Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.

Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.

Thyroid abnormalities associated with protracted childhood exposure to 131I from atmospheric emissions from the Mayak weapons facility in Russia.

Between 1948 and 1960, the Mayak nuclear weapons facility in Ozyorsk, Russia discharged relatively high levels of radionuclides, primarily (131)I, into the atmosphere, resulting in appreciable exposure to the residents of Ozyorsk. To evaluate the association between thyroid diseases and childhood exposure to radioiodines, we screened 894 Ozyorsk residents born between 1952 and 1953. The study population was comprised of 581 exposed individuals living in Ozyorsk during the years of heaviest exposure and 313 nonexposed individuals who moved to Ozyorsk when radiation exposure from Mayak largely had ended. The screening protocol included a patient interview, palpation of the thyroid, cervical lymph nodes and salivary glands, an ultrasound examination, and measurement of fT4, TSH and TPOAb. Twenty-eight percent of the study group was diagnosed with a thyroid abnormality. The prevalence of nodular disease was significantly higher in the exposed group (20.7%) compared with the nonexposed (14.4%) group (relative risk = 1.4, 95% CI = 1.1; 1.9). Risks were larger for solitary nodules and for nodules > or = 10 mm in diameter. Expansion of the study to increase the number of persons screened as well as detailed dose estimation would offer an unique opportunity to evaluate thyroid disease in relation to chronic exposure to radioiodines during childhood.

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.

The use of oral radiographic contrast agents in the management of hyperthyroidism.

Oral iodinated radiographic contrast agents such as ipodate and iopanoic acid form an important part of the armamentarium used to treat hyperthyroidism. They rapidly and dramatically reduce serum triiodothyronine (T3) levels by inhibiting conversion of thyroxine (T4) to T3 in the periphery and by blocking secretion from the thyroid. Potential risks from the large iodine load resulting from their use limit their widespread applicability. In addition, they are ineffective when used alone on a long-term basis. However, these agents may be especially useful in treating thyrotoxic patients preoperatively, in neonatal Graves' disease, in massive levothyroxine ingestion, and when other conventional antithyroid drugs are unsuccessful or contraindicated.

Dystroglycan is present in rat thyroid and rat thyroid cells and responds to thyrotropin.

Dystroglycan is a high affinity laminin-binding glycoprotein originally described as a member of the dystrophin-associated glycoprotein complex in muscle. We have demonstrated the presence of dystroglycan in the thyroid using immunocytochemistry, immunoblots, ligand binding assays, and relative quantitative RT-PCR. In intact rat thyroid glands, antibodies against the alpha (extracellular, laminin-binding subunit) and beta (cytoplasmic/membrane bound) portions of the dystroglycan protein reacted at basolateral membranes where they colocalized with laminin. Western-blotted protein from the Fischer rat thyroid cell line FRTL-5 reacted with both the alpha- and beta-dystroglycan antibodies. The alpha-dystroglycan-reactive band colocalized with laminin-binding activity, and the protein and binding activity were decreased by TSH. In contrast, in the culture medium of these cells, alpha-dystroglycan was increased by TSH. The beta-dystroglycan antibody recognized the full-length 43-kDa band and an approximately 30-kDa truncated form. The truncated form was reduced in cells cultured with TSH, whereas the full-length form was not significantly diminished by TSH. Immunofluorescence of FRTL-5 cells in the absence of TSH showed a colocalization of dystroglycan and laminin. This was disrupted by the addition of TSH and was correlated to morphological changes. PCR amplification of complementary DNA with primer pairs from alpha- and beta-dystroglycan produced appropriately sized bands, whose sequence had identical protein-coding sequences and more than 96% nucleotide homology to mouse dystroglycan sequences. Relative quantitative RT-PCR of beta-dystroglycan messenger RNA showed reduced expression in cells cultured with TSH. We conclude that dystroglycan is present in rat thyroid and in FRTL5 rat thyroid cells and that TSH reduces its expression.

