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INTRODUCTION

Early investigations, both experimental and clinical,created the impression that the thyroid gland is relativelyresistant to injury by ionizing radiation (86, 87). Theresults of the many studies carried out during the pastdecade, however, not only have reversed this view, buthave, in fact, emphasized that destructive lesions of thegland can be readily produced in man and several speciesof animals by various forms of irradiation. Thus, injuryin the human thyroid gland was observed after its irradiation for thyrotoxicosis, thyroid carcinoma, and cardiacdisease. The most recent developments in this field mdicate: (a) that benign and malignant neoplasms can bemade to appear in rat thyroid glands by exposing themto I's' or x-rays (54, 56, 69) ; and (b) that benign nodulesand at least one malignant nodule have been found in thethyroid glands of patients long after I― treatment forthyrotoxicosis (75, 76). The administration of evenminute doses of I―—l @tc.,for example—has now beenshown to have a carcinogenic effect on the thyroid glandof the Long-Evans rat (34), and it is equally significantthat thyroid carcinomas have been observed in patientswho, during infancy or childhood, were exposed to lowdosages of x-radiation to the thyroid area (21). Theseobservations in both animals and man can leave littledoubt that irradiation is an important factor in carcinogenesis of the gland.

In this review we have dealt primarily with three aspects : (a) Histogenesis of the destructive lesions inducedin the thyroid gland by various types of internal andexternal irradiation is discussed. (b) The secondarythyroid epithelial proliferative processes that presumablyresult from thyrotropic hormone stimulation of portions

Received for publication December 16, 1963.

of the gland still capable of responding to growth stimuliafter radiation injury are described. These proliferativelesions are generally focal and may lead to development ofbenign nodules or adenomas and, possibly, of carcinomas.The decided similarity in the patterns of obvious injuryand proliferative reactions (benign and malignant neoplasms) induced by irradiation in the glands of animalsand man is emphasized. (c) The induction of thyroidcarcinomas by low doses of irradiation which apparentlydo not cause other changes in the gland—at least that canbe demonstrated microscopically—is described.

RADIATION-INDUCED DEGENERATIVELESIONS IN THE THYROID GLAND

Destructive lesions in the thyroid gland resulting fromirradiation with I's' have been studied extensively in fish(49), mice (35, 36, 81), rats (24, 25, 29, 33, 54, 56, 61, 69),rabbits (39), dogs (32, 39, 43, 57), sheep (9, 63), and cows(28). The effects of external irradiation on the dog thymid, produced by x-rays, have also been described (82).Thyroid injury induced by alpha radiation from astatinehas been reported for rats and monkeys (40-42). In thehuman being the effects of I's' irradiation in normal thymid glands of patients treated for cardiac disease havebeen described by Freedberg et al. (26). Andrews et al.(2) also reported pathologic lesions in normal humanglands that were irradiated with 1131. Various effects ofradiation from radioactive iodine on human hyperplasticglands have been presented by Dailey et at. (14), Chapman and Maloof (10), and Dobyns et at. (16). A cornparison of radiation effects induced by I's', x-rays, radon,and neutrons on normal and hyperplastic human thyroidglands has been made by Lindsay et at. (53). Although nosystematic studies of the effects of irradiation on malignantneoplastic thyroid tissue have appeared, Lindsay et al.

1099

The Effects of Irradiation on the Thyroid Glandwith Particular Reference to the Induction

of Thyroid Neoplasms: a Review

STUART LINDSAY AND I. L. CHAIKOFF

(Departments of Pathology, the School of Medicine, San Francisco, and Physiology, Berkeley, University of California)

CONTENTS

IntroductionRadiation-induced Degenerative Lesions in the Thyroid GlandRadiation-induced Thyroid Neoplasms in the RatRadiation-induced Thyroid Neoplasms in Other AnimalsThyroid Nodules in Children Following Therapy with I's'Relation of Irradiation of the Head and Neck Area in Children to Development of

Thyroid CarcinomasRelation of External Irradiation of Head and Neck Areas in Adults to Develop

ment of Thyroid CarcinomasRésuméReferences

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compared biopsies of cervical lymph nodes containingmalignant thyroid tissue, before and after irradiation with1131.1

