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Radiation Exposure and other Factors that Predispose to Human Thyroid Neoplasia
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ENDOCRINE SURGERY
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RADIATION EXPOSURE AND
OTHER FACTORS THAT PREDISPOSE TO HUMAN THYROID NEOPLASIA Douglas L. Fraker, MD
The incidence of thyroid neoplasia is variably dependent upon gender, ethnicity, and geographic region. 4 Although there was a slight trend toward an increased incidence of thyroid cancer predominantly in females from 1960 to the mid-1970s, the incidence rates have generally been stable for any given geographic region during the past 40 years. In the United States, the annual incidence of thyroid cancer for males varies between 1.62 and 2.6 cases per 100,000 population and between 2.6 and 6.0 cases per 100,000 for females. 4 The only factor definitively shown to cause increased thyroid cancer incidence is thyroid exposure to various forms of radiation,16 although other environmental factors have been evaluated (Table 1). RADIATION EXPOSURE FOR MEDICAL TREATMENT Radiation for Benign Childhood Diseases
The initial epidemiologic observation connecting external beam radiation exposure and thyroid cancer was made by Duffy and Fitzgerald in 1950. 3 They reviewed cases of childhood thyroid cancer, which included 28 of 430 thyroid carcinomas seen at Memorial Hospital in New York between 1932 and 1948. Nine of these 28 patients under age 18 All material in this article, with the exception of borrowed figures, tables, or text, is in the public domain.
From the Surgical Metabolism Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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Table 1. FACTORS POTENTIALLY ASSOCIATED WITH THE DEVELOPMENT OF THYROID NEOPLASIA Radiation Exposure External Medical treatment for benign conditions Medical treatment for malignancies Environmental exposure-nuclear weapons or accidents Internal Medical treatment of benign condition with 131 1 Diagnostic tests with 131 1 Environmental-fallout from nuclear weapons Other Factors Diet-iodine-deficient, goitrogens Hormonal factors-female gender predominance Benign thyroid disease Alcohol
had radiation exposure to treat an enlarged thymus prior to developing the thyroid malignancy. Duffy wrote in his conclusions "to propose a cause and effect relationship between thymic irradiation and the development of cancer would be quite unjustified on the basis of the data at hand and . . . relationships as those of thymic irradiation in early life and development of thyroid or thymic tumors might be profitably explored."3 Following this initial observation, several other investigators found a similar connection between neck irradiation and subsequent thyroid cancer. For example, Clark2 found that all 13 cases of childhood thyroid cancer at the University of Chicago between 1926 and 1951 had external beam radiation for a variety of benign conditions, including an enlarged thymus (n = 3), enlarged tonsils (n = 5), cervical adenitis (n = 3), and sinusitis (n = 2). Winship and Rosvo1l20 kept a national registry of childhood thyroid cancer through 1970 and noted that only isolated reports totaling 14 cases occurred between 1900 and 1930. From 1930 to the late 1950s the annual incidence of reported childhood cancer rose to 60 to 70 reported cases per year in the United States and then rapidly declined by the end of the 1960s. This curve of thyroid cancer incidence paralleled the use of radiation therapy to treat a variety of benign conditions in infancy or early childhood between 1920 and 1950, with a lag time of 5 to 20 years. 20 These various single institution reviews as well as the national registry clearly identified radiation therapy as a major risk factor for development of childhood thyroid cancer. To analyze more critically the relationship of radiation therapy and thyroid neoplasia, including the dose response and the impact on radiation therapy for adults, casecontrolled studies comparing the incidence of thyroid neoplasms between large irradiated populations and similar nonirradiated control populations have been performed. The results of two large-scale studies of pediatric populations are shown in Table 2. Ron et all3 studied a population of children receiving low-dose radiation for scalp ringworm
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Table 2. SELECTED LARGE CASE-CONTROLLED STUDIES OF THE EFFECT OF CHILDHOOD IRRADIATION ON THE INCIDENCE OF THYROID NEOPLASIA
Reason for radiation Thyroid dose (rads) Mean dose Irradiated patients Number Number of thyroid Number of thyroid Control population Number Number of thyroid Number of thyroid Relative risk Thyroid adenoma Thyroid cancer
Reference 13
Reference 17
Scalp ringworm 5-50 9
Enlarged thymus 5-1000 120
adenomas cancers
10,834 98 (0.9%) 43 (0.4%)
2,650 59 (2.2%) 30 (1.1%)
adenomas cancers
16,226 57 (0.35%) 16 (0.1%)
4,800 8 (0.17%) 1 (0.2%)
2.6 4.0
12.9 55
in Israel. The thyroid exposure dose ranged between 5 and 50 rads, with a mean dose of 9 rads. Even at this relatively low dose the relative risk of thyroid cancer was 4.0 compared with a control population. A similar study by Shore et aP7 of children irradiated for an enlarged thymus in upstate New York reported a relative risk of 15 for thyroid cancer and 5 for benign thyroid nodules. The higher relative risk in this study reflects a higher mean radiation dose of 120 rads, compared with 9 rads for the Ron study (Table 2). A consistent finding in all studies of childhood irradiation is that the relative increased risk of thyroid neoplasia is directly proportional in a linear manner to the dose of radiation exposureY-15, 17 The Ron study estimated the excess relative risk for thyroid cancer to be 0.3 per rad of childhood radiation exposure, In the Shore study,17 in which patients were exposed to a wider range of radiation doses, the relative risk was 12.9 for exposure less than 50 rads and increased to 196 for patients receiving greater than 600 rads. The excess cancer per 1 million patient-years per rad exposure was relatively constant across the range of exposure between 1.5 and 2.8, indicating the linear dose responseY A second feature of radiation-induced thyroid neoplasia that was clear from the studies of childhood irradiation for benign conditions is that exposure at a young age increases the relative risk. In the Ron study,13 for benign nodules there is a linear inverse relationship between age at exposure and relative risk. For thyroid cancers the linear inverse relationship exists until radiation exposure at age 5, when the relative risk abruptly decreases. Schneider and co-workers 14, 15 at the University of Chicago have extensively studied, with long-term follow-up, a population of over 3000 patients who underwent childhood irradiation at their institution. In this population 1145 of 3042 patients developed thyroid nodules; 318 have been proved to be thyroid cancer, for an overall incidence of 10.5%.14
