TREATMENT OF RADIATION-INDUCED NODULAR GOITERS

ZsoltG. de Papp,RalphA. Pincusand LouisH. Hempelmann University of Rochester School of Medicine and Dentistry, Rochester, New York

Retrospective and prospective epidemiological all patients presented to palpation as solitary or mul studies have shown that prior radiation exposure is tiple nodulesrangingin size from somethat were an important factor in the development of barely palpable to one massive nodular goiter meas cancer and multinodular goiter in adolescents and uring 6 X 8 X 2 cm. Prior to start of therapy, all young adults (1 ) . In retrospective studies of young patients were examined at least twice by the two persons with thyroid cancer, a history of antecedent senior authors to check on the accuracy and re radiation therapy to the neck or upper chest can producibility of the clinical findings. In each patient usually be elicited by specific questioning (2) . In with a palpably abnormal gland, the serum PB! and prospectivesurveysof selectedpopulationsof young 24-hr 131Juptake were determined, and a “scintiscan― adults with known radiation exposure, the incidence of the gland was carried out. In all but one patient, of neoplasticthyroid diseasecan be remarkably there was no evidence of . high (1 ) . For example, in the 19 young Marshall In seven patients with nonfunctioning, fixed, stony, Islanders whose thyroid glands were heavily irradi hard or rapidly enlarging nodules, surgery was per ated during childhood by radioactive fission products formed. This was followed by suppressive therapy from a nuclear explosion in 1954, 15 or 78% de with L-thyroxin (0.2 mg daily) for 10 days; then, veloped nodular by 1967 (3) . Simi the daily dose was increased to 0.3 mg if the patient larly, in a subgroup of persons in Rochester, New had no toxic symptoms. Nineteen additional patients York, treated with x-rays in infancy for alleged with suppressive therapy were treated. without sur thymic enlargement,almost 5% have developed gery. The remaining three patients who refused thyroid cancer and 28% , nodular thyroid disease treatment were examined repeatedly several times a (4,5). year. In studying the Rochester subgroup with a high After 3 months of treatment with 0.3 mg L-thy risk of developing nodular thyroid disease, the cmi roxin daily, the patients were reexamined to deter cal managementof patientswith radiation-induced mine changes in the size of the gland and nodules nodular lesions became an important consideration. and to check for clinical evidence of toxicity. The The question that arose was whether all such lesions dose of 0.3 mg was well tolerated by all but one should be removed surgically or whether careful patient whose daily dose had to be reduced to 0.2 followup alone or combined with suppressive thyroid mg. If the thyroid lesions did not respond after 6 therapy would be sufficient. The present report deals months of therapy, the PB! and 1311uptake were with the authors' experience with the clinical care rechecked to determine the degree of suppression of of 29 patients in the Rochester series with radiation thyroid function. induced nodular thyroid disease. RESULTS METHODS Surgery followed by suppressive therapy with thy Of the 105 young adults in the high-risk, thymus roxin (Table 1). Seven patients were treated surgi irradiated subgroup (5), 35 are known to have or cally (Case 1603F in Table 3 was not included in to have had nodular goiters.All patientshad re this group because of the long period of suppressive ported no thyroid problems on a mail questionnaire therapy preceding surgery) . On the initial examina in 1963. Twenty-nine of these patients are consid tion, the findingsin five patientswereconsistentwith ered in this article; the other six have been lost to followup or have not been followed long enough Received July 23, 1969; revision accepted Feb. 5, 1970. to merit inclusion in this study. Except for one gland For reprints contact: Louis H. Hempelmann, The Uni versity of Rochester School of Medicine and Dentistry, 260 that was diffusely enlarged, the thyroid lesions in Crittenden Blvd., Rochester, N.Y. 14620.

