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.

Dose-response relationships for radiation-induced thyroid cancer and thyroid nodules: evidence for the prolonged effects of radiation on the thyroid.

The risk of developing thyroid cancer and other thyroid neoplasms after radiation exposure is well known, but specific modifiers of the dose-response relationship are not. We have identified 4296 subjects who received treatment before their sixteenth birthday with orthovoltage radiation for benign conditions in the head and neck area. Individual thyroid dose estimates were calculated for 3843 subjects. Of the 2634 subjects who have been found, 1043 have developed thyroid nodules of all types, and 309 have developed thyroid cancer. The radiation dose-response relationship was consistent with a linear excess relative risk model for thyroid cancer and thyroid nodules within the range of observed doses. Women developed thyroid cancer and thyroid nodules at a higher rate, but the slopes of the dose-response curves were the same for men and women. Age at radiation exposure was a significant factor of the risk, with a lower age at exposure associated with a higher risk. To determine the effect of the wide publicity and our screening program, which began in 1974, we compared the dose-response relationship for cases diagnosed before and after 1974. The overall rates increased dramatically after 1974, but the estimates of the slopes of the dose-response curves were not statistically different. The slope of the dose-response curve for thyroid neoplasms appears to have reached a maximum 25-29 yr after radiation exposure, but the dose response continued to be elevated at the end of follow-up. These data are consistent with the tumorigenic effects of radiation lasting at least 40 yr.

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.

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.

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.

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.

Childhood thyroid cancer. Characteristics and long-term outcome in children irradiated for benign conditions of the head and neck.

OBJECTIVE: To determine the characteristics and long-term outcome of radiation-induced thyroid cancer in children. DESIGN: Retrospective review of a cohort of 4296 irradiated patients who received childhood radiation treatment to the head and neck area at the same hospital. PATIENTS: Forty-one children who were younger than 20 years when thyroid cancer developed in them and 77 adults in whom thyroid cancer developed. All 118 cases were diagnosed before 1974 and were followed up for a median of 19.4 years. RESULTS: Children presented with clinically palpable lymph nodes more often than adults (30.7% vs 15.1%, P = .05) and had more recurrences (39% vs 16%, P = .05). Despite these frequent recurrences, only one patient (an adult) died of thyroid cancer. Seventy percent of the recurrences occurred during the first 10 years of follow-up, but recurrences continued after 20 years. The adults had previously identified factors that predicted the risk of recurrences, but none could be identified in the children. CONCLUSION: The presentation and relatively good outcome of radiation-induced thyroid cancer in children is similar to that in nonirradiated children. Frequent and late recurrences call for lifelong follow-up.

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.

A prospective study of hyperparathyroidism in individuals exposed to radiation in childhood.

To determine the effects of childhood irradiation on the parathyroid glands, a cohort of 4297 patients who received radiation to the tonsils before the age of 16 years has been followed-up prospectively. Among the 2923 patients who were located and provided information, 32 patients developed clinical hyperparathyroidism. The incidence of clinical hyperparathyroidism was 18.7 per 100,000 person-years below the age of 40 years and 171 per 100,000 person-years in the age range of 40 to 60 years. This represents a 2.9-fold (95% confidence interval, 1.6 to 4.3) and 2.5-fold (95% confidence interval, 1.1 to 3.9) increase in the incidence of hyperparathyroidism compared with that among the general population. In addition, 31% of the patients who developed hyperparathyroidism also developed thyroid cancer, which is higher than the 11.2% prevalence of thyroid cancer in the patients who received radiation therapy who did not develop parathyroid tumors. Patients with a history of head and neck irradiation should have their parathyroid glands evaluated on a regular basis.

Benign thyroid tumors: general risk factors and their effects on radiation risk estimation.

The authors examined risk factors for benign thyroid nodules and their influence on radiation effects among 544 subjects who were exposed to childhood radiation treatment for benign head and neck conditions at a Chicago, Illinois hospital during 1939-1962. In follow-up through 1991, benign thyroid nodules were diagnosed in 131 patients. The risk of benign nodules was elevated in women (relative risk (RR) = 2.2, 95% confidence interval (CI) 1.6-3.2), Jews (RR = 1.7, 95% CI 1.2-2.5), college graduates (RR = 1.8, 95% CI 1.2-2.8), and subjects whose mother had cancer (RR = 1.7, 95% CI 1.2-2.5). There were increasing trends for risk with increasing body mass index in women and decreasing height in men. Risk was increased for women who never married (RR = 3.7, 95% CI 1.6-7.3) or who never had a full-term pregnancy (RR = 2.0, 95% CI 1.1-3.3). A significant radiation dose-response relationship was observed that was not modified by sex, education, Jewish religion, or reproductive factors. The data suggest that there are genetic, life-style (including ascertainment), and hormonal factors associated with the development of benign thyroid nodules.