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This relatively high proportion of cancers, compared with the studies discussed above (Table 2), partially reflects the long-term follow-up for the Schneider series and partially may be due to selection bias in obtaining follow-up in this non-case-controlled study. Nevertheless, the detailed analysis in a series of reports by Schneider and co-workers provides a valuable data base for the biology of radiation-induced thyroid neoplasia. 14, 15 A recent report confirms the linear relationship between dose of radiation exposure and relative thyroid neoplasia risk for both benign and malignant nodules. 15 Also this report shows that the latent period between the time of radiation exposure and the occurrence of thyroid neoplasia extends beyond 40 years. That is, the subgroup that has now been followed for up to 40 years since radiation exposure continues to have an increased incidence of thyroid neoplasia. At 40 years following radiation exposure, over 60% of patients have thyroid nodules and over 15% of these are thyroid cancers.15
Radiation Therapy for Malignant Disease
The detailed studies of large patient populations receiving childhood irradiation for benign conditions dearly identify a link of radiation exposure and thyroid neoplasia. Primarily because of these early reports, the practice of radiation therapy for benign conditions ceased around 1960. However, radiation therapy continues to be an important tool for the regional treatment of a variety of malignant conditions. As noted from the studies of childhood irradiation, younger age at the time of radiation exposure augments the risk of thyroid cancer ..In the past two decades, radiation therapy has become part of multimodality treatment for several childhood malignancies which have led to long-term cure rates. Also other malignancies that may occur in adolescents or young adults, such as lymphoma or cervical cancer, may be treated primarily by radiation therapy. Although radiation exposure for benign conditions has not occurred for over 30 years, there is an increasing population of patients who have received radiation therapy for malignant conditions who are now potentially at increased risk for thyroid neoplasia. Several recent epidemiologic reports have examined this issue. A multi-institutional study by Tucker and co-workersl8 from the National Cancer Institute looked at a pediatric patient population treated with radiation therapy for a variety of malignancies (Table 3). The relative risk for thyroid cancer following treatment of neuroblastoma and Wilms' tumors was 350 and 132, respectively. Although the estimated radiation exposure dose to the thyroid was only 660 and 310 rads for these malignancies, the mean age at the time of treatment was 2 or 3 years (Table 3).18 As with radiation for benign conditions, the age at the time of exposure appears to be inversely related to the increased risk of thyroid cancer. In the Tucker study,18 higher doses of thyroid radiation for the treatment of Hodgkin's and non-Hodgkin's lymphoma were associated with less, although still significant, increased risk of
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Table 3. EFFECTS OF EXTERNAL BEAM RADIATION THERAPY FOR TREATMENT OF CANCER ON THE SUBSEQUENT DEVELOPMENT OF SECONDARY THYROID CANCER
Ref. 18 18 18 18 7 1
Histology Neuroblastoma Wilms' tumor Non-Hodgkin's lymphoma Hodgkin's disease Hodgkin's disease Cervical cancer
No. Mean Age of at Patients Treatment 790 1248 422 1036 1677 150,000
2 yr 3 yr 11 yr 9 yr 29 yr NA
Mean Rads'
No. of Thyroid Cancers
Relative Riskt
660 310 2400 3100 4400 11
7 4 2 5 6 43
350 132 81 67 156 2.35
NA = Not available. 'Estimated mean thyroid exposure. tRelative risk estimated in relation to predicted incidence of thyroid cancers.
thyroid cancer (Table 3). A study by Hancock et aF from Stanford University evaluated the impact of radiation treatment for Hodgkin's disease and the subsequent development of thyroid cancer. In this study of predominantly young adults with Hodgkin's disease (mean age 29), the relative risk of thyroid cancer was increased at 15.6. This increase is less than the relative risk in a younger patient population (mean age 9) with Hodgkin's disease receiving similar radiation exposure, for whom the relative risk was 67 (Table 3),7, 18 This difference highlights the importance of age at the time of radiation exposure as a significant factor for later risk of thyroid cancer. Finally, a large study of secondary malignancies of all types following radiation treatment for cervical cancer in more than 150,000 women reported a moderately increased relative risk of thyroid cancer of 2.35. 1 The total estimated exposure to the thyroid in this population was 11 rads, and the study demonstrated the decreased relative risk at a lower exposure dose in an older group of patients. Not surprisingly, the results from studies of long-term survivors following radiation treatments for a variety of malignancies show that external beam radiation treatments with thyroid exposure lead to an increased risk of cancer (Table 3). Although the dose of radiation exposure is generally quite high for therapeutic radiation treatments, the age at the time of exposure in general is significantly greater for patients receiving radiation for malignant disease as opposed to the patients receiving radiation for benign conditions such as enlarged thymus or tonsils, However, a growing and significant population of young patients, exemplified in the Tucker report/8 that may survive childhood cancers after significant radiation therapy are at increased risk of thyroid neoplasia in the future. Radiation Exposure from Nuclear Medicine Scans or Treatment A second category of medical radiation exposure is radioactive iodine compounds for either therapeutic or diagnostic purposes. The
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most pertinent agent used in these studies is 1311, which is taken up specifically by the thyroid. Medical treatment with 1311 to ablate the thyroid gland in Graves' disease exposes the thyroid to the equivalent dose of 6,000 to 10,000 rads. 8 A study of 3000 patients treated with highdose 131 1 in Sweden showed no increase risk of thyroid cancer, with four cases developing in this population versus 3.2 cases predicted. 8 Although external beam radiation exposure at similarly high doses causes a significant risk of subsequent thyroid cancer, perhaps the desired effects of toxic doses of 1311 prevent thyroid cancer by effectively damaging the majority of thyroid tissue. 8 Contrary to therapeutic doses of 1311, a diagnostic nuclear medicine scan exposes the thyroid to a dose equivalent to 50 rads of external beam radiation. 9 A study from Sweden of 35,074 patients who underwent thyroid scans between 1951 and 1969 shows only a slight increase in the incidence of thyroid cancer.9 The patient population developed 50 cases of thyroid cancer, compared with 39.4 predicted cases (standardized incidence ratio (SIR) of 1.27).9 One notable finding of this study is that the risk tended to be significantly higher in males (SIR = 2.70) than in females, who did not have an increased incidence of thyroid cancer after 1311 scans (SIR = 1.12). One criticism of a study of this type is that patients who undergo thyroid scans represent a highly selected population. That is, the patients who compose this population have some evidence of thyroid disease which generates the need for the diagnostic scan. In the subgroup of patients who were scanned because of the suspicion of thyroid neoplasia, the SIR was 2.77. The other major group in this population were those patients scanned because of functional thyroid diseases, for which the SIR was 0.62, showing, if anything, a decreased incidence of thyroid cancer. The conclusion from this study is that low-dose 131 1 does not appear to significantly increase the risk of thyroid cancer. The authors note that the risk of 131 1 is at least fourfold lower than the risk of an equivalent dose of external beam x-rays or gamma rays based on findings from the childhood irradiation studies. 9