496 JOURNAL OF NUCLEAR MEDICINE TABLE 1. SURGICALLYEXCISED NODULES*

CaseAgeMonthsNo/Sex(yr) Initial physical findings HistologyCurrent status postoperative

0347M 26 50-gm nodular gland, very Macrofollicular New 4-cm cysticlesion 3 yr after thy 50 mo. firm, It. lower lobe nodule adenoma roidectomy while on continuous sup pression with Proloid 2 gr and L-thyroxin 0.2 mg; shrank to 3 cm on most recent exam 1789F 17 Hard 0.8-cm nodule in rt. Focal adenomatous Not on thyroid for first 24 months post 60 mo. lobe hyperplasia operative; now on L-thyroxin 0.3 mg; no new nodules 3024F 34 3-cm firm nodule in It. lobe. Colloid nodule and Private physician says no new nodules; 10 mo. Nonfunctional on scan follicular adenoma 1 gr thyroid 164SF 26 3-cm firm nodule in rt lobe. Adenoma On 0.3 mg L.thyroxin, no palpable 27 mo. Nonfunctional on scan thyroid tissue 0368M 26 1.5-cm stony, hard nodule Follicular adenoma No thyroid treatment for first 40 months 58 mo. in It. lobe with ossification postoperative;on re-examination re sidual rt. lobe is enlarged; after L-thyroxin therapy (0.3 mg daily) gland shrank 1735M 24 Massive goiter > 125 gm Adenomatous goiter On 2 gr thyroid; only remnant of gland 39 mo. post-traumatic palpable 0385M 31 Granular gland. Four years Papillary and follicu On 0.3 mg L-thyroxin; no palpable 20 mo. later, 2 cm stony, hard br carcinoma rt. residual tissue; no metastases cvi nodules in rt. lobe; soft lobe dent 3.5-cm nodule on left; both were nonfunctional on scan.

* Nodules were functional on scintiscan unless otherwise indicated. thoseof malignantdiseaseand, in the sixthpatient, 1% of the 13lJ administered at this time was taken an enormous goiter was present. The weight of the up by the gland indicating that thyroid function was excised thyroid tissue of the last patient exceeded completely suppressed. The patient refused a second 125 gm. The lesions of all six patients proved to be operation. benign on histologic examination. In the seventh Suppressive therapy without surgery. Nine patients patient (0385M), the initial examination revealed with solitary nodules, nine with multinodular glands a normal sized gland with multiple small lobulated and one with a diffusely enlarged gland were treated areas. Since no definite nodules or changes in con with levothyroxin. sistency could be found, it was decided to follow Patients with solitary nodules (Table 2). The nod him without therapy. The patient did not return for ules of all patients were “warm―on scintiscan. All examination by the authors for 4 years by which but the one patient mentioned above were able to time two stony, hard, nonfunctioning nodules were tolerate 0.3 mg of L-thyroxin daily. Even though the present. A total thyroidectomy was performed and daily dose was reduced to 0.2 mg, the thyroid nod a papillar-follicular carcinoma was removed; there ules of this patient (Case 1722M) regressed almost was no evidence of metastasis. All patients were completely. In one patient ( 1728F) there was a given levothyroxin to suppress function of the re complete spontaneous regression of a sizable nodule maining thyroid tissue. during a 3-year observation period prior to treat Repeated examination of five of the patients over ment. When the lesions recurred 1 year later, treat periods up to 60 months disclosed no recurrence of ment with thyroxin was begun. the nodular lesions. One female patient (Case 3024) The lesions in all but one patient responded to did not return to us but her private physician re therapy by shrinking to less than half of the initial ported that there was no recurrence of nodularity 10 size. In two patients under treatment, the lesions months after thyroidectomy. Three years after sur disappeared completely and in three others, almost gery, one patient (0374M) on suppressive therapy completely. In three patients, the nodules were re (Proloid 2 grains and thyroxin 0.2 mg), developed a duced in size to about half that observed at the onset cystic lesion in the remnant of the thyroid gland. of treatment and, in one patient, the size of the The cystic lesion transilluminated readily. Less than nodulewas unchangedafter 10 monthsof therapy.

