CLINICALSCIENCES

ThERAPEUTIC NUCLEAR MEDICINE PureFollicularThyroidCarcinoma:Impactof Therapyin 214 Patients

RobertL. Young,ErnestL. Mazzaferri,AltonJ. Rahe,andSteven0. Dorfman

Wilford Hall USAF Medical Center, Lackland AFB, Texas, Brooks AFB, Texas, and University of Nevada, Reno, Nevada

Recordsof 214 patientswith pure follicularthyroidcarcinomawere reviewed in detailto evaluatethe circumstancesof Initial presentationandtherapyon ulti mate outcome.Mean foIiowupwas 8.8 yr. The onlydeathsdirectlyattributableto the thyroidcarcinomaoccurredin patientswith distantmetastasesat the time of presentation.Therewere 20 recurrencesinthe 182 patientsconsideredfree ofdis ease after initialtherapy.Overallrecurrencerate was notaffectedbythe presence of positivecervical nodesor extent of thyroidsurgery.Postoperativerecurrence rate was decreasedby both radiolodineand thyroid-hormonetherapy. Extensive histologicinvasionof the capsuleof the noduleandthyroidappearedto be associ ated with an increase in recurrence rate. Postoperativethyroid-hormoneis re quiredtherapy in all patientswith pure follicularthyroidcarcinoma.Radioiodine therapy is indicatedin patientswith extensiveinvasionand we favor its use in all patients.

J NucI Med 21: 733—737,1980

It isgenerallyconsideredthatpurefollicularthyroid manner, reflecting the clinical situation as well as the carcinoma is more malignant than the papillary forms. bias ofthe attending physician. We evaluated the bearing Previous studies have indicated that a major determinant of clinical presentation, pathology, and various forms of in prognosis in follicular carcinoma is the extent of local therapy on survival and recurrence rate. Major emphasis invasion within the thyroid at the time ofdiagnosis (1, is on recurrence rate, since very few patients died of the 2). The relative role of various forms of therapy in de disease. termining prognosis is not clear. Reasons for the lack of clarity include the indolent nature of the disease and METHODS reportsemphasizingonlyoneor twoaspectsof therapy. We have previously discussed these concepts in detail for Details of method of analysis have been published papillary carcinoma (3). In addition, follicular carci previously (3). Basically, microfilm records of all pa noma is less common than papillary and it is difficult to tients entered into the armed forces tumor registry were acquire a series large enough for meaningful statistical reviewed by one of the authors. At the time ofour orig analysis. Some older series pooled mixed papillary-fol inal report, there were not sufficient patients with pure licular carcinoma with pure follicular, which even further follicular carcinoma for analysis. Since that time, the confuses analysis. registry was expanded to include some Army and Navy This report is a retrospective analysis of 214 patients hospitals in addition to new cases entered from Air Force with follicular thyroid carcinoma who were treated by hospitals. The pathologic classification used in this study a number of different physicians in many different was that approved by a committee of the American hospitals. Patients were treated in an individualized Thyroid Association with slight modification by Hazard (4). All surgical specimens identified as cancer, or pos sibly cancer, at any military hospital are routinely re Received Oct. 25, 1979; revision accepted March 3, 1980. For reprints contact: Colonel Robert L. Young, USAF, MC, viewed at the Armed Forces Institute of Pathology Chairman, Dept. of Endocrinology and Metabolism (SGHME), (AFIP). For the purpose ofthis study, the AFIP inter Wilford Hall USAF Medical Ctr., LacklandAFB, TX 78236. pretation was used. For inclusion here, all available