ENVIRONMENTAL RADIATION EXPOSURE
A second major category of radiation exposure which may increase the risk of thyroid cancer is environmental exposure. As with medical exposure, environmental exposure can be classified as external radiation or internalized uptake of radioactive compounds that may concentrate in the thyroid. The most-studied and best-known environmental exposure to acute total body radiation is in the survivors of the atomic weapon explosions at Hiroshima and Nagasaki in 1945. Long-term follow-up of this patient population exposed to gamma and neutron radiation shows a significantly increased risk of thyroid cancer, with 62 cases in the Hiroshima population and 50 cases in the Nagasaki population. l l The relative risk is higher for patients who were younger «30 years of age) at the time of exposure, similar to the findings of medical
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x-rays. Also, there appears to be a linear dose relationship to gammaray exposure but not to neutron exposure (Table 4),u Although acute gamma-ray exposure appears to increase the incidence of thyroid cancer, chronic exposure does not seem to have this effect. A study of a population in South China with high chronic background radiation due to gamma rays from radioactive sand showed no increase in thyroid neoplasia compared with a control population. 19 The estimated exposure was 0.33 rads/year with a lifetime exposure up to 14 rads (Table 4). Although this is a relatively low dose, acute exposure at this level causes a significantly increased risk of thyroid cancer (see Table 2). The observed rate of nodular thyroid disease compared with control populations was 1.02, although karyotype examination of circulating lymphocytes showed a higher incidence of chromosome abnormalities than in controls. 19 A second type of environmental radiation exposure which leads to increased thyroid neoplasia is ingestion of radioisotopes that produce beta particles from nuclear fallout. The best data for this type of exposure come from a 1954 hydrogen bomb test at the Bikini Atoll in the Marshall Islands. 6 More than 7000 Marshallese people were exposed to 131 1 as well as to short-lived isotopes of radioactive iodine such as 1321, 1331, and 1351 (Table 4).6 This population has an increased incidence of thyroid nodules with a risk estimate of 11 excess cases/rad/year/1 million patients. In the islands closest to the blast test site with the highest estimated exposure, 33% of the population have developed thyroid nodules and 63% of the population under 10 years of age at the time of exposure now have thyroid nodules. 6 A similar type of exposure occurred in
Table 4. SUMMARY OF REPORTS OF ENVIRONMENTAL RADIATION EXPOSURE AND THE SUBSEQUENT RISK OF DEVELOPING THYROID CANCER Reference
Location
Exposure Event
Type of Exposure
Relative Risk
11
Hiroshima/ Nagasaki
1945 atomic bombs
Acute gamma and neutron radiation
19
South China
Radioactive sands/soil
Marshall Islands
1954 nuclear weapons test
Lifetime exposure to 0.33 rad/ year (primarily gamma rays) Predominantly fallout with radioactive iodine 1311.
Nevada
1951-1958 nuclear weapons fallout
6
Increased risk inversely proportional to age and directly proportional to dose of gamma irradiation No increased risk of thyroid nodules but increased chromosome abnormalities
11 thyroid nodules/rad/ yr/million people
1321, 1331, 135 1
10
Fallout with 1311, 1321, 133 135 1
1,
Relative risk of 3.4 for thyroid nodules when exposure was > 40 rads
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persons living near atomic weapons test sites in Nevada during the 1950s.1O A recent report of this patient population showed a relative increased risk of 3.4 for development of thyroid nodules when an exposure was estimated to be greater than 40 rads (Table 4).10 These positive results for increased incidence of thyroid cancer in populations exposed to nuclear fallout contrast with the lack of increased risk in patients who undergo diagnostic 1311 scans. The most likely explanation for these discordant data is that nuclear weapons fallout contains many active beta emitters other than 1311. It is known that nuclear fallout also exposes patients to high-energy, short-half-life radioactive iodine compounds such as 1321, 1331, and 1351, which may account primarily for the increased risk of thyroid neoplasia in these patients. A recent environmental exposure that has yet to mature in terms of final outcome is the April 26, 1986 Chernobyl nuclear reactor disaster. The majority of radiation exposure in this accident was similar to other nuclear accidents or atomic bomb explosions which contained radioactive iodine including the short-lived isotopes. A recent international NIH conference reported early data regarding thyroid neoplasia following the Chernobyl disaster (Table 5). An important feature learned already from this population is that the increased incidence of thyroid cancer began around 1989, with a latent period of only 3 years after exposure. This short interval from time of radiation exposure to development of thyroid cancer is less than that found in other studies in which the latent period ranges from 5 to 10 years following acute medical radiation exposure. 13, 16, 17 As with other types of radiation exposure, the predominant histology of thyroid cancer in the Chernobyl population is papillary, with a high proportion of lymph node metastases (Table 5). Summary of Radiation Exposure and Thyroid Neoplasia
As stated earlier, the only definitive known environmental risk factor for developing thyroid cancer is some type of radiation exposure. The types of exposure and the characteristics of the radiation-induced cancer are summarized in Table 6. The greatest risk occurs with acute exposure to gamma rays or x-rays, primarily from medical radiation,
Table 5. DATA REGARDING THE APRIL 26,1986 CHERNOBYL NUCLEAR DISASTER
Initial thyroid cancers noted in 1989 (less than 3-year latent period) Incidence of new cases increasing through 1993 primarily in younger age groups Short-lived isotopes-1321, 1331, 135I-appear to be major effectors Predominant histologic type is papillary with high incidence of lymph node metastases but no apparent difference in natural history compared with agematched cases Data from NIH International Conference on Chernobyl, September 1993, provided by Dr. Jack Robbins.
