salivary gland tumors and radiation exposure. Although most salivary gland tumors are benign and are usually readily detected, they may cause morbidity, and people who have been irradiated in the area should be monitored for their occurrence.

Thyroid nodules in the follow-up of irradiated individuals: comparison of thyroid ultrasound with scanning and palpation.

In 1974 we began a prospective study of a cohort of 4296 individuals exposed to therapeutic head and neck irradiation during childhood for benign conditions. To define the role of thyroid ultrasonography in following irradiated individuals, we studied a subgroup of 54 individuals. They all had been screened between 1974-1976 and had normal thyroid scans and no palpable nodules at that time. Thyroid ultrasonography, thyroid scanning, physical examination, and serum thyroglobulin measurements were performed. One or more discrete ultrasound-detected nodules were present in 47 of 54 (87%) subjects. There were a total of 157 nodules, 40 of which were 1.0 cm or larger in largest dimension. These 40 nodules occurred in 28 (52%) of the subjects. Thirty (75%) of these 1.0-cm or larger nodules matched discrete areas of diminished uptake on corresponding thyroid scans. The 10 that did not match (false negative scans for > or = 1.0-cm nodules) were the only nodules of this size in 7 subjects. Of 11 nodules 1.5 cm or larger, only 5 were palpable. Serum thyroglobulin correlated to the number (P = 0.04; r2 = 0.10), but not the volume of the thyroid nodules (P = 0.07; r2 = 0.08). We conclude that thyroid nodules are continuing to occur and are exceedingly common in this irradiated cohort of individuals. The results confirm that thyroid ultrasonography is more sensitive than physical examination and scanning. However, thyroid ultrasound is so sensitive and nodules so prevalent that great caution is needed in interpreting the results.

Multiple schwannomas and meningiomas associated with irradiation in childhood.

OBJECTIVE: To determine the pattern of neural tumors (schwannomas, vestibular schwannomas [acoustic neuromas], and meningiomas) that developed in 3013 people who received radiation treatment with x-ray beam therapy for benign conditions of the head and neck area before their 16th birthday. METHODS: The surgical and pathology reports and pathology slides were reviewed for all neural tumors in the cohort. Patients with more than 1 neural tumor were compared with those with 1 neural tumor and those with no neural tumors. RESULTS: There were 7 patients with multiple neural tumors and 63 with single neural tumors. The distribution of tumors in these 2 groups differed. The group with multiple tumors had more spinal nerve root schwannomas, while the group with single tumors had more cranial nerve schwannomas. Six of the 7 patients did not meet the diagnostic criteria for neurofibromatosis type 2. CONCLUSIONS: Our findings suggest that host factors that increase susceptibility to radiation may be involved in the development of the multiple neural tumors. Clinically, patients with multiple neural tumors who do not meet the diagnostic criteria for neurofibromatosis type 2 should be questioned about radiation exposure. If exposure is confirmed, then screening for other radiation-related tumors should be initiated.

Dose-response relationships for radiation-induced hyperparathyroidism.

It has been hard to establish with certainty that radiation exposure is a risk factor for developing hyperparathyroidism. In part this is because many cases of hyperparathyroidism remain asymptomatic and escape clinical detection. We present results from a study of 2555 subjects who received external beam radiotherapy to the head and neck area for benign conditions before their 16th birthday between 1939 and 1962. The average length of follow-up was 36.6 yr. There were 36 confirmed cases of hyperparathyroidism. Based on a relative risk model, the excess relative risk increased significantly by 0.11/centigray; however, the confidence interval was wide (95% confidence interval, 0.0-17.2). The hyperparathyroidism rates and dose-response relationships were not affected by gender or age at first radiation treatment. The demonstration of a dose-response relationship within an irradiated cohort supports an association between radiation exposure and hyperparathyroidism and suggests that the calcium levels of individuals irradiated to the head and neck area should be monitored.

Recurrence of thyroid nodules after surgical removal in patients irradiated in childhood for benign conditions.