Volume 11, Number 8 497 DE PAPP, PINCUS AND HEMPELMANN

The last patient was pregnant, and it is possible that disappeared and then reappeared. At the last exami this might have had something to do with the failure nation, only the smooth residual left lobe could be to respond. In one patient ( 161 SM) the size of the palpated. initial lesion decreased to about half during 20 Complete remission was not achieved in any pa months of treatment but a small new nodule ap tient, but partial response occurred in all but two peared. cases. In three patients, the response to treatment Patients with multinodular goiters (Table 3). The was good with almost complete disappearance of nodulesof most patientswere diagnosedas func the lesions;in four, the lesionsbecamesomewhat tional on scan, but hypofunctional nodules were dis smaller and, in two, there was little, if any, response. covered in two patients. In four patients, the thyroid In one patient showing a partial response,the dose gland was normal on the initial examination but of thyroxinwas increasedto 0.4 mg and in another becamemultinodularduring pretreatmentfollowup a presumptive diagnosis of Hashimoto's disease was periodsof 1—3½years.In one patient with a dif made on the basis of the antithyroid antibody titer, fusely enlargednodular goiter, there was complete a normal PB!, an elevated 24-hr 131! uptake and spontaneous remission with recurrence of the lesion lack of TSH dependence.in one patient whosele 1 year later. While under treatment, the nodules sions did not respond during 4 years of complete

TABLE 2. SOLITARY NODULES

atDurationCaseAge of thyroid glandFollow exam up T@R1 therapy No./Sexinitial(yr)DescriptionResponseInitialStart of therapy (mo.)Dose(mg)of (mo.) Results

1615M 29 Normal gland (4 yr later) 71 0.3 20 Rt. lobe nodule now Partial 4-cm nodule rt. 1.5 cm; new 0.5- lobe; PBI 4.4, RAI cm nodule in 18% isthmus 1728F 25 2.5-cm nodule, It. (4 yr later) 64 0.2 17 Normal gland Complete lobe; 3 yr later, 0.5-cm isthmus gland normal nodule; PBI 6.2, without R@ RAI 37% 1724F 27 2.5 X 3.cm nod (3 yr later) 69 0.3 32 1 X 1.5-cm nodule. Partial ule, rt. lobe Diffusely enlarged rt. lobe (pregnant) (X 1'@)gland with 2 X 3 cm rt. lobe nodule; PSI 4.7, RAI 33% 1798F 21 2-cm nodule rt. (1 mo. later) 32 0.3 31 NI. gland Complete lobe; PBI 5.3, 2-cm nodule rt. RAI 11% lobe; PBI 5.3, RAI 11% 1807F 20 0.5-cm nodule In (3 yr later) 43 0.3 7 1-cmnodule, It. Partial isthmus; PBI 2-cm nodule, It. lobe 8.1, RAI 36% lobe; PBI 6.3, RAI 35% 1799F 21 Normal gland; (1 (2 yr later) 34 0.3 10 No change (pa Poor yr later) 0.5-cm 1.0-cm nodule in tient pregnant) nodule in isth isthmus mus;PBI4.0 1722F 26 NI gland (3 yr later) 64 0.2 28 Only an indurated Almostcomplete 1 X 1.5-cm nodule area; It. lobe rt.lobe;RAI 35% 1744F 21 2-cm nodule, rt. (5 mo.later) 31 0.3 26 > 0.5-cm nodule, Almostcomplete lobe; PBI 4.9, Same. Patient dis rt.lobe RAI 20% continuedthyroxin for 4 mo. 1805M 29 1.5-cm nodule, rt. (1 mo.) 14 0.3 13 > 0.5-cm nodule, Almostcomplete lobe; PBI5.2, Same rt.lobe RAI 23°!.

. All nodules were functional on scintiscan.