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Table 6. CONCLUSIONS REGARDING RADIATION EXPOSURE AND THYROID CANCER
Known to be carcinogenic: Acute external medical radiation Environmental exposure from atomic weapons and fallout Not known to be carcinogenic: Medical treatment with 131 1 Chronic low-dose environmental exposure Characteristics of radiation-induced thyroid cancer Latent period of at least 3 to 5 years Increased risk continues through 40 years after exposure Linear dose-response curve Inversely related to age Chiefly papillary histology Natural history not different from non-radiation-induced age-matched thyroid cancer
although acute environmental exposure also increases risk. Medical treatment with 131 1 either at low doses for diagnostic imaging or high doses for thyroid ablation does not appear to increase the incidence of thyroid cancer. On the other hand, nuclear fallout that contains 131 1 and other isotopes of radioactive iodine is associated with an increased risk of thyroid neoplasia. The characteristics of radiation-induced thyroid cancer are noted in Table 6. There is a clear linear dose-response curve, the risk is inversely related to age at exposure, and the pathology is primarily papillary with a natural history not different from nonradiation-induced age-matched histology-matched tumors. A future question regarding radiation-induced thyroid cancer is whether the population of infants irradiated 30 to 50 years ago continue to have an increased incidence of tumors. Early data from the Schneider series indicate that this increased risk will persist. 15 If this population continues to have new thyroid cancers occurring at an older age, it will be interesting to see whether they follow the same aggressive natural history as other non-radiation-induced thyroid cancers occurring in older patients. OTHER RISK FACTORS
Although the data linking radiation exposure to thyroid cancer are overwhelming, little is known regarding other factors that may predispose to development of thyroid cancer (see Table 1). One probable association with increased risk of thyroid cancer is a previous history of thyroid adenoma and, to a lesser degree, multinodular goiter. s Functional thyroid disorders are not associated with increased risk. Casecontrolled studies of dietary factors at present are controversial, with different reports showing that an iodine-rich diet decreases, increases, or does not change the incidence of thyroid cancer. 4 Alcohol intake may increase the incidence of thyroid cancer, possibly via the known effects of ethanol on the release of TSH from the anterior pituitary. Smoking is not associated with increased thyroid cancer risk. 4 Because the incidence
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of thyroid cancer is greater in women, several variables relating to hormonal levels (age at menarche, parity, use of exogenous estrogens) have been evaluated but no clear relationship between any factor and thyroid cancer incidence has been found. 4 In conclusion, the thyroid is clearly a radiosensitive organ, and radiation exposure at a young age predisposes to the development of thyroid cancer. However, recent reviews from the Connecticut Tumor Registry indicate that only 9% of all well-differentiated thyroid cancers could be related to known radiation exposure. 12 The only other documented risk factor is prior nodular thyroid disease, but the majority of thyroid cancers cannot be explained by any known environmental exposure at this time. Further studies, particularly on the molecular biology of thyroid cancer, may give insight to other unrecognized etiologic factors, either genetic or environmental, which lead to thyroid neoplasia. References 1. Boice JD Jr, Engholm G, Kleinerman RA, et al: Radiation dose and second cancer risk in patients treated for cancer of the cervix. Radiat Res 116:3-55, 1988 2. Clark DE: Association of irradiation with cancer of the thyroid in children and adolescents. JAMA 159:1007-1009, 1955 3. Duffy BJ Jr, Fitzgerald PJ: Cancer of the thyroid in children: A report of 28 cases. J Clin Endocrinol Metab 10:1296-1308, 1950 4. Franceschi S, Boyle P, Maisonneuve P, et al: The epidemiology of thyroid carcinoma. Crit Rev Oncogen 4:25-52, 1993 5. Goldman MB, Monson RR, Maloof F: Cancer mortality in women with thyroid disease. Cancer Res 50:2283-2289, 1990 6. Hamilton TE, van Belle G, LoGerfo JP: Thyroid neoplasia in Marshall Islanders exposed to nuclear fallout. JAMA 258:629-636, 1987 7. Hancock SL, Cox RS, McDougall IR: Thyroid diseases after treatment of Hodgkin's disease. N Engl J Med 325:599-605, 1991 8. Holm LE, Dahlqvist I, Israellson A, et al: Malignant thyroid tumors after iodine-131 therapy. N Engl J Med 303:188-191, 1980 9. Holm LE, Wiklund KE, Lundell GE, et al: Thyroid cancer after diagnostic doses of iodine-131: A retrospective cohort study. J Nat! Cancer Inst 80:1132-1138, 1988 10. Kerber RA, Till JE, Simon SL, et al: A cohort study of thyroid disease in relation to fallout from nuclear weapons testing. JAMA 270:2076-2082, 1993 11. Prentice RL, Kato H, Yoshimoto K, et al: Radiation exposure and thyroid cancer incidence among Hiroshima and Nagasaki residents. Nat! Cancer Inst Monogr 62:207212, 1982 12. Ron E, Kleinerman RA, Boice JD Jr, et al: A population-based case-control study of thyroid cancer. J Natl Cancer Inst 79:1-12, 1987 13. Ron E, Modan B, Preston D, et al: Thyroid neoplasia following low-dose radiation in childhood. Radiat Res 120:516-531, 1989 14. Schneider AB, Recant W, Pincky SM, et al: Radiation-induced thyroid carcinoma. Clinical course and results of therapy in 296 patients. Ann Intern Med 105:405-412, 1986 15. Schneider AB, Ron E, Lubin J, et al: Dose-response relationships for radiation-induced thyroid cancer and thyroid nodules: Evidence for the prolonged effects of radiation on the thyroid. J Clin Endocrinol Metab 77:362-369, 1993 16. Shore RE: Issues and epidemiological evidence regarding radiation-induced thyroid cancer. Radiat Res 131:98-111, 1992 17. Shore RE, Woodard E, Hildreth N, et al: Thyroid tumors following thymus irradiation. J Nat! Cancer Inst 74:1177-1184, 1985
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18. Tucker MA, Jones PHM, Boice JD Jr, et al: Therapeutic radiation at a young age is linked to secondary thyroid cancer. Cancer Res 51:2885-2888, 1991 19. Wang Z, Boice JD Jr, Wei L, et al: Thyroid nodularity and chromosome aberrations among women in areas of high background radiation in China. J Nat! Cancer Inst 82:478-485, 1990 20. Winship T,Rosvoll RV: Thyroid carcinoma in childhood: Final report on a 20 year study. Clinical Proceedings, Children Hospital 26:327-348, 1970
Address reprint requests to Douglas L. Fraker, MD Surgical Metabolism Section Surgery Branch National Cancer Institute/NIH Building 10, Room 2B07 Bethesda, MD 20892-1502
ENDOCRINE SURGERY
+ .20
RADIATION EXPOSURE AND
OTHER FACTORS THAT PREDISPOSE TO HUMAN THYROID NEOPLASIA Douglas L. Fraker, MD
The incidence of thyroid neoplasia is variably dependent upon gender, ethnicity, and geographic region. 4 Although there was a slight trend toward an increased incidence of thyroid cancer predominantly in females from 1960 to the mid-1970s, the incidence rates have generally been stable for any given geographic region during the past 40 years. In the United States, the annual incidence of thyroid cancer for males varies between 1.62 and 2.6 cases per 100,000 population and between 2.6 and 6.0 cases per 100,000 for females. 4 The only factor definitively shown to cause increased thyroid cancer incidence is thyroid exposure to various forms of radiation,16 although other environmental factors have been evaluated (Table 1). RADIATION EXPOSURE FOR MEDICAL TREATMENT Radiation for Benign Childhood Diseases
The initial epidemiologic observation connecting external beam radiation exposure and thyroid cancer was made by Duffy and Fitzgerald in 1950. 3 They reviewed cases of childhood thyroid cancer, which included 28 of 430 thyroid carcinomas seen at Memorial Hospital in New York between 1932 and 1948. Nine of these 28 patients under age 18 All material in this article, with the exception of borrowed figures, tables, or text, is in the public domain.