Thyroid tissue in animals and human beings is severelyinjured by the administration of high doses of I's'. Ultramicroscopic studies of rat thyroids irradiated with radioiodine indicate that the earliest changes are alterations inthe endoplasmic reticulum, involving formation ofspherical vesicles. The mitochondria swell and formspherical vesicles, and membrane-like structures appear inthe cytoplasm (64). The earliest changes in the thyroidepithelial cells observed by light microscopy are similarto those shown to occur in other tissues that were irradiated—namely, cytoplasmic swelling, vacuolization, nuclearpyknosis, and fragmentation (33, 53). These degenerativealterations were found in all types of thyroid epithelialcells (normal, hyperplastic, and malignant) and arecharacteristic of irradiation changes generally observed inepithelial cells (37, 53).' The disintegration of theseepithelial cells leads to disruption of fofficles, accompaniedby an acute inflammation characterized by a fibrinous andneutrophiic leukocytic infiltration and edema. Endothelial swelling and necrotizing vasculitis with thrombosismay persist for considerable periods. Vascular, fibrousthickening occurs, but this is not a prominent feature ofthe late irradiation changes observed in the thyroid gland.

Eventually the lobular structure of the gland disappears,cells and follicles being no longer visible. Stromal condensation is associated with the appearance of mucoidground substance, and chronic inflammatory cells eventually replace neutrophilic leukocytes. Six to 8 monthsafter the irradiation, the thyroid gland is fibrotic. Thefew distorted epithelial cells that remain frequently display nuclear hyperchromatism and pleomorphism consistent with Askanazy changes (nuclear pleomorphism andhyperchromatism, oxyphylia). Dobyns and Didtschenko(15) have demonstrated a significant increase in deoxyribonucleic acid in the abnormal epithelial nuclei of irradiatedrat thyroid glands. Since the cells that contain thesenuclei are usually devoid of mitoses, nuclear chromatinpresumably accumulates without cellular division.Maloof et al. (61) have shown that these nuclear changesin the irradiated rat thyroid may be prevented by administration of thyroid hormone.

Early regenerative phenomena have been found inhuman thyroid glands that were treated with large doses ofradioiodine (14) and in thyroid glands of sheep that werefed small doses of radioiodine daily (63). These consisted of intrafollicular proliferation of syncytial groups ofepithelial cells that extended into follicular spaces, areaction closely resembling that observed in earlier stagesof subacute thyroiditis.

In the human being the lesions found in the thyroidgland long after administration of large doses of 1131showchronic inflammation, interlobular and perifollicularfibrosis, follicular atrophy, and frequent Askanazy changesin the remaining epithelial cells (53). These lesions cannotalways be ascribed to irradiation, for they have also beenobserved singly or in combination in a variety of thyroid

1 5@ Lindsay, E. R. Miller, and M. E. Dailey, unpublished obser

diseases of nonirradiated patients. The use of a test, retest method demonstrated objectively that acute necrosis,pronounced fofficular atrophy, and extensive perifofficularfibrosis could be reliably identified as having resulted fromirradiation with high doses of I'' (65).

The degree of injury produced by ionizing radiationprobably depends upon the type and structure of thethyroid gland irradiated, the amount and distribution ofradiation delivered to and absorbed by the gland, and theduration of the reaction induced by the radiation.Probably other factors also influence the effects of irradiation on the thyroid gland. In the human being the effectson thyroid tissue of particle radiation and of gamma orroentgen rays appear to be qualitatively similar (53).Lippincott et al. compared the effects of astatine and I―@on rat thyroid glands and concluded that the degree ofinjury was not related to the type of radiation, but ratherwas correlated, both qualitatively and quantitatively,with the equivalent energy released from the two isotopes(58).

Studies at the University of California Hospitals (14)showed that most hyperthyroid patients treated with I's'became euthyroid. Since only nine of 24 irradiated glandsshowed histologic lesions regarded as having been causeddirectly by I's', decreased hormone production apparentlyresulted from cellular injury not demonstrable by ordinaryhistological methods. Seven of the 24 glands showedpredominantly the pattern of involuting hyperplasia,suggesting not only that cellular injury was accompaniedby decreased thyroid hormone production but also thatthe injury may have prevented further stimulation ofthyroid epithelial cells by thyrotropic hormone ( 14). Tenof 24 patients with diffuse toxic goiter, who had beentreated with I's', presented the typical pattern of chronicthyroiditis of the Hashimoto type. The frequency of thischronic inflammatory reaction was significantly greater inhyperplastic glands irradiated with I'' than in diffuse toxicgoiters not treated by irradiation ( 14). In the light of thestudies by Doniach and Roitt ( 19), irradiation of thehyperplastic thyroid gland may increase the loss of thyroglobulin from follicles and thus accentuate the development of an autoimmune reaction in the gland (6).