To determine the incidence of benign thyroid nodules and the risk factors for their recurrence after surgical removal, we followed 511 patients for 1 to 40.6 years (median, 11.2) after surgery for benign thyroid nodules arising after local irradiation for unrelated benign diseases in childhood. Recurrent thyroid nodules developed in 100 patients (19.5 percent). The risk of recurrence correlated inversely with the amount of thyroid tissue removed. Women had a higher recurrence rate than men (28.4 percent vs. 10.3 percent; P less than 0.05). Among the 299 patients who had been treated with thyroid hormone at the discretion of their physicians to suppress thyroid-stimulating hormone, 25 had recurrences (8.4 percent), as compared with 72 of 201 patients who did not receive thyroid hormone (35.8 percent) (hazard ratio taking into account the extent of surgery and the patient's sex, 2.5; 95 percent confidence interval, 1.5 to 4.1). Histologic analysis of the 73 tissue samples from patients with recurrences showed that 14 samples (19.2 percent) were malignant. Thyroid hormone treatment had no effect on the rate of thyroid cancer. We conclude that radiation-associated benign thyroid nodules have a high recurrence rate, similar to that reported among nonirradiated patients with benign thyroid nodules. We also conclude that treatment with thyroid hormone decreases the risk of benign recurrences, particularly in women, but not the risk of cancer.

Radiation-induced thyroid neoplasms: evidence for familial susceptibility factors.

To determine if there is a familial component to susceptibility to radiation-induced thyroid neoplasms, we studied 572 individuals who were members of 286 sibpairs who received childhood radiation treatment and for whom follow-up information was obtained. Of these 572 individuals, 240 (42.0%) had thyroid neoplasms (benign and malignant), and 75 (13.1%) had surgically confirmed thyroid cancer. To test the null hypothesis, that neoplasm occurred without regard to family membership, it was necessary to take into account each individual's years at risk and known risk factors. These risk factors, analyzed by the proportional hazards model of Cox, were sex, age at time of radiation treatment, and treatment dose. For each individual, we calculated the cumulative hazard that a neoplasm would occur from that individual's specific risk factors and years at risk. Each individual was also assigned an indicator, D = 1 or 0, according to whether a neoplasm had occurred. Finally, for each individual we computed a residual, D minus the cumulative hazard. In the absence of familial effects, positive and negative residuals would be distributed without regard to family membership, whereas residuals would tend to have concordant signs and magnitudes within families if familial effects were present. Permutational methods, therefore, were used to determine whether the sum among families of the products of residuals within sibpairs was too large, compared to random pairing. For all thyroid neoplasms (both benign and malignant), within-family concordance was significant (P = 0.05, the observed sum among families of the products of residuals was larger than 9468 of 9999 permutations). For thyroid cancer considered alone, the same analysis did not demonstrate familial concordance conclusively, but the results were suggestive (P = 0.18). We conclude that in addition to the previously described risk factors of female sex, younger age at radiation exposure, and higher dose, it is likely that there are independent familial risk factors for developing thyroid neoplasms. Whether these are genetic or environmental factors remains to be determined.

Radiation-induced thyroid carcinoma. Clinical course and results of therapy in 296 patients.

Of 5379 patients who had received radiation treatment at our institution for benign conditions of the head and neck, 318 developed thyroid cancer 3 to 42 years later. We report follow-up observations (median interval from diagnosis to recurrence or last contact, 10 years; longest interval, 31) for 296 of these patients. Three patients died of thyroid cancer and 40 had recurrences. The rate of recurrence during the 10 years after the detection of thyroid cancer, determined by life-table analysis, was 1.1%/yr. Factors that correlated with the risk of recurrence were tumor size, histologic type, number of lobes involved, vessel invasion, and lymph node metastases. The time from radiation exposure to the discovery of thyroid cancer (latency) and the age at diagnosis both inversely correlated with recurrence. The administration of thyroid hormones reduced the number of recurrences in patients with combined papillary and follicular cancer, but no reductions could be associated with the extent of surgery done or the prophylactic use of radioactive iodine ablation. We conclude that the course of radiation-induced thyroid cancer is the same as that of thyroid cancer found in other settings. We advocate a conservative approach to the treatment of small tumors that have no associated risk for thyroid cancer other than that they developed many years after the patient had been exposed to radiation.

Radiation-induced thyroid and other head and neck tumors: occurrence of multiple tumors and analysis of risk factors.