Volume 21, Number 8 733 YOUNG, MAZZAFERRI, RAHE. AND DORFMAN histologic material, including lymph nodes and recurrent of undifferentiatedsmall- or large-cellcarcinomain or metastatic disease, had to contain only follicular dc additiontothefollicularcomponents.Threeof thefour ments. subsequently have died of undifferentiated carcinoma. Tumor recurrence was judged to have occurred if a Statusof thepatientswasthat recordedasof March biopsy-proven lesion was documented in a patient con 1978. Only patients with at least 1yr of follow-up were sideredfreeofdiseasefollowinginitialtherapy.A patient included. Follow-up was obtained in 95% of patients. All was defined as being free of disease after therapy if the thoselostto follow-upwerefreeof diseaseat the time surgeon stated that all gross tumor was removed and that lost. Mean follow-up was 8.8 yr, with a standard devia physicalexamination2—3moaftersurgerywasnormal tionof 5yr. Meanagewas35±I2yr at thetimeof di except for postoperative changes. All recurrences were agnosis.Seventy-twopercent of the patients were initially identified as new abnormalities in the physical women. Men and women did not differ significantly (p examination or chest radiogram in patients who had > 0.1)in ages,clinicalpresentation,or recurrence,and normal examinations postoperatively. Four patients were the sexes were therefore combined for analysis. judged to have recurrence without histologic confirma Patients presenting with distant metastases. Seven tion. They were free of disease as defined above, and patients had distant metastases at the time of initial developed new clinically enlarged lymph nodes 2-5 yr diagnoses,andtheonlydeathsdueto follicularthyroid after initial therapy. The nodes were visualized with carcinomawerein theseseven.Their briefcase histories I- I31 scanning and disappeared after I- 131 therapy. follow. Extent of thyroid surgery was judged from review of Case 1. A 68-year-old man presented in 1967 with two operativereportsanddividedinto lobeandisthmusor vertebral fractures. In 1961 , he had had a subtotal thy less (limited thyroidectomy) compared with total thy roidectomy for thyrotoxicosis. Details of the specimen roidectomy.In manycases,it wasnot possibleto tell from this operation were not available, but no malig whetherthe total thyroidectomywasintra- or extra nancywasdiagnosed.Biopsiesof thevertebrae,andof capsular. For the purpose of the report, total thyroid the cervical and mediastinal lymph nodes, all showed ectomy means that the operative report indicated re follicular thyroid carcinoma. He had a total thyroidec moval of all or almost all thyroid tissue and the surgeon tomy, with no carcinoma identified in the thyroid. He stated that this constituted a total thyroidectomy. was treated with a total of 500 mCi of iodine-I 31 and Size of the malignant nodule and extent of capsular 2,300 rads of cobalt-60 to each bone lesion. Progressive orvascularinvasionofthemalignantnodulewasjudged involvement of the spine occurred, and he died 5 yr later from the original pathology report and AFIP report. at home. Only those with extensive description and specific Case2.A 79-year-oldwomanwithnopreviousknown comments about the degree of histologic invasion were thyroid disease presented with a pathologic fracture of used for analysis. Histologic invasion was classified as the pelvis. She had an enlarged left lobe of the thyroid. “little―if therewereonly a few isolatedmicroscopic The entire lobe was involved with follicular carcinoma, areas of infiltration of capsule, which did not penetrate which invaded surrounding musculature. There was no into the surrounding thyroid parenchyma. “Moderate obvious lymph-node involvement. No pulmonary lesions invasion―was defined as isolated microscopic areas of were definitely identified. She was treated with 190 mCi invasion through the capsule of the nodule, with minimal of iodine-i 31. She remained bedridden and had a pro or no infiltration of parenchyma. “Extensiveinvasion― gressive downhill course, dying ofcongestive heart fail was defined as several areas of microscopic and occa ure2yr afterdiagnosis.No autopsywasperformed. sionally gross capsular invasion, with extensive in Case3.A 43-year-oldwomanpresentedwitha6-mo volvement of parenchyma and vesselsoutside the capsule history of an enlarging sternal mass and a 3-mo history of the nodule. of thyrotoxicosis.On presentation,shewasclinicallyand biochemically thyrotoxic, with a large right lobe of the thyroid, a 5- X 7-cm sternal mass, and multiple pulmo RESULTS nary nodules. Total thyroidectomy and biopsy of the Of the I,500 patients with primary thyroid neoplasm mass both showed follicular thyroid carcinoma. Thyro in the registry, 2 14 ( I4%) were finally judged to have toxicosis recurred 1 mo postoperatively. Over the next follicular carcinoma. One hundred and sixty (40%) pa year, she received a total of 950 mCi of iodine- 131and tients initially diagnosed by local pathologists as follic 5,200 rads of cobalt-60 irradiation to the sternal mass. ular carcinoma were reclassified by the AFIP as mixed The mass resolved and there was a partial but transient papillary-follicular tumors. Reclassification was highest response in both the lung lesions and the thyrotoxicosis. in patients diagnosed before I970, but occasionally pa Ultimately, she was treated with methimazole and tients diagnosed after I970 were also reclassified. An combination chemotherapy. She died of pulmonary additional four patients were reclassified because the hemorrhage 2 yr after diagnosis. AFIP diagnosis indicated the presence ofdefinite areas Case 4. A 46-year-old man presented with a 3-cm