RADIATION-INDUCED THYROIDNEOPLASMS IN THE RAT

The relation between thyroid irradiation and the subsequent development of thyroid neoplasms in the rat hasbeen studied extensively. Goldberg and Chaikoff werethe first to demonstrate malignant thyroid neoplasmsdeveloping about 2 years after a single injection of I's'(30, 31). Doniach ( 17, 18) induced benign and malignantneoplasms in rat thyroid glands, mainly by combiningmethylthiouracil feeding and thyroid irradiation witheither I's' or x-rays. Although one malignant tumor wasfound in a rat in which only external x-radiation wasapplied to the thyroid gland, none was found in rats treatedonly with I'' (17, 18). Lindsay et cii. (54) and Potter et al.(69) reported the highest incidence of thyroid neoplasmsin Long-Evansrats that receivedlowdosesof I―—eithera single dose of 25 microcuries or four separate doses of10 @c.—atweekly intervals. The failure of Frantz et al.vations.

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noma was found among 61 rats that were subtotallythyroidectomized and also received 1 @c.of I's'. Thefeeding of the desiccated thyroid powder did not preventdevelopment of this neoplasm.

Of considerable interest was the finding of one papillaryand one fofficular carcinoma among 94 rats that had beengiven injections of a single @c.of I―. One of these animalshad been fed the desiccated thyroid-containing diet.Thus, in this recent study, the appearance of two papillarycarcinomas in the residual thyroid tissue following subtotal thyroidectomy alone suggests that stimulation ofthe thyroid gland by thyrotropic hormone can result inthe development not only of benign neoplasms but ofmalignant papillary carcinomas as well. On the otherhand, the finding of one papillary and one follicular carcinoma in intact thyroid glands of rats that had receivedonly 1 ,@tC.of I― suggests that these malignant neoplasmshad been induced by thyroid irradiation. It is of interestthat rats treated with a single, very small dose of I's' (1zc.) did not develop benign thyroid neoplasms and failedto show evidence of thyrotropic effects in their thyroidglands (Askanazy cells) and of increased thyrotropic activity in their pituitary glands. It was concluded fromthis study that thyrotropic hormone stimulation must be apromoting factor in development of both benign andmalignant thyroid neoplasms in the rat, and may alsoinitiate the development of thyroid malignant neoplasms

(34, 38). It also seems clear that the administration of 1Me. of I―alone may initiate the development of malignantthyroid neoplasms. In this case, the promoting factormight be normal thyroid growth, as suggested by Doniach(18). The possibility, however, of other initiating andpromoting factors must be considered because of the consistently high incidence, in Long-Evans rats, of naturallyoccurring, low-grade, malignant, thyroid neoplasms. Itshould be emphasized that the latter neoplasms differdistinctly from those induced by subtotal thyroidectomyor by irradiation. It is important to note that we havenever observed papillary or follicular carcinomas in LongEvans control rats (34, 54—56,69).

Although the follicular and papillary carcinomas induced in the rat by irradiation closely resembled thoseobserved in the human being, several neoplasms in the ratclearly had arisen in pre-existing, benign nodules. Although follicular carcinomas in human beings may originate in adenomas, papillary carcinomas are not usuallyderived from pre-existing benign nodules (51). In humanbeings, thyroid carcinomas appear more frequently infemales than in males (51), but in rats the administrationof low doses of radioiodine results in a higher frequency ofmalignant thyroid neoplasms in males than in females(55).

RADIATION-INDUCED THYROID NEOPLASMSIN OTHER ANIMALS

Reports that neoplasms also develop in thyroid glandsof mice, sheep, and dogs given injections of I's' haveappeared. Speert et at. (81) studied the thyroid glands ofmice born to mothers given injections of I's' during pregnancy. The offspring showed thyroid changes consisting

(25) and Field et al. (23) to induce thyroid carcinomas inLong-Evans rats by administration of I's' was apparentlydue to the very high doses of radiation they employed.Our studies in rats have clearly shown that the higherdoses of I'@'—200 or 400 @c.—completely or almost completely destroy the thyroid glands and prevent the epithelial regeneration which seems to initiate the development of benign and malignant thyroid neoplasms (54).