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.

Thyroid cancer following exposure to radioactive iodine.

The thyroid gland is one of the most sensitive organs for radiation-induced oncogenesis and the magnitude of the risk from external radiation is well understood. This is not the case for internal radiation derived from the radioiodines, a matter of practical importance because of medical use and potential accidental exposure. This article reviews current knowledge derived from the follow-up of patients receiving diagnostic or therapeutic 131I and populations exposed to radioactive fallout. The latter includes the nuclear power station accident at Chernobyl and the results of atomic bomb development and testing at Hanford, the Nevada Test Site and the Marshall Islands. The most cogent information comes from Chernobyl where an epidemic of childhood thyroid cancer has followed exposure to radioiodine that was mainly 131I. Although much has been learned from this experience about the nature of radioiodine induced thyroid cancer in young children, the reconstruction of thyroid radiation doses is too preliminary to provide accurate knowledge of the risk in comparison to that from external radiation. In the Marshall Islands, much of the exposure was from short-lived radioiodines as well as external radiation, obviating the possibility to determine the risk from 131I. Exposure to 131I in the continental United States from atomic bomb testing is expected to have caused some thyroid cancers, but only in the immediate vicinity of the Nevada Test Site has any evidence of radiation-induced thyroid neoplasms been adduced. This evidence is minimally significant statistically, and not significant for thyroid cancer per se. Medical use of radioiodine has not been observed to cause thyroid cancer but very few of the patients studied were young children, the group most sensitive to thyroid radiation. Despite these limitations, this information is sufficient to make some suggestions concerning protective measures in the case of nuclear accidents and the follow up of individuals who have been exposed.

Selective endocytosis of thyroglobulin: a review of potential mechanisms for protecting newly synthesized molecules from premature degradation.

In 1976 Cortese, Schneider and Salvatore (Eur. J. Biochem. 68 (1976) 121-129) showed that the thyroid gland protects newly synthesized, iodine and hormone poor thyroglobulin from immediate degradation. Since then there has been substantial progress in understanding the mechanism by which this selectivity of degradation occurs. Thyroglobulin in the follicular lumen is internalized mainly by receptor-specific endocytosis. Recycling of immature, poorly iodinated thyroglobulin back to the follicular lumen is the pathway most likely responsible for selectivity. Since additional carbohydrate groups are added to the immature thyroglobulin, it appears that this recycling occurs via the Golgi compartment. The molecular signal for recycling most likely involves the complex carbohydrates and probably is exposed GlcNAc groups. A thyroid-specific GlcNAc receptor has been identified and cloned. Other Tg-binding sites have been identified in the thyroid, but their physiological role remains to be determined.

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.

Radioiodine-induced thyroid cancer: Studies in the aftermath of the accident at Chernobyl.

While a great deal is known about the relationship between external radiation exposure and thyroid cancer, much less is known about the oncogenic effects of internal radiation exposure from isotopes of iodine. The accident at the Chernobyl nuclear power plant released massive quantities of radioiodine isotopes into the atmosphere. The large number of ensuing thyroid cancers in exposed children leaves little doubt that these malignancies have occurred as a result of the accident. However, carefully planned epidemiological studies are needed to confirm that these are due predominantly to I-131 exposure, to determine the dose-response relationship, to monitor for continuing effects and to evaluate other contributing factors. Preliminary evidence indicates that there is a distinct pattern of somatic genetic changes in the thyroid cancers from the Chernobyl area.

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.

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.

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.

p53 gene mutations in radiation-induced thyroid cancer.