734 THE JOURNAL OF NUCLEAR MEDICINE CLINICALSCIENCES THERAPEUTIC NUCLEAR MEDICINE

thyroid nodule and multiple pulmonary metastases. 34 71@t0l.@ !)*;Mr@ ,@9 There were no nodes involved at the time of surgçrybut 31 there was local invasion of the tumor into the sur rounding neck muscles. He had a total thyroidectomy. Postoperatively he had a total of I75 mCi of iodine- 131 26 therapy and over 7,000 rads ofcobalt-60 to multiple lung 24 ports. He died 3.5 yr after diagnosis, ofpulmonary fail 22 @ ure with persistent carcinoma in the lung. 20 Case 5. A 69-year-old woman presented with a large @ multinodular thyroid with signs of local invasion and :: @ pulmonary metastases. The only histology available was ‘4 @ from an open thyroid biopsy, which revealed follicular I! I I*18@lI)P0t8& N I 6 thyroid carcinoma with no papillary elements. The pa 8 @ tient was treated with I00 mCi of iodine- I 3 1 and 3,000 -I @j'@ @- - - rads of cobalt therapy. She died of a myocardial in 6 @ farction I .5 yr after diagnosis. There was residual active 4 i; carcinoma in the lungs at the time of death. —,@o@——@ @ Cases 6 and 7. Two patients presented with a single I 1 4 S b 7 q so ii u ii i.. . 7

focus of apparently metastatic carcinoma, with no pri YI:,J( or mary found after total thyroidectomy. One patient was FIG.1.Cumulativerecurrencerate,dividedaccordingtotypeof a 57-year-old woman found to have a solitary lung medical therapy usedpostoperatively. nodule. She had had a subtotal thyroidectomy I I yr earlier for goiter. She was not told of any malignancy, cases. Recurrence rate in the 23 patients with nodules and the pathology report was not available. The lung under 1.5 cm was 10%,compared with 8% in the 79 pa lesionwasa well-differentiatedfollicular masshisto tientswith nodulesoverI .5 cm (p 0.86). Oneof the logically indistinguishable from normal thyroid. The five patients with nodules under 0.5 cm had a recurrence. other patient was a 43-year-old man with a similar his Neitherthepresenceof positivelymphnodesnorextent tologic lesion in the right humerus and no prior history of lymph-node surgery affected recurrence rate. Re of thyroid disease. Both lesions were surgically excised. currence rate was 7% with positive nodes as opposed to Neither patient had any primary found at time of total I 1%with negative nodes (p 0.42). thyroidectomy, nor were metastases visualized after Following initial thyroid surgery, prognosis was im iodine- I 3 1 ablation of all thyroidal uptake in the neck. proved by the use of both radioiodine and thyroid hor Both patients remain free ofdisease, at 3 and 8 yr after mone (Fig. 1). Patients were included in the groups with diagnosis. thyroid-hormone therapy only if they received the Patients presenting with disease confined to the neck. equivalent of three grains (I 95 mg) of thyroid hormone Baseline presentation of this group was as follows. or more. Two patients received two grains ( 130 mg) or Eighty-five percent presented with a solitary thyroid less and were excluded from the analysis. The highest nodule. Seventy percent of the nodules were less than 3 recurrenceratewasin theninepatientswhodidnotre cm in diameter. Nineteen patients had clinically palpable ceivepostoperativethyroid hormone.The lowestre lymphnodesand29hadhistologicallypositivenodes. currence rate was in the 51 patients who received both Among the 100 patients who had thyroid scans preop radioiodine and thyroid hormone postoperatively. Uti eratively, 73 had cold nodules, 21 had normal scans, and lizinga threefoldx2 analysis,the p valuefor lowerre six had patchy or irregular uptake. currence comparing iodine-I 31 plus thyroid, against One hundred and eighty-two patients had disease thyroid only, againstno thryoid therapy was 0.048. confined to the neck, were judged to be free of disease Analysis of each subgroup by x2 revealed a p of 0.056 after initial therapy, and had adequate information to for no therapy against thyroid hormone only; 0.28 for evaluatetheeffectof therapyonrecurrencerate.There thyroid hormone only against thyroid hormone and ra were 20 recurrences among these I82 patients. Eight dioiodine; and 0.01 1 for no therapy against thyroid recurrences were in the opposite lobe of the thyroid; ten hormone and radioiodine. The two patients who devel in regional lymph nodes, and two in distant sites (one o_ distant recurrence had only one lobe involved at lung and one lung and bone). Recurrences were scattered initial operation, and no adenopathy. They had total relatively evenly over the first 9 yr after therapy; 50% had thyroidectomies followed by thyroid hormone only occurred in the first 4 yr, and all but one by 9 yr. The postoperatively, with recurrence at 6 yr in both. In the longest interval between initial therapy and recurrence 5 1 patients treated with radioiodine, I 8 showed no up was 16 yr. take in neck scans (performed I mo after replacement Pathology reports stated the size of the nodule in 102 thyroid was stopped) at 2 to 12 mo after therapy. Two