Frantz et al. (25) found four carcinomas, papillary andfollicular, in thyroid glands of Long-Evans rats that hadbeen irradiated with x-rays. Lindsay et al. (56) describedbenign nodules or adenomas in 30 of 74 rats, and papillaryor follicular carcinomas in nine of 74 rats in which thethyroid glands had been subjected to external x-radiation.

Naturally occurring thyroid carcinomas frequentlyfound in Long-Evans rats (54—56,69) have been designatedlobular or alveolar carcinomas (54), microadenomas (18),-V nodules (3), or solid carcinomas (25). The high doses

of J131either destroy them or prevent their development(54).

A sequence of changes from focal regenerative hyperplasia to benign nodule formation has been clearly demonstrated in the rat thyroid gland treated with low doses ofI― (25—40sc.) or x-rays (500—2000 r) (54—56,69). Thebenign neoplasms probably arose from focal areas thatwere still able to respond to prolonged thyrotropic hormone stimulation by epithelial proliferation—despite theinjury by irradiation. Both the benign adenomas andthe papillary and follicular carcinomas observed in thesestudies closely resembled those in animals that had received goitrogens or that had been subjected to chroniciodine deficiency (5, 66). In rats in which the glands werex-radiated but in which one lobe was shielded, identicalfocal hyperplasia resulting in development of benignadenornas was found in both lobes, the irradiated and theshielded (56). This indicates that at least the focal hyperplasia and benign nodule formation are probably thyrotropic hormone effects. Carcinomas were found only inthe nonshielded lobes, but it could not be decided whethercarcinogenesis was the result of continued thyrotropichormone stimulation of benign nodules or adenomas, orwhether x-radiation per se had induced the malignantprocess (56).

A report that thyroid neoplasms that appear in partiallythyroidectomized rats are identical with those found afterirradiation (20) led us to compare the pathogenesis ofthyroid neoplasms induced by (a) subtotal thyroidectomy,(b) irradiation with I's', and (c) a combination of theseprocedures (34). Single and multiple adenomas werefound in the thyroid remnants of the rats that had beensubjected to subtotal thyroidectomy only, but their mcidence was significantly higher in rats that had been subjected to subtotal thyroidectomy and, in addition, injectedwith 1 @ic.of 1131. The development of these adenomascould be largely prevented both in rats that were subtotally thyroidectomized only, and in those also giveninjections of 1 @c.of J131, by feeding them desiccatedthyroid powder. Two papillary carcinomas were observed in thyroid glandular remnants of 68 rats subjectedto subtotal thyroidectomy alone. One papillary carci

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of early fibrosis, later compensatory hyperpla.sia withadenoma formation, and eventually colloid goiters.

Bustad et al. (9) encountered thyroid adenomas and afibrosarcoma in five sheep that were exposed to 5 @c.ofIll' per day for their lifetime. In a later study, Marksand Bustad (62) found thyroid adenomas in eleven sheep,4—8years old, that had been fed daily quantities of I's'ranging from 1.5 to 135 tic. The exposure was either continuous from conception or was initiated at 15 months ofage. Thyroid adenomas in control animals were limitedto those 10 years of age or older. The patterns of theseadenomas in irradiated sheep thyroids were macro- ormicrofollicular, trabecular or papillary. Several showedinvasive perforation of their capsules, and two showedintravascular invasion. One thyroid neoplasm was apoorly differentiated follicular carcinoma that had metestasized widely to the liver, cervical lymph nodes andother sites.

Andersen (1) described thyroid adenomas in five of eightdogs (beagles) after administration of 0.3—0.6mc. of I'@'/kg as a single dose.

THYROID NODULES IN CHILDREN FOLLOWINGTHERAPY WITH I's'

Thyroid nodules have been found in human beingsseveral years after they were treated with I's' for hyperthyroidism (75, 76). At the University of California Hospitals, such nodules were discovered in eight of 256 patientswith Graves' disease, 5—14years after the beginning ofI's' therapy. Six patients were less than 18 years of ageat the time of the I's' administrations, and two were between 25 and 30 years. Apparently, the younger thepatient, the greater the chance of development of thyroidnodules following I's' therapy for thyrotoxicosis. At thetime the nodules appeared, none of the patients was hypothyroid, and none had been treated with thyroid hormone.