From the Surgical Metabolism Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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Table 1. FACTORS POTENTIALLY ASSOCIATED WITH THE DEVELOPMENT OF THYROID NEOPLASIA Radiation Exposure External Medical treatment for benign conditions Medical treatment for malignancies Environmental exposure-nuclear weapons or accidents Internal Medical treatment of benign condition with 131 1 Diagnostic tests with 131 1 Environmental-fallout from nuclear weapons Other Factors Diet-iodine-deficient, goitrogens Hormonal factors-female gender predominance Benign thyroid disease Alcohol
had radiation exposure to treat an enlarged thymus prior to developing the thyroid malignancy. Duffy wrote in his conclusions "to propose a cause and effect relationship between thymic irradiation and the development of cancer would be quite unjustified on the basis of the data at hand and . . . relationships as those of thymic irradiation in early life and development of thyroid or thymic tumors might be profitably explored."3 Following this initial observation, several other investigators found a similar connection between neck irradiation and subsequent thyroid cancer. For example, Clark2 found that all 13 cases of childhood thyroid cancer at the University of Chicago between 1926 and 1951 had external beam radiation for a variety of benign conditions, including an enlarged thymus (n = 3), enlarged tonsils (n = 5), cervical adenitis (n = 3), and sinusitis (n = 2). Winship and Rosvo1l20 kept a national registry of childhood thyroid cancer through 1970 and noted that only isolated reports totaling 14 cases occurred between 1900 and 1930. From 1930 to the late 1950s the annual incidence of reported childhood cancer rose to 60 to 70 reported cases per year in the United States and then rapidly declined by the end of the 1960s. This curve of thyroid cancer incidence paralleled the use of radiation therapy to treat a variety of benign conditions in infancy or early childhood between 1920 and 1950, with a lag time of 5 to 20 years. 20 These various single institution reviews as well as the national registry clearly identified radiation therapy as a major risk factor for development of childhood thyroid cancer. To analyze more critically the relationship of radiation therapy and thyroid neoplasia, including the dose response and the impact on radiation therapy for adults, casecontrolled studies comparing the incidence of thyroid neoplasms between large irradiated populations and similar nonirradiated control populations have been performed. The results of two large-scale studies of pediatric populations are shown in Table 2. Ron et all3 studied a population of children receiving low-dose radiation for scalp ringworm
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Table 2. SELECTED LARGE CASE-CONTROLLED STUDIES OF THE EFFECT OF CHILDHOOD IRRADIATION ON THE INCIDENCE OF THYROID NEOPLASIA
Reason for radiation Thyroid dose (rads) Mean dose Irradiated patients Number Number of thyroid Number of thyroid Control population Number Number of thyroid Number of thyroid Relative risk Thyroid adenoma Thyroid cancer
Reference 13
Reference 17
Scalp ringworm 5-50 9
Enlarged thymus 5-1000 120
adenomas cancers
10,834 98 (0.9%) 43 (0.4%)
2,650 59 (2.2%) 30 (1.1%)
adenomas cancers
16,226 57 (0.35%) 16 (0.1%)
4,800 8 (0.17%) 1 (0.2%)
2.6 4.0
12.9 55
in Israel. The thyroid exposure dose ranged between 5 and 50 rads, with a mean dose of 9 rads. Even at this relatively low dose the relative risk of thyroid cancer was 4.0 compared with a control population. A similar study by Shore et aP7 of children irradiated for an enlarged thymus in upstate New York reported a relative risk of 15 for thyroid cancer and 5 for benign thyroid nodules. The higher relative risk in this study reflects a higher mean radiation dose of 120 rads, compared with 9 rads for the Ron study (Table 2). A consistent finding in all studies of childhood irradiation is that the relative increased risk of thyroid neoplasia is directly proportional in a linear manner to the dose of radiation exposureY-15, 17 The Ron study estimated the excess relative risk for thyroid cancer to be 0.3 per rad of childhood radiation exposure, In the Shore study,17 in which patients were exposed to a wider range of radiation doses, the relative risk was 12.9 for exposure less than 50 rads and increased to 196 for patients receiving greater than 600 rads. The excess cancer per 1 million patient-years per rad exposure was relatively constant across the range of exposure between 1.5 and 2.8, indicating the linear dose responseY A second feature of radiation-induced thyroid neoplasia that was clear from the studies of childhood irradiation for benign conditions is that exposure at a young age increases the relative risk. In the Ron study,13 for benign nodules there is a linear inverse relationship between age at exposure and relative risk. For thyroid cancers the linear inverse relationship exists until radiation exposure at age 5, when the relative risk abruptly decreases. Schneider and co-workers 14, 15 at the University of Chicago have extensively studied, with long-term follow-up, a population of over 3000 patients who underwent childhood irradiation at their institution. In this population 1145 of 3042 patients developed thyroid nodules; 318 have been proved to be thyroid cancer, for an overall incidence of 10.5%.14
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This relatively high proportion of cancers, compared with the studies discussed above (Table 2), partially reflects the long-term follow-up for the Schneider series and partially may be due to selection bias in obtaining follow-up in this non-case-controlled study. Nevertheless, the detailed analysis in a series of reports by Schneider and co-workers provides a valuable data base for the biology of radiation-induced thyroid neoplasia. 14, 15 A recent report confirms the linear relationship between dose of radiation exposure and relative thyroid neoplasia risk for both benign and malignant nodules. 15 Also this report shows that the latent period between the time of radiation exposure and the occurrence of thyroid neoplasia extends beyond 40 years. That is, the subgroup that has now been followed for up to 40 years since radiation exposure continues to have an increased incidence of thyroid neoplasia. At 40 years following radiation exposure, over 60% of patients have thyroid nodules and over 15% of these are thyroid cancers.15
Radiation Therapy for Malignant Disease
