INTRODUCTION — Radiation exposure of the thyroid during childhood is the most clearly defined environmental factor associated with benign and malignant thyroid tumors. The risk of thyroid nodules and thyroid cancer following irradiation is related to radiation dose and age (greater for children exposed early in life), and the risk persists throughout life. Radiation exposure also increases the risk of benign thyroid nodules and hypothyroidism.
This topic will review radiation-related thyroid disease, including the approach to a patient with a history of thyroid radiation exposure as well as prevention of radiation-related thyroid disease. Acute radiation injury to other organs and risk of secondary malignancy after radioiodine treatment of differentiated thyroid cancer are reviewed separately. (See "Clinical manifestations, evaluation, and diagnosis of acute radiation exposure" and "Differentiated thyroid cancer: Radioiodine treatment", section on 'Secondary malignancy'.)
RADIATION EXPOSURE
Tumorigenesis
●Thyroid – Available data make the relationship between thyroid radiation and thyroid tumorigenesis incontrovertible. Pooled analyses of studies with a wide range of exposures (atomic bomb survivors, children treated for tinea capitis or enlarged tonsils, infants irradiated for an enlarged thymus gland, children treated for cancer) have shown the following [1-4]:
•Thyroid nodules of all types and sizes, including small ones only detected by screening methods, are increased by radiation exposure.
•The thyroid is among the most radiation-sensitive tissues in the body, with excess cancers occurring at doses as low as approximately 40 mGy.
•After low-dose exposure, there is a linear dose-response curve with essentially no evidence of a threshold.
•The risk of thyroid cancer is higher with younger age at exposure.
•The effects of radiation persist for several decades and then eventually wane. It is still elevated at 45 years, and data from studies of atomic bomb survivors show persistent effects at >50 years [2,5].
•The association between thyroid radiation and thyroid cancer may be enhanced in individuals who receive chemotherapy in addition to radiation [2].
●Other radiation-related tumors – Radiation exposure is also associated with increases in:
•Parathyroid adenomas – The association between head and neck radiation and hyperparathyroidism has been confirmed by studies establishing a dose-response relationship. Patients with radiation-related thyroid cancer should have a measurement of serum calcium prior to surgery as some patients may require concomitant parathyroidectomy and thyroidectomy. Occasionally, a nonfunctioning parathyroid adenoma is discovered during thyroid surgery. Whether these adenomas are related to radiation or have any clinical importance is not known. (See "Primary hyperparathyroidism: Pathogenesis and etiology", section on 'Radiation exposure'.)
•Salivary gland tumors. (See "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging".)
•Schwannomas and meningiomas. (See "Vestibular schwannoma (acoustic neuroma)", section on 'Pathogenesis and risk factors' and "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Ionizing radiation'.)
Type of exposure — Radiation exposure may be external or internal.
●External – The predominant types of external radiation are diagnostic radiographs, therapeutic radiation for the treatment of cancer, and historical use of external radiation to treat a wide variety of nonmalignant conditions. External radiation also includes brachytherapy, whereby a sealed radiation source is placed adjacent to a treatment area.
●Internal – Internal radiation exposure includes ingestion of foods or liquids contaminated with radioactivity or by inhalation of radioactive gases or particles. Internal radiation occurs after exposure to nuclear fallout (from testing and accidents at operating nuclear power plants or above ground nuclear explosive testing) or after ingestion of radioiodine for therapy of hyperthyroidism. (See "Radioiodine in the treatment of hyperthyroidism", section on 'Cancer'.)
External or internal radiation exposure may result in thyroid nodules, thyroid cancer, and hypothyroidism. (See 'Approach to the patient with a history of thyroid radiation exposure' below.)
Magnitude of exposure — The risk of radiation-induced thyroid neoplasms is more common after childhood than adult radiation exposure and is, in part, related to radiation dose [1,2]. In this topic, radiation exposure is categorized as very low dose, low dose, and high dose, as follows.
●Very low dose – Ionizing radiation from medical imaging (ie, diagnostic radiology)
●Low dose – Exposure from nuclear fallout (from testing, accidents, or in Japanese survivors of atomic bombing) or from radiation for nonmalignant conditions
●High dose – Therapeutic radiation for the treatment of cancer
Very low-dose exposure — Diagnostic radiology is an ever-increasing source of radiation exposure, including to the thyroid gland. Ionizing radiation from medical imaging now accounts for nearly one-half of the radiation exposure experienced by the population in the United States.
Concern has been raised about a potential increase in risk of thyroid cancer in children receiving frequent diagnostic radiographs, particularly computed tomography (CT) scans. Thus far, the potential risk has been calculated assuming the widely accepted, but somewhat controversial, linear extrapolation dose-response model [6]. A retrospective study in Taiwanese adults (including more than 22,000 cases of thyroid cancer) found an association between prior CT scans and risk of developing thyroid cancer [7]. The results of ongoing, large epidemiologic studies are needed to confirm the risk of thyroid cancer from radiographs [8-10]. (See "Radiation-related risks of imaging", section on 'Children and adolescents'.)