Histologic examination of the glands of these eight patients revealed typical irradiation effects in their thyroidparenchyma. The lesions consisted of follicular atrophy,perifollicular fibrosis and mild chronic inflammatory infiltration. As a rule the remaining thyroid epithelial cellsin the irradiated thyroid lobules displayed severe Askanazy changes. Pronounced activity of a number ofintracellular enzymes was demonstrated in these Askanazycells by histochemical methods (52, 75, 76). The nodulespresent seemed to have originated mainly in focal hyperplastic and regenerating segments of the lobules. Thenodules varied from microstructures to grossly visible andpalpable nodules measuring up to 2 cm. or more in diameter. The majority of the nodules had macrofollicular ormicrofofficular patterns, but some were trabecular. 0thers showed papillary hyperplasia. One nodule showedextension of neoplastic epithelium beyond the capsule, aprocess regarded as evidence of an early, low-grade carcinoma (75). In another patient, the neoplastic tissueextended into the capsule of the nodule (76). In six ofthe eight glands the pattern of Hashimoto's thyroiditiswas also present, and in one gland, which showed the mostpronounced thyroiditis, a similar inflammatory reactioninvolved the nodules as well as the parenchyma. Similarnodules with trabecular and follicular patterns have been

observed in nonirradiated thyroid glands after surgicalthyroidectomy. Askanazy changes both in epithelial cellsof the nodules and in the parenchyma of these glands wereas pronounced as those seen in irradiated glands.2 Thesefindings indicate that the Askanazy changes are only indirectly due to irradiation and presumably represent aneffect of prolonged stimulation by thyrotropic hormone.Nodules did not occur in patients who developed hypothyroidism following I's' therapy for thyrotoxicosis, afinding which suggests that, in these individuals, theadministered radiation had so injured the gland that itwas rendered incapable of regeneration and nodule formation (76). The glands in these patients resembled thoseof rats that had received higher doses (400 j@c.)of I's' (54).Although some epithelium remained and, as a rule, displayed distinct Askanazy changes, it showed little or noevidence of regenerative activity.

It has been recommended that young patients not betreated with I's' for thyrotoxicosis because of the possibledevelopment of thyroid neoplasms. If such treatmentshould be necessary, doses large enough to destroy allthyroid tissue completely should be administered so thatregeneration and nodule formation will be prevented (76).

RELATION OF IRRADIATION OF THE HEAD ANDNECK AREA IN CHILDREN TO DEVELOPMENT

OF THYROID CARCINOMAS

The possibility of a relation between irradiation of thethymus gland in infancy and the subsequent developmentof thyroid carcinoma was first pointed out by Duffy andFitzgerald (21). Ten of their 28 patients who developedthyroid carcinomas before 18 years of age had had theirchests irradiated during infancy for thymic enlargement.Clark (11) later reported that in all fifteen children hetreated for thyroid carcinoma, x-rays had been applied totheir head and neck or upper thorax during their first 6years. The interval between irradiation and the diagnosisof thyroid carcinoma ranged from 3 to 10 (average, 7)years.

Among 1400 of 1722 children whose thymus glands hadbeen treated with x-rays between 1925 and 1951, Simpsonet al. (79) found seven cases of leukemia and six of thyroidcarcinoma. This incidence of neoplastic disease was muchhigher than that among either the children's untreatedsiblings or the general population. Simpson and Hemplemann (78) later investigated these same 1722 children whohad received roentgen-ray irradiation in the thoracic areaduring infancy. Of these, 1502 were traced for subsequent study. Nineteen had developed thyroid carcinomas, and six were found with thyroid adenomas. Theseinvestigators concluded that their study provided strongcircumstantial evidence for the view that therapeuticirradiation is an etiologic factor in thyroid cancer in children and adolescents. They indicated that the x-raydosages employed were generally smaller than thoseusually considered harmful.

Fetterman (22) reported on ten children with thyroidcarcinoma; eight had received irradiation to the neck 3—12years previously. Three of eight patients under 14 years

2 5@ Lindsay, unpublished data.