The detailed studies of large patient populations receiving childhood irradiation for benign conditions dearly identify a link of radiation exposure and thyroid neoplasia. Primarily because of these early reports, the practice of radiation therapy for benign conditions ceased around 1960. However, radiation therapy continues to be an important tool for the regional treatment of a variety of malignant conditions. As noted from the studies of childhood irradiation, younger age at the time of radiation exposure augments the risk of thyroid cancer ..In the past two decades, radiation therapy has become part of multimodality treatment for several childhood malignancies which have led to long-term cure rates. Also other malignancies that may occur in adolescents or young adults, such as lymphoma or cervical cancer, may be treated primarily by radiation therapy. Although radiation exposure for benign conditions has not occurred for over 30 years, there is an increasing population of patients who have received radiation therapy for malignant conditions who are now potentially at increased risk for thyroid neoplasia. Several recent epidemiologic reports have examined this issue. A multi-institutional study by Tucker and co-workersl8 from the National Cancer Institute looked at a pediatric patient population treated with radiation therapy for a variety of malignancies (Table 3). The relative risk for thyroid cancer following treatment of neuroblastoma and Wilms' tumors was 350 and 132, respectively. Although the estimated radiation exposure dose to the thyroid was only 660 and 310 rads for these malignancies, the mean age at the time of treatment was 2 or 3 years (Table 3).18 As with radiation for benign conditions, the age at the time of exposure appears to be inversely related to the increased risk of thyroid cancer. In the Tucker study,18 higher doses of thyroid radiation for the treatment of Hodgkin's and non-Hodgkin's lymphoma were associated with less, although still significant, increased risk of
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Table 3. EFFECTS OF EXTERNAL BEAM RADIATION THERAPY FOR TREATMENT OF CANCER ON THE SUBSEQUENT DEVELOPMENT OF SECONDARY THYROID CANCER
Ref. 18 18 18 18 7 1
Histology Neuroblastoma Wilms' tumor Non-Hodgkin's lymphoma Hodgkin's disease Hodgkin's disease Cervical cancer
No. Mean Age of at Patients Treatment 790 1248 422 1036 1677 150,000
2 yr 3 yr 11 yr 9 yr 29 yr NA
Mean Rads'
No. of Thyroid Cancers
Relative Riskt
660 310 2400 3100 4400 11
7 4 2 5 6 43
350 132 81 67 156 2.35
NA = Not available. 'Estimated mean thyroid exposure. tRelative risk estimated in relation to predicted incidence of thyroid cancers.
thyroid cancer (Table 3). A study by Hancock et aF from Stanford University evaluated the impact of radiation treatment for Hodgkin's disease and the subsequent development of thyroid cancer. In this study of predominantly young adults with Hodgkin's disease (mean age 29), the relative risk of thyroid cancer was increased at 15.6. This increase is less than the relative risk in a younger patient population (mean age 9) with Hodgkin's disease receiving similar radiation exposure, for whom the relative risk was 67 (Table 3),7, 18 This difference highlights the importance of age at the time of radiation exposure as a significant factor for later risk of thyroid cancer. Finally, a large study of secondary malignancies of all types following radiation treatment for cervical cancer in more than 150,000 women reported a moderately increased relative risk of thyroid cancer of 2.35. 1 The total estimated exposure to the thyroid in this population was 11 rads, and the study demonstrated the decreased relative risk at a lower exposure dose in an older group of patients. Not surprisingly, the results from studies of long-term survivors following radiation treatments for a variety of malignancies show that external beam radiation treatments with thyroid exposure lead to an increased risk of cancer (Table 3). Although the dose of radiation exposure is generally quite high for therapeutic radiation treatments, the age at the time of exposure in general is significantly greater for patients receiving radiation for malignant disease as opposed to the patients receiving radiation for benign conditions such as enlarged thymus or tonsils, However, a growing and significant population of young patients, exemplified in the Tucker report/8 that may survive childhood cancers after significant radiation therapy are at increased risk of thyroid neoplasia in the future. Radiation Exposure from Nuclear Medicine Scans or Treatment A second category of medical radiation exposure is radioactive iodine compounds for either therapeutic or diagnostic purposes. The
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most pertinent agent used in these studies is 1311, which is taken up specifically by the thyroid. Medical treatment with 1311 to ablate the thyroid gland in Graves' disease exposes the thyroid to the equivalent dose of 6,000 to 10,000 rads. 8 A study of 3000 patients treated with highdose 131 1 in Sweden showed no increase risk of thyroid cancer, with four cases developing in this population versus 3.2 cases predicted. 8 Although external beam radiation exposure at similarly high doses causes a significant risk of subsequent thyroid cancer, perhaps the desired effects of toxic doses of 1311 prevent thyroid cancer by effectively damaging the majority of thyroid tissue. 8 Contrary to therapeutic doses of 1311, a diagnostic nuclear medicine scan exposes the thyroid to a dose equivalent to 50 rads of external beam radiation. 9 A study from Sweden of 35,074 patients who underwent thyroid scans between 1951 and 1969 shows only a slight increase in the incidence of thyroid cancer.9 The patient population developed 50 cases of thyroid cancer, compared with 39.4 predicted cases (standardized incidence ratio (SIR) of 1.27).9 One notable finding of this study is that the risk tended to be significantly higher in males (SIR = 2.70) than in females, who did not have an increased incidence of thyroid cancer after 1311 scans (SIR = 1.12). One criticism of a study of this type is that patients who undergo thyroid scans represent a highly selected population. That is, the patients who compose this population have some evidence of thyroid disease which generates the need for the diagnostic scan. In the subgroup of patients who were scanned because of the suspicion of thyroid neoplasia, the SIR was 2.77. The other major group in this population were those patients scanned because of functional thyroid diseases, for which the SIR was 0.62, showing, if anything, a decreased incidence of thyroid cancer. The conclusion from this study is that low-dose 131 1 does not appear to significantly increase the risk of thyroid cancer. The authors note that the risk of 131 1 is at least fourfold lower than the risk of an equivalent dose of external beam x-rays or gamma rays based on findings from the childhood irradiation studies. 9