498 JOURNAL OF NUCLEAR MEDICINE TREATMENT OF RADIATION-INDUCED NODULAR GOITERS

TABLE 3. MULTINODULAR GOITERS

atDoseDurationCaseAge thyroid gland°Follow exam up roxin therapy No/Sexinitial (yr)DescriptionofResponseInitialStart of therapy (mo.)L-thy(mg)of (mo.) Results 1603F 36 4-cm nodule, It. Treatmentstarted 62 0.3 48 No change in nod Poor;subtotal lobe; 2 small after initial exam ules;complete thyroidectomy nodules in enl. suppressionof after 4 yr of rt.lobe RAI function; 3% RAI Rx;multiple 24%; all nod uptake microfollicular ules @warm― and papillary adenomas with chronic inflammation and fibrosis 1694M 20 2-cm nodule, ii. (3 yr later) 64 0.3 6 Nodule in it. lobe Partial lobe; 1-cm nod Rt.lobe,4cm; 0.4 16 2.5 X 1-cm; ules in It. lobe other nodules Un other nodules and isthmus Pt. changed; PBI, 3.2 smaller refused treat mg; RAI 14%; one ment initially nodule hypofunc tional 1642M 18 Normal (3 yr later) 47 0.3 14 Onlyslightreduc Poor Nodules, 2.3 cm in tion in gland both lobes size; all nodules still prominent 1674F 29 Glanddiffusely (3 yr later) 68 0.3 33 After R. for 1 yr Almostcomplete enlarged X 3 distinctnodules nodules disap normal peored but reap peared 1 yr later; only residual left lobe now palpa ble, no nodules 1711F 18 Normal gland (2 yr later) 60 0.3 3 No nodules Partial (Hashi 1 X 2-cm nodule ot 2 moto'sdis in It. lobe; (3@/2yr 0.2 6 ease) antithy later) multiple nod of 2 roid A.B., ules; PBI4.6; 0.2 5 h512 RAI 62%; no TSH 18 response 1783F 23 Normal (1 yr later) 28 0.3 13 3 nodules < 1 cm Partial 1.5 X 2-cm nodule If. lobe; no nod in each lobe; PSI ules in rt. lobe 7.0; RAI 23%; ii. nodule hypofunc tional on scan 1784F 26 Diffuselyenlarged (2 yr later) 68 0.3 33 After 1 yr of R., Almostcomplete with nodules in Complete spon nodulesdisop both lobes; PSI taneous regression; peored but reap 6.2, RAI 26%; (3 yr later)sameas peored 1 yr later; all nodules on initial exam now no nodules and only residual It. lobe palpable 1794F 25 2-cm nodule, It. (2 yr later) 61 0.3 33 Only 0.5-cm nodule Almostcomplete lobe; 0.5-cm Same as on initial in isthmus re nodule, isth exam mains mus;PBI6.3, RAI 24% 3375M 30 Normal (2 yr later) 40 0.3 10 Hard nodule, < 1 Partial 2 nodules1 X 1.5- cm remainsin cm in isthmus;PSI isthmus;? palpa. 5.0, RAI21%; ble IgI. both nodules warm lymph node

S All nodules were functional except where indicated. t Treatmentwas discontinuedby the patient@sobstetricianduring pregnancy.

Volume 11, Number 8 499 DE PAPP, PINCUS AND HEMPELMANN

TABLE 4. DiFFUSELYENLARGED GLAND

of ofNo/Sex(yr)Cas.AgeInterval followupDose and duration Initial physicalfindings (mo.)L-thyroxin treatment Results Response

0384F 30 NoComplete(2—3X)lobulargland;PBI0.3mgnodules,diffuselyenlarged 442 grthyroid for 14 mo.; Normal gland mo.2J T4 for1

TABLE 5. UNTREATED PATIENTS WITH NODULES°

of followupNo./Sex(yr)CaseAgeInterval Initial physical findings (mo.)Current status Change

NodulebarelyMinimalpalpable.0407M300.7-cm1711M190.5-cm nodule in isthmus42Slightly enlarged gland.

lobe49UnchangedNone0402M2750-gmnodule rt. rt.upperlobeProgression. firm gland; two 1-cm 2-cmnodule in in isthmusnodules30New

Allnodules were functional on scintiscan.