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of age, with thyroid carcinoma, were reported by Buckwaiter (8) to have received radiation for thymic enlargement. Ten of fifteen childhood thyroid cancer cases wereshown by Majarakis et al. (60) to have a history of irradiation to the head or neck administered between 2 monthsand 6 years of age. The doses of irradiation varied between 200 and 625 r. Of the fifteen patients, five wereover 15 years of age at the time of diagnosis, and none hadbeen irradiated. All under 15 years of age at the time ofdiagnosis had been irradiated.

In a study of 100 cases of thyroid carcinoma, Kilpatrick et al. (48) found that three of eight patients whohad developed thyroid carcinomas before 35 years of agepresented a history of irradiation of the neck duringchildhood.

In their study of eleven cases of thyroid carcinomas inpatients under the age of 21, Petit et al. (67) found thatnine had received irradiation of the head and neck areasbetween 1 and 8 years of age; the carcinomas were discovered 4—14years later. Wilson and Asper (89) described thyroid carcinomas in seven patients, including twochildren, all of whom had had preceding irradiation of theneck. Rooney and Powell (72) found that seven of tenpatients under the age of 17 years, with thyroid carcinoma,had received previous irradiation of the neck. Latouretteand Hodges (50) reported that in 1867 of 1958 patientsirradiated in the thymic region, malignant lymphomasdeveloped in two and a thyroid carcinoma in one. Theseinvestigators suggested that the increased incidence ofneoplasia resulted from the irradiation.

Wilson et al. (90) note that of 37 patients under the ageof 25, with thyroid carcinoma, sixteen, or 43 per cent, hadbeen previously irradiated. In the patients under 17years of age, 72 per cent had had their head, neck, orupper chest irradiated, whereas only 3 per cent of thepatients over 17 years of age received such irradiation.These findings led Wilson et al. (90) to conclude that theincidence of preceding irradiation was significantly higherin children with thyroid carcinomas than in the generalhospital population and that x-rays can be a causativefactor in the development of thyroid carcinomas in youngpersons.

A group of 2300 children whose thymus glands had beenirradiated between the years 1925 and 1951 was studied bySimpson (77). Ten thyroid carcinomas and nine thyroidadenomas were detected in those who had received morethan 200 r. The smallest ports employed measured6 X 8 cm. No thyroid neoplasms were encountered inthe untreated siblings. The younger children who developed thyroid tumors were all boys, whereas the olderones were mostly girls. Conti et al. (12) studied 1564children, 95 per cent with normal-sized thymus glands and5 per cent with enlarged thymus glands. Between 1938and 1946 the former received 75—100r of x-rays as aprophylactic radiation procedure, and the latter were given200-450 r. The ports measured 4 X 4 cm. Conti et al.(12) found that, whereas the incidence of malignant neoplasms was not significantly lower than in the group ofuntreated siblings, the incidence of thyroid carcinomawas significantly below that in children treated throughlarger ports.

Howard (46) reports on three children with thyroidcarcinomas, all of whom had had their necks irradiatedduring the first year of their lives. Saenger et al. (74)studied the medical histories of 1644 patients out of 2230in whom the head and neck areas had been irradiated during infancy and childhood, and compared them with thoseof 3777 untreated siblings. Although eleven cases ofthyroid carcinoma were found in the irradiated group andone in sibling controls, and although thyroid cancer appeared to increase significantly following irradiation (ascompared with the general population), these authorsconcluded that irradiation was not the sole factor responsible for the increased tumor incidence, but rather a contributing one. Winship and Rosvoll (91, 92) showed that,in 562 patients in whom thyroid carcinoma had appearedbefore the age of 15, 79 per cent of those from whom histories were obtained received irradiation during infancy orchildhood. Malignant neoplasms appeared about 9 yearsafter irradiation.

Eight of Cahan's and Venet's3 25 patients who developedthyroid carcinomas after irradiation for benign neck conditions had been treated after the age of 18. The cancersdeveloped more than 6 years after the irradiation.