ENVIRONMENTAL RADIATION EXPOSURE
A second major category of radiation exposure which may increase the risk of thyroid cancer is environmental exposure. As with medical exposure, environmental exposure can be classified as external radiation or internalized uptake of radioactive compounds that may concentrate in the thyroid. The most-studied and best-known environmental exposure to acute total body radiation is in the survivors of the atomic weapon explosions at Hiroshima and Nagasaki in 1945. Long-term follow-up of this patient population exposed to gamma and neutron radiation shows a significantly increased risk of thyroid cancer, with 62 cases in the Hiroshima population and 50 cases in the Nagasaki population. l l The relative risk is higher for patients who were younger «30 years of age) at the time of exposure, similar to the findings of medical
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x-rays. Also, there appears to be a linear dose relationship to gammaray exposure but not to neutron exposure (Table 4),u Although acute gamma-ray exposure appears to increase the incidence of thyroid cancer, chronic exposure does not seem to have this effect. A study of a population in South China with high chronic background radiation due to gamma rays from radioactive sand showed no increase in thyroid neoplasia compared with a control population. 19 The estimated exposure was 0.33 rads/year with a lifetime exposure up to 14 rads (Table 4). Although this is a relatively low dose, acute exposure at this level causes a significantly increased risk of thyroid cancer (see Table 2). The observed rate of nodular thyroid disease compared with control populations was 1.02, although karyotype examination of circulating lymphocytes showed a higher incidence of chromosome abnormalities than in controls. 19 A second type of environmental radiation exposure which leads to increased thyroid neoplasia is ingestion of radioisotopes that produce beta particles from nuclear fallout. The best data for this type of exposure come from a 1954 hydrogen bomb test at the Bikini Atoll in the Marshall Islands. 6 More than 7000 Marshallese people were exposed to 131 1 as well as to short-lived isotopes of radioactive iodine such as 1321, 1331, and 1351 (Table 4).6 This population has an increased incidence of thyroid nodules with a risk estimate of 11 excess cases/rad/year/1 million patients. In the islands closest to the blast test site with the highest estimated exposure, 33% of the population have developed thyroid nodules and 63% of the population under 10 years of age at the time of exposure now have thyroid nodules. 6 A similar type of exposure occurred in
Table 4. SUMMARY OF REPORTS OF ENVIRONMENTAL RADIATION EXPOSURE AND THE SUBSEQUENT RISK OF DEVELOPING THYROID CANCER Reference
Location
Exposure Event
Type of Exposure
Relative Risk
11
Hiroshima/ Nagasaki
1945 atomic bombs
Acute gamma and neutron radiation
19
South China
Radioactive sands/soil
Marshall Islands
1954 nuclear weapons test
Lifetime exposure to 0.33 rad/ year (primarily gamma rays) Predominantly fallout with radioactive iodine 1311.
Nevada
1951-1958 nuclear weapons fallout
6
Increased risk inversely proportional to age and directly proportional to dose of gamma irradiation No increased risk of thyroid nodules but increased chromosome abnormalities
11 thyroid nodules/rad/ yr/million people
1321, 1331, 135 1
10
Fallout with 1311, 1321, 133 135 1
1,
Relative risk of 3.4 for thyroid nodules when exposure was > 40 rads
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persons living near atomic weapons test sites in Nevada during the 1950s.1O A recent report of this patient population showed a relative increased risk of 3.4 for development of thyroid nodules when an exposure was estimated to be greater than 40 rads (Table 4).10 These positive results for increased incidence of thyroid cancer in populations exposed to nuclear fallout contrast with the lack of increased risk in patients who undergo diagnostic 1311 scans. The most likely explanation for these discordant data is that nuclear weapons fallout contains many active beta emitters other than 1311. It is known that nuclear fallout also exposes patients to high-energy, short-half-life radioactive iodine compounds such as 1321, 1331, and 1351, which may account primarily for the increased risk of thyroid neoplasia in these patients. A recent environmental exposure that has yet to mature in terms of final outcome is the April 26, 1986 Chernobyl nuclear reactor disaster. The majority of radiation exposure in this accident was similar to other nuclear accidents or atomic bomb explosions which contained radioactive iodine including the short-lived isotopes. A recent international NIH conference reported early data regarding thyroid neoplasia following the Chernobyl disaster (Table 5). An important feature learned already from this population is that the increased incidence of thyroid cancer began around 1989, with a latent period of only 3 years after exposure. This short interval from time of radiation exposure to development of thyroid cancer is less than that found in other studies in which the latent period ranges from 5 to 10 years following acute medical radiation exposure. 13, 16, 17 As with other types of radiation exposure, the predominant histology of thyroid cancer in the Chernobyl population is papillary, with a high proportion of lymph node metastases (Table 5). Summary of Radiation Exposure and Thyroid Neoplasia
As stated earlier, the only definitive known environmental risk factor for developing thyroid cancer is some type of radiation exposure. The types of exposure and the characteristics of the radiation-induced cancer are summarized in Table 6. The greatest risk occurs with acute exposure to gamma rays or x-rays, primarily from medical radiation,
Table 5. DATA REGARDING THE APRIL 26,1986 CHERNOBYL NUCLEAR DISASTER
Initial thyroid cancers noted in 1989 (less than 3-year latent period) Incidence of new cases increasing through 1993 primarily in younger age groups Short-lived isotopes-1321, 1331, 135I-appear to be major effectors Predominant histologic type is papillary with high incidence of lymph node metastases but no apparent difference in natural history compared with agematched cases Data from NIH International Conference on Chernobyl, September 1993, provided by Dr. Jack Robbins.