Low-dose exposure — After low-dose exposure in childhood, there is a linear dose-response curve for thyroid cancer, with essentially no evidence of a threshold at low doses (approximately 40 mGy) [1,4]. There is inconclusive evidence for a risk of thyroid cancer, albeit a small one, after low-dose exposure in adulthood.
The risk of thyroid nodules and cancer has been investigated in many radiation-exposed groups, including children irradiated for benign diseases (enlarged thymus glands or tonsils, hemangiomas of the face and neck, tinea capitis of the scalp) [11]; survivors of atomic bombing in Japan [5]; Marshall Islanders exposed to nuclear test fallout [12]; and children living in the area of Chernobyl, Three Mile Island, or Fukushima, sites of a nuclear accident [13,14]. Virtually all of the previous indications for external radiation treatments in this range (eg, to shrink an "enlarged" thymus gland) have been abandoned [15]. However, environmental exposures largely due to accidents remain possible.
●Childhood – Exposure of a cohort of children to low doses of iodine 131 (I-131; estimated mean thyroid dose of 174 mGy) over a prolonged period of time (13 years as a result of releases from the Hanford nuclear facility) was not associated with an increased risk of thyroid disease in one study [16]. On the other hand, children exposed to radiation, predominantly I-131, after the Chernobyl accident have developed thyroid cancer [17-21]. Additionally, among 1494 subjects aged 16 to 20 years who were exposed to I-131 fallout from the Chernobyl accident in utero, there was an increase in thyroid cancer; this is consistent with other data, but the risk estimate was based on only eight cases and was not statistically significant [22]. It is not clear how far the Chernobyl experience can be extrapolated, because other factors, such as iodine deficiency [17], which may increase the uptake of radioiodine by the thyroid gland, as well as exposure to other short-lived higher energy iodine isotopes, may come into play.
●Adult – Assessment of the possible risk for thyroid cancer in exposed adults largely comes from pooled analyses, atomic bomb survivor studies, and Chernobyl liquidator studies.
•In the pooled analyses described above, there was a decrease in risk of thyroid cancer with increasing age of exposure, with no demonstrable risk found above an exposure age of approximately 20 years [2,3].
•In adult survivors exposed to atomic bomb fallout, the risk appears to depend on the endpoint used for the estimate. For thyroid cancers ≥10 mm, no statistically significant risk was evident [5]. For papillary microcarcinomas (<10 mm) identified in autopsy specimens, a dose-response relationship was found (estimated excess odds ratio/Gy 0.57, 95% CI 0.01-1.55) [23,24].
•Some evidence of a risk from adult exposure comes from a study of 107 thyroid cancer cases and 423 controls among Chernobyl liquidators. The median thyroid dose was estimated to be 69 mGy, and the observed, excess relative risk (RR) at 100 mGy was 1.38 (95% CI 1.10-2.09) [25]. However, studies of Chernobyl liquidators are susceptible to ascertainment bias.
High-dose exposure — High-dose exposure in childhood increases the risk of thyroid nodules and thyroid cancer [3]. There appears to be much less risk (if any) when exposure occurs after age 30 years [26].
High-dose head and neck radiation also increases the risk of hypothyroidism. (See 'Surveillance for functional thyroid abnormalities' below and "Disorders that cause hypothyroidism", section on 'External neck irradiation' and "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood".)
The increasing success of treating children for a variety of malignancies, often using radiation, has resulted in studies of their risk for developing thyroid cancer [27,28].
●Childhood – Studies in childhood cancer survivors have shown an increased risk of thyroid cancer after radiotherapy (head/brain, neck, spine, total body irradiation) [3,29-34], as illustrated by the findings of a pooled analysis of four observational studies of childhood cancer survivors (16,757 patients with 187 developing primary thyroid cancer) [3]:
•The risk of thyroid cancer after radiotherapy:
-Increased with radiation dose (RRs of 6.8 for 2 to 4 Gy and 14.9 for 5 to 9 Gy)
-Plateaued between a dose of 10 and 30 Gy (RRs of 14.8 at 10 to 19 Gy and 15.2 at 20 to 29 Gy)
-Declined with the highest doses (RRs 9.3 at 30 to 39 Gy and 5.1 at >40 Gy), presumably due to cell destruction (figure 1)
•The pooled excess absolute risk at 10 Gy was 12.4 per 10,000 patient-years.
•The risk increased significantly with decreasing age at exposure (RR 17.5 and 3.9 for age at exposure <5 years and >15 years, respectively).