Volume 21, Number 8 735 YOUNG, MAZZAFERRI, RAHE, AND DORFMAN

extensive invasion was 9 yr. Recurrence incidence in such TABLE1. RECURRENCERATEIN PATIENTS patients with various types of medical therapy was as WIThVARYINGDEGREESOF CAPSULAR follows:no medical therapy, one patient, one recurrence; AND VASCULARINVASION thyroid hormone only, nine patients, two recurrences; DegreeofNo.ofNo.ofinvasionpatientsrecurrences radioiodine and thyroid hormone, five patients, no re currence. Little 39 3(7)' All 20 patients with recurrences were subsequently Moderate 32 2 (7) treated with thyroid hormone. Additional therapy was Extensive 15 3 (20) radioiodine only in 10 patients, radioiodine and surgical 86 excision in five, and surgical excision only in five. 5ev enteenarefreeofdiseaseat anaverageof 9 yr following . ( ) = percentage of patients with recurrence. recurrence; three are living with persistent disease one to I6 yr after recurrence. of these 18 had a recurrence compared with one recur DISCUSSION rence in the 33 who had no scan after iodine- I 3 1 treat ment. Four additional patients had cobalt-60 irradiation The results reported here indicate that patients who plus thyroid hormone, with one recurrence. In all cate are likely to die of follicular thyroid carcinoma have gories above, patients who developed recurrence were distant metastatic disease at the time of initial presen clinically indistinguishable from those who did not. tation. If the disease is initially confined to the neck, When considered as an isolated variable, the extent overall prognosis is good, but the type of medical therapy of thyroid surgery did not affect recurrence rate, which can alter prognosis. Radioiodine therapy and thyroid was I I.9% in the 67 patients with limited thyroidectomy hormone therapy both decrease recurrence rate. against 10.5% in the I 14 with total thyroidectomy (p = The duration of the follow-up was not sufficient to 0.7). The extent of thyroid surgery was also evaluated permitanyconclusionsregardingimprovedsurvivalin in conjunction with medical therapy. The groups having patients with little or moderate invasion. However, the various kinds of postoperative medical therapy were zero death rate in the I5 patients identified with exten divided into subgroups of limited and total thyroidec sive invasion is less than would be expected from series tomy. There was no significant difference (p > 0.1) gatheredbeforethecommonuseofthyroidhormoneand comparingtotalandlimitedthyroidectomywithinany iodine- I31. Patients were entered into the Mayo Clinic of the subgroups of medical therapy. Patients who re and University of California series between I920 and ceivedpostoperativethyroid hormoneas their only 1960 (1,2). During much ofthat time, iodine-13l ther medical therapy formed the largest subgroup analyzed. apy was not available. Use of thyroid hormone was not Thosewith total thyroidectomieshadthesamesizeof specified, but may not have been given to those euthyroid lesions as those who had limited thyroidectomies. In after thyroid surgery. Mortality rate in the patients with patients treated with thyroid hormone, there were three extensive invasion in these series was over 50%, with al recurrences in the 45 with limited thyroidectomy against most all deaths occurring in the first 10 yr after initial tenrecurrencesin the69withtotalthyroidectomy(p> therapy. Part of the poor prognosis in older series at 0. 1). Patients who received no postoperative thyroid tributedto degreeof localinvasionmay bedueto the hormone therapy had lesions of the same size as those inclusion of patients with distant metastases, but this who were treated with thyroid hormone. Those who did cannot account for all the discrepancy. In the Mayo not receive thyroid hormone all had limited thyroidec Clinic's series there were 37 patients in the extensive tomy, with a recurrence rate that was significantly higher invasion group who had recurrent or inoperable disease (p < 0.05) than patientshavelimited thyroidectomy (I ). There were a total of 51 deaths due to thyroid car plus thyroid hormone therapy. The highest recurrence cinoma with a mean survival of 6 yr. Even if one assumes rate (33%) was in the nine patients who had subtotal that all 37 patients with recurrent or inoperable disease thyroidectomy and no postoperative thyroid therapy. The died, this still leaves 14 deaths in the 67 patients with lowest recurrence rate (4.7%) was in the 42 patients who extensive invasion initially considered surgically re had total thyroidectomy, iodine-l 31, and thyroid-hor movable. Likewise, in the University of California series, monc therapy. only four of the 26 patients with extensive invasion had Pathologic reports were sufficient to evaluate extent distant metastases but there was an overall mortality of of capsular invasion of the nodule and thyroid paren 69% at 10 yr (2). The University of Michigan series chyma in 86 patients (Table I ). Patients with extensive providesfurtherevidencethat, if radioiodineis given, invasion had a threefold increase in recurrence rate. This extentof localinvasionisnotasgravea prognosticsign difference was not significant (p > 0.1), possibly due to as the older series indicates (5). They did not separate the small sample size. Average follow-up in patients with papillaryfrom follicularcarcinoma,but did find that