In 2561 patients who received conventional external radiation treatment before age 15 yr for benign conditions of the head, neck, and upper thoracic area, we found an increase in the number of salivary gland tumors and benign neural tumors of the head and neck area. To determine whether patients who developed these relatively uncommon tumors were more susceptible to the long term effects of radiation, we analyzed how frequently these patients also developed benign and malignant thyroid neoplasms. Compared to the remainder of the irradiated population, the patients with salivary and neural tumors had an increased frequency of thyroid disease (19.4% vs. 11.2% for thyroid cancer and 52.4% vs. 39.9% for all thyroid nodules). Various risk factors were studied to determine whether they were related to the eventual occurrence of thyroid disease. Higher doses, being female, and lower ages at time of treatment were associated with increased risk. However, these factors did not fully explain the differences in the frequency of coexisting tumors, suggesting that additional factors, such as radiation sensitivity, may account for the increased risk.

Prospective serum thyroglobulin measurements in assessing the risk of developing thyroid nodules in patients exposed to childhood neck irradiation.

We examined 327 patients with a history of cervical radiation treatment for benign conditions and followed them for an average of 5.6 yr. These patients were selected because they initially had normal examinations and normal serum thyroglobulin levels. Of the 327 patients, 48 developed thyroid nodules, and an additional 30 had other clinical changes in their thyroids. Serum thyroglobulin increased by 4.0 +/- 0.6 (+/- SEM) ng/ml in those who remained normal, by 13.4 +/- 5.2 ng/ml in those who were no longer normal, and by 17.1 +/- 8.2 ng/ml in those who developed nodules. We conclude that increasing levels of serum thyroglobulin identify patients who should be examined and followed more carefully for thyroid nodules and thyroid cancer.

Radiation-induced tumors of the head and neck following childhood irradiation. Prospective studies.

Nodules were found in 1108 subjects who received childhood radiation for benign conditions of the cervical area at our institution. This is 37.5% of 2958 subjects, out of a total of 5379, for whom there is follow-up information. Of the 848 subjects who have had thyroidectomies, 297 (35.0%) had thyroid cancer. In addition to thyroid tumors, salivary, neural, and probably parathyroid tumors also occurred as a late consequence of childhood radiation. Prospective studies of the subjects indicate that thyroid nodules are continuing to occur at a constant rate. The measurement of serum thyroglobulin is helpful in identifying individuals for whom the risk of developing a nodule is increased. Follow-up of patients with nonsurgically-treated nodules indicates that some of their nodules are progressive. At the present time there is no indication that radiation-induced cancers behave differently than ones in other settings. However, some of their characteristics, especially their multicentricity and occurrence in younger individuals, indicate that continued follow-up is necessary. On the basis of the data generated by the follow-up program at our institution and programs elsewhere, recommendations for screening, treatment, and follow-up are made. The recommendations stress the importance of estimating risk based on radiation dose, previous tumors, and serum thyroglobulin, in arriving at clinical decisions for these subjects.

Neurilemomas and salivary gland tumors of the head and neck following childhood irradiation.

In a program to contact and examine 4180 individuals with a history of childhood irradiation treatment for enlarged tonsils and adenoids, the authors have discovered 29 neurilemomas, two neurofibromas, and one ganglioneuroma in the 2311 subjects who have been found. Ten of these presented as acoustic neuromas, 21 presented as cervical mass lesions, and one was found in the superior posterior mediastinum. Because of their numbers and their strict localization to the area of treatment, it was concluded that they were radiation-induced. Analysis of the latency of these tumors indicates that they continue to occur for at least 30 years after the radiation exposure. In the same group of individuals, there have been 54 confirmed salivary gland tumors, 40 benign and 14 malignant. These tumors are also continuing to occur many years after the radiation exposure.

Scintigraphic thyroid abnormalities after radiation. A controlled study with 99mTc pertechnetate scanning.

We did 99mTc-pertechnetate thyroid scintigraphy on 99 subjects with no history of therapeutic irradiation to the head or neck. They were compared with 198 irradiated patients selected from a group of over 1700 who were evaluated because of radiation treatment for benign head and neck conditions during childhood. The two groups were similar with respect to age and sex distribution. There were significantly more abnormal scintigrams in the irradiated group (55 of 198 patients versus one of 99 controls). Even after patients and controls with palpable nodules were excluded from the analysis there were still more abnormal scintigrams in the irradiated group (16 of 150 irradiated versus one of 97 control subjects). We conclude that thyroid nodules, including the smaller, nonpalpable nodules discovered by scintigraphy, are related to previous radiation therapy. For persons at substantial risk, such as those who received high-dose treatment (greater than 700 R) during childhood, the data support the use of screening scintigraphy, even with normal findings on palpation.