Beach and Dolphin (4) summarized the findings ofSimpson et al. (79), Simpson (77), and Latourette andHodges (50). Twenty-three malignant and sixteen nonmalignant thyroid neoplasms were encountered among4673 irradiated children. Those with thyroid carcinomahad received between 90 and 1270 rads absorbed in thegland, whereas those with benign thyroid nodules had received between 70 and 630 rads. The mean latent periodafter irradiation was 11 years, but the actual period mighthave been as long as 25 years. No significant differences inlatent period distribution were observed: (a) between casesin upper and lower dose ranges, (b) between cases treatedbefore 1 year of age and those treated after 1 year; and (c)between sexes. On the basis of the dose-response (a linearrelation was assumed) Beach and Dolphin (4) indicated anincidence of about 1 .7 per cent per 500 rads.

Among 458 patients whose necks had been irradiated forbenign conditions (mainly enlarged thymus glands, toxicgoiter, and tuberculous adenitis), Hanford et al. (44) reported that the actual number of thyroid cancers far exceeded the expected number. A significant increase inthe incidence of thyroid carcinoma was found only in thegroup suffering from tuberculous adenitis. These cancersoccurred 10—27years after irradiation. The radiationdoses were between 500 and 1500 r.

Among 216 patients affected by thyroid carcinoma,Rose et al. (73) reported that 70 gave a history of priorirradiation to the head and neck. Two children under 10years of age, thirteen of seventeen under 15 years of age,and twenty of 23 under 20 years of age at the time of dingnosis gave such a radiation history. The latent intervalbetween irradiation and apparent onset of thyroid carcinoma averaged 12 years. These authors suggested caution in the use of irradiation in the management of benignconditions of the head and neck of infants and children.

S@ G. Cahan, and L. Venet, Carcinoma of the Thyroid Follow

ing Radiation Therapy for Benign Head and Neck Conditions (tobe published, cited by Hanford et at. [441).

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A recent report of Toyooka and co-workers (83, 84) andPifer et al. (68) deals with the incidence of tumors among2809 children who had been treated with x-rays for thymicenlargement during infancy. Benign and malignant thyroid neoplasms comprised about half (43 per cent) of alltumors found. These workers encountered nine thyroidcarcinomas and 21 adenomas, six of the latter beingregarded as possibly malignant. The incidence of thyroidtumors was considerably higher in patients who receivedhalf the radiation anteriorly and half posteriorly than inthose who received the entire dose anteriorly.

Thyroid carcinoma may also follow irradiation formalignant disease of the head and neck area. Raventosand Duszynski (71) described two instances of thyroidcarcinoma that appeared 7 and 11 years after irradiationfor medulloblastoma.

Despite the considerable body of evidence cited above,favoring the view of a relation between irradiation of thehead and neck during infancy and childhood and subsequent development of thyroid carcinoma, Uhlmann (85)denies such a relation and cites a number of reports ofthyroid carcinoma in which previous irradiation was notmentioned. One of these reports was from the Universityof California Hospitals (13), where the majority of patientshad been studied before the initial report of Duffy andFitzgerald (21). Since 1950, however, a significant number of patients at the University of California Hospitals,under the age of 21 and found to have thyroid carcinomas,particularly of the papillary type, had histories of previousirradiation of their head and neck areas (51). Uhlrnann(85) cites a number of instances in which thyroid carcinomas were already present in children referred to him forirradiation of adenoid tissue, and expresses the belief thatthyroid carcinomas found after irradiation probably hadbeen present at the time of irradiation therapy. Uhlmann(85) also states that the amount of irradiation applied forthe treatment of thymic enlargement is generally less thanthat received during chest fluoroscopy and that the thyroidgland receives only scattered radiation. Recently, Garland (27) studied 1780 patients who had received thymicirradiation, and he also denies an etiologic connection between irradiation of the neck area and development ofthyroid carcinoma.

RELATION OF EXTERNAL IRRADIATION OFHEAD AND NECK AREAS IN ADULTS TODEVELOPMENT OF THYROID CARCINOMA

Thyroid cancer following external irradiation of thehead or neck has been observed on a few occasions inadults. As early as 1949, Quimby and Werner (70) wereconcerned with the question of the late development ofthyroid neoplasia from irradiation. In surveys made byradiologists and thyroid specialists they found ten cases inwhich carcinomas in the thyroid gland had developedafter irradiation with x-rays for hyperthyroidism ; but inonly three did they concede the possibility that irradiation might have been responsible for development of thethyroid carcinomas. Later, Jelliffe and Jones (47) reviewed eleven cases of thyroid carcinoma that appeared atintervals ranging from 8 to 41 years after application ofexternal x-radiation to the neck. In eight patients