suppression of thyroid function, partial thyroidectomy induced cellular damage, presumably chromosomal was performed. Besides multiple microfollicular in nature. The second or promoting factor is stimu and papillary adenomas and a large cyst, the dis lation of the damagedbut viable cells to divide. eased tissues showed considerable fibrosis and Proliferation of these cells allows the inherent cellu chronic inflammation.The structuralchangescon lar injury to be expressedasgrossneoplasticlesions. sisting of fibrosis and cystic degeneration in the gland Since adult thyroid cells rarely divide spontaneously, of the last patient presumablyaccount,at least in mitosis must be stimulated by thyrotropic hormone part, for the lack of response. secreted by the pituitary gland. For the neoplastic Patient with diffuse goiter and hypothyroidism process to develop fully, thyrotropic stimulation must (Table 4). This 30-year-old woman with a diffuse be continued until the disease is well along into the goiter, low PB! and elevated TSH was clearly hypo malignant stage. Such neoplasms requiring continued thyroid. The goiter disappeared completely during stimulation are said to be hormone-dependent. the first year of therapy, and the gland has remained Studies in man suggest that the development of normal in size for 32 months. radiation-induced thyroid neoplasms also follows the Patients with nodules not given thyroid replace multistage transformation process just described (4). ment (Table 5). In two of these three patients, soli The extremely high incidence of chromosome aberra tary nodules did not change in size or consistency tions in cells cultured from surgically excised thyroid over observation periods of 42 and 49 months. In tissues of two of our patients ( 1603F and 0385M) the third patient, a new nodule 2 cm in dia appeared, irradiated many years before is indicative of pri and the two existing nodules increased in size during mary, lasting cellular damage (7). The striking in the 30-month observation period. crease in incidence of radiation-induced thyroid neoplasms during the teens in the total irradiated DISCUSSION Rochester population suggests that thyroid stimula The pathogenesis of radiation-induced thyroid tion during adolescence is the secondary or pro neoplasms has been thoroughly studied in rats by moting factor (4) . Similar stimulation of nonirradi Furth and his colleagues (6). They describe pro ated thyroid glands is sometimes manifested by the gressive change in the character of the lesions which development of so-called adolescent goiters. The begin as localized areas of hyperplasia, progress histology of the disease seen in these and other pa through an adenomatous stage to become ultimately tients (3—5)is heterogenous and includes a spectrum metastatic carcinoma. The studies in rats show that of lesionsranging from localized areas of hyper the pathogenesis of the neoplastic process involves plasia to frank carcinoma. The disease process is two steps. The first or primary event is radiation multicentric as can be seen on gross pathologic