The risk of thyroid cancer does not appear to decrease over time [3,31].
●Adult – Thyroid cancer following high-dose adult exposures have not been studied as extensively as childhood exposures.
•In a study of patients treated with hematopoietic cell transplantation (including total body irradiation), compared with nonirradiated patients, the risk of developing a second cancer was higher among patients irradiated at <30 years of age, whereas there was no difference between nonirradiated and irradiated patients when treatments were given at >30 years [26,35]. The majority of second cancers, including thyroid, occurred among children <17 years at the time of hematopoietic cell transplantation. (See "Second malignancies after treatment of classic Hodgkin lymphoma", section on 'Thyroid cancer' and "Secondary cancers after hematopoietic cell transplantation", section on 'Solid tumors'.)
GENETICS OF RADIATION-INDUCED THYROID CANCER — Somatic mutations play a central role in the genesis of radiation-induced cancers. Even though radiation can cause the entire range of possible mutations, those resulting in breakage and rejoining of the DNA chain are most important [36,37].
These assumptions about radiation carcinogenesis are supported by work on the papillary thyroid cancers found in children in the aftermath of the nuclear power plant accident at Chernobyl in 1986 [37-39].
●In some papillary thyroid cancers, a translocation of the RET gene occurs, resulting in its constitutive expression and activation; this gene is not expressed in normal thyroid cells. The RET translocation has been found in a higher proportion of Chernobyl-related cancers than those not associated with radiation. Similarly, the frequency of RET translocations is increased in thyroid cancer cases associated with external radiation treatment for benign and malignant conditions [40,41].
●The specificity of RET and other translocations is illustrated by the observation that point mutations in the BRAF gene, the other common genetic driver in papillary thyroid cancer, are rarely found in radiation-related cases [42,43]. (See "Oncogenes and tumor suppressor genes in thyroid nodules and nonmedullary thyroid cancer", section on 'Papillary thyroid cancer'.)
The effects of radiation on these alterations is more pronounced at younger ages of exposure. Proliferative activity of normal human thyroid cells decreases with increasing age [44]. This could explain, in part, the higher risk of radiation-related thyroid cancer in children rather than adults. Some people may have increased susceptibility to radiation effects related to a polymorphism upstream to the FOXE1 (TTF-2) gene on chromosome 9q22 [45]. In a large study of people with Chernobyl-related thyroid cancers, three polymorphisms have been tentatively identified, including at 9q22, as associated with this susceptibility [37]. Thus far, it is not clear whether radiation-related papillary thyroid cancers containing translocations behave differently from cancers without them. Also, it is still not possible to use patterns of somatic mutations to distinguish radiation-related from sporadic thyroid cancers [37].
APPROACH TO THE PATIENT WITH A HISTORY OF THYROID RADIATION EXPOSURE
Who might benefit from surveillance?
●Individuals with a childhood history of therapeutic radiation exposure to the neck region (high dose) or environmental radiation exposure (low dose) are candidates for long-term surveillance for thyroid cancer. They require regular physical examination of the thyroid gland. Their medical records should be reviewed to determine, as best as possible, the dose and site of radiation, as well as the age at the time of the radiation exposure. Such patients with high-dose exposure should be monitored annually for hypothyroidism.
●Individuals with similar exposure as adults are at lower risk than those exposed as children, and there is no convincing rationale for thyroid cancer screening beyond routine medical care. Such patients with high-dose exposure should be monitored annually for hypothyroidism.
It is likely that some people are genetically disposed to developing radiation-induced thyroid cancer [37], but identifying them is currently not feasible and likely not advisable.
●The thyroid doses from diagnostic procedures (very low dose) are not high enough to suggest that the benefit of surveillance would exceed the risks and costs. However, it should be kept in mind that multiple radiograph examinations may result in cumulative doses that reach the low-dose category (≥100 mGy). (See 'Prevention of radiation-related thyroid disease' below.)
General evaluation — Surveillance typically includes [34]:
●Annual history and physical examination of the neck, as part of routine medical care (all individuals with a history of childhood low- or high-dose radiation exposure to the thyroid)
●Assessment of thyroid function tests (all individuals with a history of high-dose exposure)
When, if ever, to screen with thyroid ultrasound to detect nonpalpable nodules in patients with a history of childhood thyroid radiation exposure is controversial. (See 'Surveillance for structural thyroid abnormalities' below.)
The increased risk of thyroid cancer resulting from radiation exposure during childhood persists for at least four decades [4,46]. Thereafter, it begins to decline but has not reached baseline for as long as observations have been made; therefore, surveillance is continued indefinitely.