x-radiation had been administered for thyrotoxicosis, inone for “thyroid swelling,― in another for tuberculouscervical lymphadenitis, and in one for a keloid. Of 293patients with thyroid carcinoma reported from the University of California Hospitals, two had been previouslytreated with x-rays during adult life for diffuse toxic goiter(51). Willis (88) discussed three patients treated withirradiation for thyrotoxicosis who, after a significantlatent period, developed thyroid carcinoma. Since allthree patients were females and since the carcinomas weresimilar to those occurring in nonirradiated thyroid glands,Willis was reluctant to ascribe their development toirradiation.

That thyroid irradiation in the adult can cause carcinoma still lacks proof, but the implications that such isthe case are nevertheless suggestive. The probabilityseems greater in children because mitotic growth of thechild's thyroid gland may be a promoting factor in thedevelopment of thyroid carcinoma, whereas mitotic activity does not occur in the normal, adult thyroid gland(18). The occurrence of occult scierosing carcinomas, insome instances of multicentric origin, in nonirradiatedhyperplastic glands of patients with thyrotoxicosis maycast some doubt upon the relation of irradiation forGraves' disease to the subsequent development of thyroidcarcinoma. Such small scierosing carcinomas might conceivably grow slowly for many years before becomingevident clinically.

Recently, Socolow et al. (80) presented data suggesting asignificant correlation between irradiation exposure during the atomic bombing in Japan and the development ofthyroid carcinoma. Of their nineteen patients, eightwere under the age of 21 at the time of the exposure.Hollingsworth et al. (45) found twelve patients withthyroid carcinoma in the Hiroshima Adult Health StudyGroup. These constituted 7 per cent of the total numberof patients with thyroid disorders. The frequency ofthyroid nodules was greater among those more closelyexposed to the radiation than among the less closelyexposed. Despite the greater number of thyroid malignancies among the most heavily exposed, the differencesbetween groups with different amounts of exposure werenot statistically significant. These investigators suggestcaution in interpretation of the data in their report.

RESUME

The mode of development of benign and malignant neoplasms in thyroid glands of rats given injections of I@(10-40 Me.) (54, 55, 69) and in glands that had been x-radiated (500—2000 r) (56) resembles that of adenomas andpossibly of a low-grade follicular carcinoma in humanthyroid glands that were irradiated with P3' (75, 76). Forexample, the parenchyma of rat thyroid glands irradiatedwith Jill or x-rays closely resembles that of human thyroidglands irradiated in a similar fashion. In both cases cvidence of irradiation injury, Askanazy changes in epithelialcells, chronic thyroiditis, and the development of neoplasms have been observed. In the human being anamount of irradiation comparable with that which regularly induces thyroid carcinomas in rats is generally de

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LINDSAY AND CH@uKoFF—Effects of Irradiation on the Thyroid Gland 1105

livered by I― or x-radiation in treatment for diffuse toxicgoiter.

In contrast, the development of malignant thyroid neoplasms in the rat 2 years after administration of only 1 .ic.of I@ appears comparable with the situation in children inwhom malignant neoplasms were found some 7—10yearsafter irradiation of their thymus glands, cervical lymphnodes, or nasopharyngeal lymphoid tissues. No cvidence of radiation injury or Askanazy changes in thethyroid epithelial cells are found in rats that received thesevery small ( 1 j.ic.) doses of J131•Neither are degenerativechanges that can be ascribed to irradiation evident in thethyroid glands of children developing thyroid carcinomafollowing thymic irradiation, although these malignantneoplasms have probably been initiated by such radiationtherapy. These findings suggest that, both in rats thatreceived small doses of J131(1 j@c) (34) and in infants andchildren who received low levels of irradiation in thethyroid area, a direct, nonlethal mutant effect on thyroidepithelial cells, caused by radiation, may be responsiblefor initiation and development of malignant thyroid neoplasms. The finding of chromosome aberration afterirradiation of other tissues by either x-rays (7) or Jill (59)indicates that such cellular mutations are possible.

ACKNOWLEDGMENTS

These investigations were supported in part by a contract withthe United States Atomic Energy Commission. The valuableassistance of Mr. C. W. Nichols, Jr., in the preparation of thebibliography is gratefully acknowledged.

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