Little is known about the role of specific oncogenes and tumor suppressor genes in radiation-induced thyroid cancer (RITC). In thyroid cancer, mutations in the p53 tumor suppressor gene have been largely confined to the more aggressive anaplastic forms. We studied point mutations in the p53 gene in 22 patients exposed in childhood to radiation in the head and neck area who later developed papillary thyroid cancers (RITC). Eighteen thyroid cancer patients without exposure to radiation, selected to match by gender and age the RITC group, were used as the control group. After histological identification, DNA was extracted from paraffin-embedded specimens. Exons 5-8 of p53 were PCR amplified and screened for mutations by single strand conformation polymorphism analysis and cycle sequencing. Four of 22 RITC patients (18%) showed missense point mutations. No missense mutations were found in the cancer control group. The missense mutations in the RITC group occurred at codon 208 in 2 patients, codon 177 in 1, and codon 217 in 1. The mutations were transitions from G to A and C to T. All patients with missense mutations were male and had lymph node involvement. Three of the 4 patients with p53 missense mutations had invasion of the cancer beyond the thyroid capsule compared to 2 of the 17 remaining RITC patients. None of the patients with p53 mutations had distant metastases or recurrence of the tumor. These results suggest that p53 gene point mutations may play a pathogenetic role in some radiation-induced, well differentiated thyroid cancers and in their local spread.

External radiation and thyroid neoplasia.

Radiation remains the only factor that has been shown unequivocally to cause (nonmedullary) thyroid cancer. Recent advances include the analysis of the dose-response relationship using data pooled from multiple studies. This analysis confirms that radiation-induced thyroid cancers continue to occur, with a maximum risk at approximately 30 years after exposure. Physicians asked to evaluate patients with a history of radiation exposure should attempt to estimate the dose from the history and should be familiar with the other risk factors. For some individuals, screening should include thyroid imaging, but the results of such imaging, especially with thyroid ultrasound, should be interpreted with caution. The treatment of radiation-induced thyroid cancers is based on the observation that they appear to be no more aggressive than thyroid cancers not associated with radiation. In the future, more information should emerge about the role of cancer genes and susceptibility factors in radiation-induced thyroid cancer.

Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies.

The thyroid gland of children is especially vulnerable to the carcinogenic action of ionizing radiation. To provide insights into various modifying influences on risk, seven major studies with organ doses to individual subjects were evaluated. Five cohort studies (atomic bomb survivors, children treated for tinea capitis, two studies of children irradiated for enlarged tonsils, and infants irradiated for an enlarged thymus gland) and two case-control studies (patients with cervical cancer and childhood cancer) were studied. The combined studies include almost 120,000 people (approximately 58,000 exposed to a wide range of doses and 61,000 nonexposed subjects), nearly 700 thyroid cancers and 3,000,000 person years of follow-up. For persons exposed to radiation before age 15 years, linearity best described the dose response, even down to 0.10 Gy. At the highest doses (> 10 Gy), associated with cancer therapy, there appeared to be a decrease or leveling of risk. For childhood exposures, the pooled excess relative risk per Gy (ERR/Gy) was 7.7 (95% CI = 2.1, 28.7) and the excess absolute risk per 10(4) PY Gy (EAR/10(4) PY Gy) was 4.4 (95% CI = 1.9, 10.1). The attributable risk percent (AR%) at 1 Gy was 88%. However, these summary estimates were affected strongly by age at exposure even within this limited age range. The ERR was greater (P = 0.07) for females than males, but the findings from the individual studies were not consistent. The EAR was higher among women, reflecting their higher rate of naturally occurring thyroid cancer. The distribution of ERR over time followed neither a simple multiplicative nor an additive pattern in relation to background occurrence. Only two cases were seen within 5 years of exposure. The ERR began to decline about 30 years after exposure but was still elevated at 40 years. Risk also decreased significantly with increasing age at exposure, with little risk apparent after age 20 years. Based on limited data, there was a suggestion that spreading dose over time (from a few days to > 1 year) may lower risk, possibly due to the opportunity for cellular repair mechanisms to operate. The thyroid gland in children has one of the highest risk coefficients of any organ and is the only tissue with convincing evidence for risk about 1.10 Gy.

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.