History — All patients who grew up in the era when radiation was used to treat a wide variety of nonmalignant conditions, chiefly during the 1940s and 1950s, should be asked about radiation exposure. For those who were exposed as a result of such treatments, the actual records usually are not available. Nevertheless, a few guidelines are helpful in obtaining and evaluating the history, remembering that the goal is to determine the thyroid radiation dose.
●Confirmatory history is that the caregiver was asked to leave the room when the treatment was administered. Contradictory history is memory of a purple light (ultraviolet [UV] treatment) and the presence of the caregiver or other personnel in the room during treatment.
●Dermatologists previously used radiation treatment to treat chronic cystic acne. This should be distinguished from UV treatment and nonpenetrating radiograph treatment (Grenz rays).
●Many doctors' offices were equipped with fluoroscope machines that were used during routine examinations, as may be recalled by a patient or their caregivers.
●Radium-tipped rods were placed through the nose into the posterior pharynx to shrink the tonsils and adenoids of children. During this treatment, only a very small amount of radiation reached the thyroid gland, and the risk is proportionately smaller or absent [47,48].
Patients who have been exposed to nuclear fallout (from testing, accidents, or in Japanese survivors of atomic bombing) are typically aware of the exposure and are being followed for radiation-related adverse effects [5,13,49].
Children exposed to therapeutic radiation typically have medical records detailing the dose and site of radiation, as well as the age of radiation exposure. Cranial, nasopharyngeal, oropharyngeal, neck, cervical spine, upper chest, mantle, mediastinal, and total body irradiation increases the risk of thyroid cancer [34].
Physical examination — All individuals with a childhood history of low- or high-dose radiation exposure to the thyroid should have a yearly thyroid examination as part of routine medical care. The thyroid-related physical examination is no different for radiation-exposed and nonexposed patients. The neck should be palpated to assess the size of the thyroid gland, for the presence of firm or dominant nodules, and for cervical adenopathy. In general, physical examination has a low accuracy for predicting thyroid cancer. However, a fixed hard mass, obstructive symptoms, cervical lymphadenopathy, or vocal cord paralysis all suggest the possibility of cancer. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'History and physical examination'.)
The management of patients with a suspected palpable thyroid nodule is reviewed briefly below and in more detail elsewhere. (See 'Management' below and "Diagnostic approach to and treatment of thyroid nodules", section on 'Evaluation'.)
Surveillance for functional thyroid abnormalities
●Low and very low dose – The preponderance of evidence does not support routine screening for hypothyroidism in individuals with a history of low- or very low-dose radiation exposure. (See "Pathogenesis of Hashimoto's thyroiditis (chronic autoimmune thyroiditis)", section on 'Radiation exposure'.)
●High dose – Thyroid function should be assessed annually in all patients with a history of high-dose therapeutic irradiation exposure to the thyroid. External irradiation of the neck (in doses of 25 Gy or more) causes hypothyroidism [50]. The effect is dose dependent, the onset is gradual, and many patients have subclinical hypothyroidism for several years before developing overt disease. It is a reasonable hypothesis, although unproven, that early intervention to avoid hypothyroidism could reduce the risk for thyroid nodules and cancer. (See "Disorders that cause hypothyroidism", section on 'External neck irradiation' and "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood".)
•For patients with a history of cranial or nasopharyngeal irradiation (who are at risk for central hypothyroidism), both thyroid-stimulating hormone (TSH) and free thyroxine (T4) should be measured. (See "Central hypothyroidism", section on 'Diagnosis'.)
•For patients with radiation confined to the neck area alone, measurement of TSH is sufficient. If the serum TSH concentration is elevated, the TSH measurement should be repeated along with a serum free T4 to make the diagnosis of hypothyroidism. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults", section on 'Diagnosis'.)
Testing should be initiated no later than the first year and is then repeated annually. Lifelong replacement therapy with levothyroxine is indicated for patients with hypothyroidism. Serum TSH should be monitored to assess dosing adequacy and medication compliance. (See "Treatment of primary hypothyroidism in adults", section on 'Dose and monitoring'.)
Surveillance for structural thyroid abnormalities — As part of routine clinical care, physical examination of the neck is recommended for all patients previously exposed to radiation during childhood, usually on a yearly basis. In addition, ultrasonographic evaluation is useful in patients in whom the thyroid is difficult to palpate on physical examination (eg, obesity, short neck), or in whom a structural abnormality is suspected.
The use of thyroid ultrasound to screen for nonpalpable nodules in radiation-exposed patients is controversial since it has not been shown to improve outcomes [51,52]. In the absence of data supporting routine screening of all exposed individuals, we suggest that the use of surveillance ultrasonography be individualized, guided by shared clinical decision-making with patients [53,54]. The discussion should include an assessment of each patient's risk factors, including dose of radiation to the thyroid (when it is available) and age of exposure, as well as a discussion of the potential harms and benefits of ultrasound surveillance [55]. (See 'Risk assessment' below and 'Potential benefits and harms of routine ultrasound screening' below.)