500 JOURNAL OF NUCLEAR MEDICINE TREATMENT OF RADIATION-INDUCED NODULAR GOITERS examination even in those lesions which cmnically advanced stages represented by multinodular goiter, appeared to be solitary nodules. Since the neoplasms the lesions frequently did not respond as well. in these patients and in the total Rochester series Whether or not the thyroid cells at this stage have responded so well to treatment even when malignant, lost some of their dependency on thyrotropin stimu it may be speculated that the neoplastic process in lation is not known. It seems likely, however, that a young adults is still in the hormone-dependent stage. major factor in the failure of these lesions to respond In the present study, the question arose as to is due to associated structural changes, e.g., fibrosis treatment of the nodular goiters in these youthful and cystic degeneration, which is not affected by subjects. Therapy was particularly important in the treatment. Whether suppressive therapy will reduce case of the solitary nodules which, in the young, are the chance of malignant transformation of the lesions reported to be malignant in many cases (8,9). Sur is, of course, not known at this time. The develop gery was obviously indicated in those persons whose ment of a new nodule in Case 1615M and of a cyst lesions were suspected of being malignant on clinical in Case 0347M while both patients were on thyroid grounds, e.g., firm to palpation, fixed to adjacent medication suggests that the treatment may not structures, unable to take up 1311or associated with block completelythe progressionof the disease. enlarged regional lymph nodes. Alternative treat The case of hypothyroidism and presumed Hashi ment of those lesions considered to be benign was moto's disease merit comment. That the large doses to follow the patient closely without treatment or of 131! used to treat can cause hy with suppression of thyroid function by adm@nistra pothyroidism in a substantial proportion of cases is tion of thyroid hormone. Because of the relatively well known (17) . Even doses estimated to be 700— benign clinical course of all radiation-induced thy 1,400 rads of beta and gamma rays in the Mar roid neoplasms and their good response to surgical shallese children exposed to fission products in 1954 excision, the first course, i.e., careful followup with are presumed to be the cause of hypothyroidism in out treatment, did not seem unreasonable in selected two of the 19 children exposed before age 10 (3). cases. Our experience in the present study, however, In adult dogs, clinical is reported to indicated (see Table 5 and pretreatment period in develop several years after exposure of their upper Tables 2 and 3) that usually, but not always (see bodies to x-ray exposures as low as 1,000 R (18). Table 5) , the existing nodules •in the untreated pa Similar partial body exposure of a man to radiation tients enlarged and new lesions appeared. resulting from an accidental nuclear reaction was Although the alternative method of treatment, also followed by myxedema (19) . Therefore, the i.e., administration of thyroid hormone, has been hypothyroidism that developed in Case 0384F after used in treating goiters since the turn of the century exposure to 800 R in infancy is compatible with (9), suppressivetherapy of this type is often un other findings in irradiated man and animals. How satisfactory in the treatment of sporadic nodular ever, whether or not the development of Hashi goiter in older patients (10—15). In our youthful moto's diseasewas related to the x-ray treatment population with radiation-induced thyroid disease, is not known. This seems unlikely as analysis of however, there was reason to hope that replacement serum samples taken S years ago from the high risk therapy might cause regression by suppressing thy subgroup showed no abnormality of antithyroid rotropinsecretionof the pituitary.The rationalefor titer (20) . Also, the Marshallese patients showed this type of therapy is: first, the role that thyrotropin no abnormalities of antithyroid antibody titer. stimulation is suspected of playing in the pathogenesis In conclusion, the matter of the prophylactic use of the neoplastic disease and, second, the experience of suppressive therapy should be considered in all in rats given 131!which make it seem likely that thy persons with a high risk of developing nodular roid might prevent hyperplasia and subsequent neo goiters. In persons whose nodular lesions have been plastic transformation of the irradiated thyroid cells excised surgically, prophylactic use of thyroid hor (16). mone is clearly in order to prevent as far as pos Our experience with these patients indicates that sible regrowth of the non-neoplastic remnants or suppressive therapy is indeed useful in causing re further neoplastic transformation of the gland. In gression of thyroid nodules particularly when they our patients with glands that are normal to palpa present clinically as solitary lesions. In the early tion the issue is more complex. On theoretical stages, the disease process seems to be reversible as grounds, it can be argued that all of these subjects is indicated by the temporary spontaneous regression should have prophylactic treatment. Suppression of of nodules in two patients. Suppressive therapy in thyroid function might prevent hyperplastic disease such early lesions caused complete clinical regres and, presumably,neoplastictransformationof the sion. In the more extensive and presumably more irradiated gland as it does in rats (10) . It can be