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Table 6. CONCLUSIONS REGARDING RADIATION EXPOSURE AND THYROID CANCER
Known to be carcinogenic: Acute external medical radiation Environmental exposure from atomic weapons and fallout Not known to be carcinogenic: Medical treatment with 131 1 Chronic low-dose environmental exposure Characteristics of radiation-induced thyroid cancer Latent period of at least 3 to 5 years Increased risk continues through 40 years after exposure Linear dose-response curve Inversely related to age Chiefly papillary histology Natural history not different from non-radiation-induced age-matched thyroid cancer
although acute environmental exposure also increases risk. Medical treatment with 131 1 either at low doses for diagnostic imaging or high doses for thyroid ablation does not appear to increase the incidence of thyroid cancer. On the other hand, nuclear fallout that contains 131 1 and other isotopes of radioactive iodine is associated with an increased risk of thyroid neoplasia. The characteristics of radiation-induced thyroid cancer are noted in Table 6. There is a clear linear dose-response curve, the risk is inversely related to age at exposure, and the pathology is primarily papillary with a natural history not different from nonradiation-induced age-matched histology-matched tumors. A future question regarding radiation-induced thyroid cancer is whether the population of infants irradiated 30 to 50 years ago continue to have an increased incidence of tumors. Early data from the Schneider series indicate that this increased risk will persist. 15 If this population continues to have new thyroid cancers occurring at an older age, it will be interesting to see whether they follow the same aggressive natural history as other non-radiation-induced thyroid cancers occurring in older patients. OTHER RISK FACTORS
Although the data linking radiation exposure to thyroid cancer are overwhelming, little is known regarding other factors that may predispose to development of thyroid cancer (see Table 1). One probable association with increased risk of thyroid cancer is a previous history of thyroid adenoma and, to a lesser degree, multinodular goiter. s Functional thyroid disorders are not associated with increased risk. Casecontrolled studies of dietary factors at present are controversial, with different reports showing that an iodine-rich diet decreases, increases, or does not change the incidence of thyroid cancer. 4 Alcohol intake may increase the incidence of thyroid cancer, possibly via the known effects of ethanol on the release of TSH from the anterior pituitary. Smoking is not associated with increased thyroid cancer risk. 4 Because the incidence
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of thyroid cancer is greater in women, several variables relating to hormonal levels (age at menarche, parity, use of exogenous estrogens) have been evaluated but no clear relationship between any factor and thyroid cancer incidence has been found. 4 In conclusion, the thyroid is clearly a radiosensitive organ, and radiation exposure at a young age predisposes to the development of thyroid cancer. However, recent reviews from the Connecticut Tumor Registry indicate that only 9% of all well-differentiated thyroid cancers could be related to known radiation exposure. 12 The only other documented risk factor is prior nodular thyroid disease, but the majority of thyroid cancers cannot be explained by any known environmental exposure at this time. Further studies, particularly on the molecular biology of thyroid cancer, may give insight to other unrecognized etiologic factors, either genetic or environmental, which lead to thyroid neoplasia. References 1. Boice JD Jr, Engholm G, Kleinerman RA, et al: Radiation dose and second cancer risk in patients treated for cancer of the cervix. Radiat Res 116:3-55, 1988 2. Clark DE: Association of irradiation with cancer of the thyroid in children and adolescents. JAMA 159:1007-1009, 1955 3. Duffy BJ Jr, Fitzgerald PJ: Cancer of the thyroid in children: A report of 28 cases. J Clin Endocrinol Metab 10:1296-1308, 1950 4. Franceschi S, Boyle P, Maisonneuve P, et al: The epidemiology of thyroid carcinoma. Crit Rev Oncogen 4:25-52, 1993 5. Goldman MB, Monson RR, Maloof F: Cancer mortality in women with thyroid disease. Cancer Res 50:2283-2289, 1990 6. Hamilton TE, van Belle G, LoGerfo JP: Thyroid neoplasia in Marshall Islanders exposed to nuclear fallout. JAMA 258:629-636, 1987 7. Hancock SL, Cox RS, McDougall IR: Thyroid diseases after treatment of Hodgkin's disease. N Engl J Med 325:599-605, 1991 8. Holm LE, Dahlqvist I, Israellson A, et al: Malignant thyroid tumors after iodine-131 therapy. N Engl J Med 303:188-191, 1980 9. Holm LE, Wiklund KE, Lundell GE, et al: Thyroid cancer after diagnostic doses of iodine-131: A retrospective cohort study. J Nat! Cancer Inst 80:1132-1138, 1988 10. Kerber RA, Till JE, Simon SL, et al: A cohort study of thyroid disease in relation to fallout from nuclear weapons testing. JAMA 270:2076-2082, 1993 11. Prentice RL, Kato H, Yoshimoto K, et al: Radiation exposure and thyroid cancer incidence among Hiroshima and Nagasaki residents. Nat! Cancer Inst Monogr 62:207212, 1982 12. Ron E, Kleinerman RA, Boice JD Jr, et al: A population-based case-control study of thyroid cancer. J Natl Cancer Inst 79:1-12, 1987 13. Ron E, Modan B, Preston D, et al: Thyroid neoplasia following low-dose radiation in childhood. Radiat Res 120:516-531, 1989 14. Schneider AB, Recant W, Pincky SM, et al: Radiation-induced thyroid carcinoma. Clinical course and results of therapy in 296 patients. Ann Intern Med 105:405-412, 1986 15. Schneider AB, Ron E, Lubin J, et al: Dose-response relationships for radiation-induced thyroid cancer and thyroid nodules: Evidence for the prolonged effects of radiation on the thyroid. J Clin Endocrinol Metab 77:362-369, 1993 16. Shore RE: Issues and epidemiological evidence regarding radiation-induced thyroid cancer. Radiat Res 131:98-111, 1992 17. Shore RE, Woodard E, Hildreth N, et al: Thyroid tumors following thymus irradiation. J Nat! Cancer Inst 74:1177-1184, 1985
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18. Tucker MA, Jones PHM, Boice JD Jr, et al: Therapeutic radiation at a young age is linked to secondary thyroid cancer. Cancer Res 51:2885-2888, 1991 19. Wang Z, Boice JD Jr, Wei L, et al: Thyroid nodularity and chromosome aberrations among women in areas of high background radiation in China. J Nat! Cancer Inst 82:478-485, 1990 20. Winship T,Rosvoll RV: Thyroid carcinoma in childhood: Final report on a 20 year study. Clinical Proceedings, Children Hospital 26:327-348, 1970
Address reprint requests to Douglas L. Fraker, MD Surgical Metabolism Section Surgery Branch National Cancer Institute/NIH Building 10, Room 2B07 Bethesda, MD 20892-1502