Guidelines (Children's Oncology Group and American Thyroid Association [ATA]) do not recommend or equivocate (neither recommending for nor against) ultrasound screening in childhood cancer survivors with high-dose exposure [34,56,57]. The absence of data showing a benefit of thyroid ultrasound over neck palpation suggests the need for individualized decision-making.
Risk assessment — The authors consider the following risk factors when assessing an individual's risk for the development of radiation-induced thyroid nodules [3,4,58,59]:
●Age – Given the steep decline in risk with increasing age of exposure, being exposed before age 18 years is a reasonable threshold to include in the risk assessment.
●Dose – All patients who had radiation treatments during childhood, whether for malignant or benign conditions, that included the neck area should be considered at risk. The pooled analyses showed that the relative risk (RR) is proportional to the radiation dose and continues to increase up to 10 to 30 Gy [2]. There was a significantly elevated risk starting at doses as low as 40 mGy [1,2]. Based on these analyses, when it can be estimated, a dose of 40 mGy is a reasonable threshold above which confers increased risk. With some exceptions, usually when multiple examination are required, this excludes patients with exposure limited to diagnostic radiology.
●Female sex – While the radiation-associated RR is not demonstrably different for males and females, the absolute risk is higher for females because of their higher baseline risk.
In an attempt to identify patients at highest risk for the development of thyroid cancer, one group combined data from three childhood cancer survivor databases to develop risk prediction models that project the absolute thyroid cancer risk among five-year survivors of childhood cancer [60]. The model that included sex, birth after 1970, age <15 years when diagnosed with a childhood cancer, prior diagnosis of a thyroid nodule, history of radiation therapy including the neck, and history of treatment with an alkylating agent had the best overall discriminatory performance. This model performed as well as one that included a reconstructed radiation absorbed dose to the thyroid gland [60]. Further validation is required before this risk prediction tool can be used to guide clinical monitoring for thyroid cancer.
Potential benefits and harms of routine ultrasound screening — Many patients with a history of radiation exposure during childhood have nonpalpable thyroid nodules (figure 2) [61]. Ultrasound can detect small nodules not apparent on physical examination, which may or may not be related to the previous radiation exposure, as structural thyroid abnormalities are very common.
Baseline ultrasounds, performed in children who lived near the Fukushima plant and in children who lived in distant areas of Japan, showed many small, solid nodules, cysts, and other findings such as ectopic thymus tissue inclusions [62-64]. There is no evidence that these findings were more prevalent in individuals living closer to the reactor [65].
In prospective studies of children exposed to high-dose radiation for the treatment of cancer, ultrasound surveillance beginning five years after radiation therapy and repeated every one to three years for 12 to 15 years showed thyroid nodules >1 cm in approximately 36 to 42 percent [66,67]. Ultimately, thyroid cancer was diagnosed in approximately 7 percent of patients in the cohorts. Cancer cases ranged from 8 to 24 years after the exposure. In a retrospective study of 306 childhood cancer survivors treated with radiotherapy and followed with thyroid ultrasound starting at a mean of 9.1 years after exposure, 150 had thyroid nodules (49 percent) [68]. Of these, 44 had surgery and 28 had thyroid cancer (9 percent of all patients). Among those with cancer, seven were classified as ATA high-risk disease. The presence of high-risk disease was related to high dose, young age at exposure (eg, <10 years), and female sex. These observational studies are limited because they lack comparisons to other surveillance strategies, such as reserving ultrasound for palpable nodules.
In general, the outcome of thyroid cancer is better when diagnosed at an earlier stage, although the evidence is stronger for adults than for children [69]. For children exposed to radiation, there are insufficient data to determine whether the detection of thyroid cancer by screening ultrasound prior to a palpable abnormality impacts long-term outcomes [56,70]. In a study using decision analysis to compare four strategies to monitor for thyroid cancer in childhood cancer survivors, there was no difference in disease-specific survival among the different strategies, including a strategy of no surveillance [53].
Any potential benefit of earlier disease detection must be balanced against potential risks associated with excessive evaluations and treatments for ultrasonographically detected thyroid nodules and indolent thyroid cancers that may never have become clinically apparent.
The arguments for screening thyroid ultrasound are:
●Ultrasonography is the most sensitive method of imaging the thyroid, does not involve further radiation exposure, and is performed without stopping thyroid hormone therapy
●Nodules sized 1.0 to 1.5 cm, and even larger ones, are not always palpable but are easily detected by ultrasonography
The opposing arguments are:
●Most, but not all, clinically important nodules will be detected by physical examination, either in the initial examination or during follow-up
●Detection of small nodules may result in anxiety and inappropriate evaluation and treatment, and the complications of unneeded therapy may be greater than the potential risk from the nodules
●The cost of screening patients is high
Optimal timing and duration if ultrasound surveillance initiated
●Initial imaging – If surveillance ultrasound is obtained, based on the expected time course for the development of thyroid nodules after radiation exposure [1,2], we suggest that the initial surveillance ultrasound be done no sooner than 5 to 10 years after exposure. Thereafter, the frequency and method of follow-up of irradiated patients depends upon their estimated risk and the clinical findings at the initial evaluation.