Volume 11, Number 8 501 DE PAPP, PINCUS AND HEMPELMANN argued, however, that once treatment is begun, it for 4 months to see if her thyrotoxic symptoms must be continued throughout the life of the person would subside. By this time the right lobe nodule had since release of the pituitary gland from suppression begun to enlarge and had become nonfunctional on might cause increased secretion of TSH. Because scintiscan. At surgery a follicular carcinoma was of the good response of the lesions to surgery, how found with metastases to the regional nodes. ever, we have decided against prophylactic treatment. These patients will be followed closely and will be REFERENCES treated if nodules develop. This will give us a chance to determine how the disease develops as a function 1. Report of the United National Scientific Committee on the Effects of Atomic Radiation, Supplement No. 14 of age. It will also allow us to determine if these (A 5814), United Nations, New York, 1964, p. 91. patients outgrow the risk of developing neoplastic 2. WINSHIP, T. @i@wRosvoLL, R. V. : Study of thyroid diseases. The alternative is to commit these young cancer in children, Am. I. Surg. 102:747, 1961. personsto a lifetime of thyroid medication. 3. CONRAD, R. A., RALL, J. E. @i Strrow, W. W. : Thy roid nodules as a late sequelae of radioactive fallout in a SUMMARY Marshall Island population exposed in 1954. New Engi. I. The clinical management of 29 patients with Med. 274:1,391, 1966. 4. HEMPELMANN,L. H. et a!: Neoplasms in persons radiation-induced thyroid disease is described. Sur treated with x-rays in infancy for thymic enlargement. A gery was performed on seven patients whose lesions report of the third follow-up survey. I. Nat. Cancer Inst. were suspected clinically of being malignant. Only 38:317, 1967. one of these patients had carcinoma; postoperatively, 5. PiNcus, R. A., REIcisuN, S. @NDHEMPELMANN, L. H.: all were treated with suppressive doses of levothy Thyroid abnormalities after radiation exposure in infancy. Ann. Intern. Med. 66:1,154, 1967. roxin. Nineteen of the remaining patients were also 6. Fuim, I.: Vistas in the etiology and pathogenesisof treated with suppressive therapy. The clinical re tumors. Federation Proc. 20:865, 1961. sponse of solitary nodules was usually more com 7. DomA, Y. : Personal communication. plete than that of multinodular goiters. In five of the 8. SLOAN, L. W. AND FRANTZ, V. K. : Sporadic nontoxic nine patients with solitary nodules, there was com goiter. In The Thyroid, Werner, S. C., ed., 2nd ed., Harper and Row,NewYork, 1962,p. 417. plete or almost complete regression while in only 9. VANDER,J. B., GASTON,E. A. ANDDAWBER,T. R.: one pregnant woman was there no response. In Significance of@solitarynontoxic thyroid nodules. New Engi. three of the nine patients with multinodular goiter, I. Med. 251 :970, 1954. the response was almost complete, and in two, there 10. GREEx, M. A. @NiASTWOOD, E. B.: Treatment of was no response. The diffusely enlarged gland of a simple goiter with thyroid. I. Clin. Endocrinol. 13:1,312, patient with hypothyroidism also treated with sup 1953. 11. As@rwooD,E. B., CASSIDY,C. E. ANDAURBACH,G. C.: pressive therapy shrank to normal size. Two of the Treatment of goiter and thyroid nodules with thyroid. I. three untreated patients showed no progression of Am. Med. Assoc. 174:459, 1960. the lesions while one showed an increase in size 12. B@srnLLo,J. et a!: Treatment of nontoxic goiter with and number of nodules. Prior to onset of therapy, sodium liothyronine. I. Am. Med. Assoc. 184:29, 1963. there was complete spontaneous regression of two 13. FAWELL, W. N. AND CA@rz, B. : Non-toxic goiter treat ment with 1-triiodothyronine and 1-thyroxine. Calif. Med. nodular lesions with subsequent recurrence. 98:197, 1963.

The rationale of using suppressive therapy is dis 14. WELCH, E. C. : Therapy for multinodular goiter. cussed in terms of what is known of the pathogenesis I. Am. Med. Assoc. 195:339, 1966. of radiation-induced neoplastic disease of the thyroid. 15. SCHNEEBERO,N. 0. et al: Regression of goiter by whole thyroid or triiodothyroninc. Metabolism 11:1,054, ACKNOWLEDGMENT 1962. 16. MALOOF, F. : The effects of hypophysectomy and of This investigation was supported in part by research grant EC 00078 from the National Center for Radiological thyroxine on the radiation-induced changes in the rat thy (A 5814), United Nations, New York, 1964, p. 91. roid. Endocrinology 56:209, 1955. 17. HAGAN,0. A., QUELLErrE, R. P. @imCHAPMAN,E. ADDENDUM M. : Comparison of high and low dosage levels of @°‘Iin the treatment of thyrotoxicosis. New Engl. I. Med. 277:559, Since submitting our paper, Case 1724F has come 1967.

to surgery. As noted in Table 2, her gland initially 18. MICHAELSON, S. M., QTJINLAN, W. J. AND MASON, shrank on thyroid suppressive therapy. After having w. B.: Radiation-inducedthyroiddysfunctionin the dog. taken levothyroxin (0.3 mg qd) for 3 years Radiation Res. 30:38, 1967. without symptoms, she became nervous, tachycardic 19. HEMPELMANN, L. H. : The assessment of acute ra diation injury. In Diagnosis and Treatment of Acute Radi and lost weight over a period of several weeks. A ation Surgery, World Health Organization, Geneva, 1961, repeat serum thyroxin by column at this time was p. 49.

17.78 /Lg%. Suppressive therapy was discontinued 20. BARNETr, E. : Personal communication.

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