●Subsequent imaging – If the initial examination is normal and the level of risk is low, then annual palpation is reasonable. When low-dose exposure occurred years earlier (presumably in the 1940 to 1960 era when such exposures were common), usually based on an estimate of a dose at least of 100 mGy at a young age, we consider a single normal ultrasound at least 5 to 10 years after exposure as sufficient. For others, an interval of every three to five years in addition to annual palpation is preferred, especially if there are small and/or fine-needle aspiration (FNA)-benign nodules. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'Benign nodules (Bethesda II)'.)
Even if the potential benefit of ultrasonographic examination of the neck is expected to outweigh the potential risk for an individual patient, data are lacking to provide definitive recommendations with regard to the optimal timing of the initial and follow-up surveillance ultrasonographic examinations. The absence of thyroid nodules on a single thyroid ultrasound examination does not predict the absence of nodular growth and thyroid cancer development in the future. Therefore, thyroid ultrasound would have to be repeated over time. In addition, the increased risk of thyroid cancer resulting from radiation exposure during childhood persists for at least four decades [3]. Thereafter, it begins to decline but does not return to baseline for as long as observations have been made.
In a prospective study of ultrasound examination in 2637 atomic-bomb survivors during an average follow-up of 13.3 years, six thyroid cancer cases were found among 68 subjects who had a solid thyroid nodule (7.3 percent) on baseline screening, one case among 121 subjects who had a thyroid cyst (0.8 percent), and seven cases among 2434 (0.3 percent) patients who did not have any nodules on baseline examination [71]. In 140 subjects in a Chernobyl-related study with confirmed nodules, approximately 10 to 25 percent of the nodules were present on follow-up that were not diagnosed on earlier imaging [72].
Management
Thyroid nodules — The initial evaluation of a thyroid nodule (detected by physical examination or imaging) is not different from the evaluation of thyroid nodules in nonirradiated patients, and it includes measurement of TSH (if not previously obtained) and thyroid ultrasound (if not previously obtained). (See "Diagnostic approach to and treatment of thyroid nodules", section on 'Evaluation'.)
If the nodule meets sonographic criteria for sampling, the next step in the evaluation of a thyroid nodule is a palpation or ultrasound-guided FNA biopsy. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'Sonographic criteria for FNA'.)
The sensitivity of FNA appears to be similar for nodules in the general population and in patients exposed to radiation [73]. In patients with thyroid nodules, however, a history of radiation exposure increases the likelihood that the nodule is a thyroid cancer [71,74].
Although there is no evidence that subcentimetric nodules are more aggressive in irradiated patients, certain suspicious ultrasound features in high-risk patients may warrant FNA biopsy of subcentimeter nodules. Thus, in select patients, FNA should be performed in nodules <1 cm with suspicious sonographic features (eg, TR5 using American College of Radiology-Thyroid Imaging Reporting and Data System [ACR-TIRADS] sonographic risk stratification system), and, in addition, other concerning characteristics, such as subcapsular locations adjacent to the recurrent laryngeal nerve or trachea, extrathyroidal extension, or metastatic cervical lymphadenopathy. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'Sonographic criteria for FNA'.)
In a retrospective analysis of 4296 patients who received external radiation treatment before age 16 years for a variety of benign conditions, 1059 patients underwent thyroid surgery due to the presence of a suspicious thyroid lesion (detected either by physical examination or imaging) [75]. There were 612 malignant nodules in 358 patients and 2037 benign nodules in 930 patients:
●A solitary nodule had the same risk of malignancy as one of multiple nodules (18.8 versus 17.3 percent).
●Patients with multiple nodules were more likely to have cancer than those with a solitary nodule (30.7 versus 18.7 percent).
●FNA of the two largest nodules in each patient missed micropapillary cancers in 17 percent of patients.
●More than one-half of the patients had multifocal cancers.
Papillary thyroid cancer is the most common radiation-related histologic type [3,4].
Increasingly, molecular diagnostic tests are being applied to indeterminate FNAs. So far, none of these tests have been evaluated for radiation-related thyroid nodules. Because these nodules are more likely to be malignant, it is probable that the negative predictive value of these tests will be adversely affected. (See "Evaluation and management of thyroid nodules with indeterminate cytology in adults", section on 'Molecular markers'.)
Thyroid cancer — Patients with radiation-related thyroid cancer should be treated in the same way as nonexposed patients with thyroid cancer. (See "Differentiated thyroid cancer: Overview of management".)
Thyroid-specific outcomes appear to be similar in patients with and without a prior history of external radiation exposure [76-78]. As examples:
●In a study of 296 patients with radiation-related thyroid cancers, although multicentricity was frequent, the risk factors for recurrence were similar to those for thyroid-cancer patients in general [76].
●In a study of 3664 patients with differentiated thyroid cancers (116 patients with a previous history of head and neck irradiation and 3509 patients without), there was no difference in five-year, disease-specific or recurrence-free survival [78].
In addition, in studies of patients exposed to radiation as a result of the Chernobyl accident, recurrence rates were not higher in radiation-exposed patients versus patients with sporadic thyroid cancer, even though their thyroid cancers tended to have aggressive histologic features [79-81]. After an average clinical follow-up of 10 years, the disease-specific mortality rate in these thyroid cancer cases was <1 percent, and short-term recurrence rates range from 7 to 28 percent (mean 17 percent) [81].
All-cause mortality was not increased in individuals who developed thyroid cancer after they were irradiated for benign conditions during childhood compared with individuals who were similarly irradiated but did not develop thyroid cancer, a reassuring finding [82]. However, in childhood cancer survivors who develop thyroid cancer as a secondary primary malignancy mortality may be increased [83]. Several factors may contribute to overall mortality outcomes in childhood cancer survivors, including cardiovascular comorbidities and other chronic health conditions.
Benign nodules
●Benign based upon FNA results – The follow-up of patients with biopsy-proven benign nodules should include at least annual palpation and repeat ultrasonography, initially at 12 months, and then at increasing intervals over time. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'Benign nodules (Bethesda II)'.)
●Benign based upon surgical pathology – In patients with surgically confirmed benign nodules after a thyroid lobectomy (ie, nodule with suspicious cytology on FNA, which, when resected, had benign pathology), thyroid hormone administration aiming either for minimal TSH suppression or a low-normal TSH is a reasonable intervention. (See "Thyroid hormone suppressive therapy for thyroid nodules and benign goiter", section on 'Irradiated patients'.)
Postoperative thyroid hormone treatment, even if only one lobe was removed, appears to reduce recurrences. As an example, in a nonrandomized study of 632 adults who were treated prior to age 16 years with conventional radiation for nonmalignant conditions and who subsequently had benign thyroid nodules removed surgically, patients who were treated with thyroid hormone had a lower incidence of recurrent nodules than those who were not (14 versus 34 percent, RR 0.69, 95% CI 0.47-1.01) [84]. Histologic analysis of 91 tissue samples from patients with recurrent nodules showed that 18 percent were malignancies and that thyroid hormone treatment had no effect on the rate of malignancy. Thus, thyroid hormone reduced the risk of new nodules, but it did not reduce the risk of thyroid cancer.
Prevention of radiation-related thyroid disease
Medical radiation exposure — While radiation exposure of the thyroid during the treatment of benign medical conditions has decreased, exposure from diagnostic procedures (eg, computed tomography [CT]) is increasing rapidly, particularly among children [8]. In many cases, the exposure is greater than necessary. Efforts to minimize exposure include the "image gently" campaign initiated by radiologists. In addition, clinicians providing direct patient care should evaluate the risks and benefits of any procedure, explain them to the patient or caregiver, and consider strategies to reduce radiation risks to the thyroid gland. (See "Radiation-related risks of imaging", section on 'Children and adolescents'.)
Routine dental radiography (intraoral, panoramic) has not been shown to increase the risk of thyroid cancer; however, it is sensible to reduce thyroid radiation exposure (eg, thyroid collar, reduction in frequency of imaging), especially in children, as long as the dental examination is not compromised [85].
Potassium iodide for thyroid protection in a nuclear accident — When potassium iodide administration is indicated according to the anticipated thyroid dose and as announced by public health officials, it should begin as soon as possible and continued daily for the duration of the exposure [86]. Prophylaxis should be given to most individuals, with the possible exception of older adults and those with rare contraindications [86]. Potassium iodide tablets and a solution designed for children are available commercially without a prescription. Alternatively, for children, potassium iodide tablets may be dissolved according to directions found at the US Food and Drug Administration (FDA) website and the American Thyroid Association (ATA) website.
Potassium iodide tablets can decrease thyroid uptake of radioiodine. Potassium iodide can also reduce organification by way of the Wolff-Chaikoff effect so that radioiodine that enters the thyroid is not retained. By a less well-understood mechanism, the sodium-iodide symporter (NIS) is downregulated [87].
Potassium iodide can almost completely protect the thyroid if administered within 12 hours before radioiodine exposure or up to two hours after; after two hours, the degree of protection declines (80, 40, and 7 percent after 2, 8, and 24 hours, respectively) [88,89]. (See "Management of radiation injury".)
Potassium iodide is well tolerated, as shown by the experience of administering it to a large population in Poland after the Chernobyl accident [90]. It has been estimated that for the fetus, the newborn, children, and adolescents, the benefit of preventing radiation-induced thyroid cancer in the event of an accidental exposure outweighs the potential risk of hypothyroidism. In older people, especially those with goiters, one might expect rare cases of iodine-induced hyper- or hypothyroidism. Therefore, in older adults, arbitrarily taken as above 40 years, the potential benefits of potassium iodide prophylaxis probably do not outweigh the risks, except for exposure levels that threaten to produce hypothyroidism [91].
Following the Fukushima accident, potassium iodine was not widely distributed (it had not been predistributed into households and schools) and few received it. In retrospect, this was in keeping with guidelines for its use as the thyroid radiation doses were almost universally below the threshold levels. In large part, this was due to keeping radioiodine out of the food chain, in contrast with Chernobyl. This substantial mitigation of the dose has led to a reconsideration of when and how to use potassium iodide following an accident [92].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thyroid nodules and cancer".)
SUMMARY AND RECOMMENDATIONS
●Radiation exposure – External or internal radiation exposure may result in thyroid nodules, thyroid cancer, and/or hypothyroidism. (See 'Radiation exposure' above.)
•External radiation – External radiation includes therapeutic radiation for the treatment of cancer or historical use of external radiation to treat a wide variety of nonmalignant conditions. Cranial, nasopharyngeal, oropharyngeal, neck, cervical spine, upper chest, mantle, mediastinal, and total body irradiation expose the thyroid to sufficient radiation to increase the risk of radiation-related disease.
•Internal radiation – Internal radiation exposure may be due to ingestion of foods or liquids contaminated with radioactivity or by inhalation of radioactive gases or particles. Exposure may be due to nuclear fallout from testing and accidents at operating nuclear power plants, or above ground nuclear explosive testing.
●Magnitude of exposure – The risk of thyroid cancer is related to age (greater for children exposed early in life) and radiation dose to the neck (figure 1). (See 'Magnitude of exposure' above.)
•Low dose – Environmental exposure or radiation for nonmalignant conditions
•High dose – Therapeutic radiation for the treatment of cancer
●Thyroid surveillance, childhood exposure – Individuals with a childhood history of radiation exposure to the neck region are candidates for surveillance, as follows. (See 'Approach to the patient with a history of thyroid radiation exposure' above.)
•Physical examination – Annual thyroid examination as part of routine clinical care for all patients with low-dose or high-dose exposure during childhood. (See 'Physical examination' above.)
•Thyroid function tests – Annual thyroid function testing for all patients with high-dose exposure during childhood. For patients with radiation confined to the neck area alone, measurement of thyroid-stimulating hormone (TSH) is sufficient. For patients with a history of cranial or nasopharyngeal irradiation (who are at risk for both thyroid nodules and central hypothyroidism), we measure TSH and free thyroxine (T4). (See 'Surveillance for functional thyroid abnormalities' above.)
•Thyroid ultrasound – Use of thyroid ultrasound to detect nonpalpable nodules in radiation-exposed patients is controversial. In the absence of data, the use of surveillance ultrasonography should be individualized, guided by shared clinical decision-making after an assessment of each patient's risk factors, as well as a discussion regarding the harms and benefits of ultrasound screening. (See 'Surveillance for structural thyroid abnormalities' above.)
●Thyroid surveillance, adult exposure – Individuals with high- or low-dose exposure as adults are at lower risk of thyroid cancer than those exposed as children, and there is no convincing rationale for thyroid cancer screening beyond routine medical care. Such patients with high-dose exposure should be monitored annually for hypothyroidism. (See 'Who might benefit from surveillance?' above and 'Surveillance for functional thyroid abnormalities' above.)
●Management – The clinical characteristics, evaluation, and management of radiation-related thyroid nodules (discovered by palpation or through ultrasound screening) are similar to those of thyroid nodules in nonexposed patients. Patients with radiation-related thyroid cancer should be treated in the same way as nonexposed patients with thyroid cancer. (See 'Management' above and "Diagnostic approach to and treatment of thyroid nodules".)
●Prevention of radiation-related thyroid disease – In the event of a nuclear accident, potassium iodide tablets can decrease thyroid uptake of radioiodine. Potassium iodide can almost completely protect the thyroid if administered within 12 hours before radioiodine exposure or up to two hours after; after two hours, the degree of protection declines (80, 40, and 7 percent after 2, 8, and 24 hours, respectively). (See 'Potassium iodide for thyroid protection in a nuclear accident' above.)
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