736 THE JOURNAL OF NUCLEAR MEDICINE CLINICAL SCIENCES THERAPEUTICNUCLEAR MEDICINE invasion of the capsule vessels or local muscles did not tions. Recurrence rate in the present series in patients affect the prognosis in patients receiving iodine-131 who had no scans after therapy was no worse than in therapy. In addition, the overall survival in patients with those with negative scans. For these reasons our present follicular carcinoma treated with radioiodine was better policy, for patients with extensive invasion, is to do fol than in patients treated with surgery only. Previous low-up scans at 6- 12 mo after iodine- 13 I therapy. Pa studies do not allow any conclusions as to whether im tients with little to moderate invasion are treated once proved prognosis is due mainly to iodine- I 3 1 or to a with I50 to 200 mCi of iodine- I31, with repeat scans combination of iodine-131 and thyroid hormone. Our performed only if there is clinical or radiographic evi data indicate that both are important. denceof recurrence. Neitherthepresentnoranypreviousstudyprovides enough information to define exact criteria as to who REFERENCES should receive radioiodine and who should not. The majority of patients will present with disease that is ap I. WOOLNER LB: Thyroid carcinoma: Pathologic classification parently cured by initial surgery. If such patients receive with data on prognosis.Semin Nuc/ Med I :481-502, 1971 2. HIRABAYASHI RN, LINDSAY S: Carcinomaof the thyroid thyroid hormone postoperatively, they do well as a group. gland: A statistical study of 390 patients. J C/in Endocrinol Although the differences did not achieve statistical sig Metab 21:1596-1610,1961 nificance, radioiodine treated patients had the lowest 3. MAZZAFERRIEL,YOUNGRL, OERTELJE,etal:Papillary recurrence rate in every subgroup studied here. Evidence thyroid carcinoma: the impact of therapy in 576 patients. Medicine56:171—196,1977 for a beneficial effect for radioiodine is best for those 4. HAZARD JB: Nomenclature of thyroid tumors. In Thyroid with extensive histologic invasion. Radioiodine therapy Neoplasia. Loring S and Inman DR. eds. London, New York, for patients with little or moderate invasion could be Academic Press,1968,p 3 justified only as long as it does not increase complica 5. VARMA VM, BEIERWALTES WH, NOFAL MM, et al: tions. All available evidence indicates that the morbidity Treatment of thyroid cancer. Death rates after surgery and after surgery followed by sodium iodide 1-131. JAMA 214: from a single therapeutic dose of iodine-I 3 1 is essentially 1437—1443,1970 zero (6). Repeated therapeutic doses of radioiodine, 6. BEIERWALTESWH:Thetreatmentofthyroidcarcinomawith however, may be associated with significant complica radioactive iodine. Semin Nucl Med 8:79-94, 1978

RADIOPHARMACEUTICALS II: PROCEEDINGS OF THE 2nd INTERNATIONAL SYMPOSIUM ON RADIOPHARMACEUTICALS

This volume is a complete compilation of papers presented at the Second International Symposium on Radiopharma ceuticals, held March 19-22, 1979in Seattle, Washington. The more than 70 papers in this volume cover the complete spectrum of radiopharmaceuticals: from production through quality control to the latest in radionuclide agents for imaging and other studies.

The 867 page, illustrated volume contains titled: Quality Control; Organic Radiopharmaceuticals; Inor ganic Radiopharmaceuticals; Functional Imaging; RIA; Oncology; Hematology; Pharmacokinetics; Renal; Cardio pulmonary System; RES/Biliary; Skeletal; Thyroid; Pancreas, Prostate, and Adrenals; and Radionuclide Production. Also included are papers given in a panel discussion entitled “InternationalRegulatory Affairs Relating to Radiophar maceuticals,―and the Keynote Address by Dixy Lee Ray.

867 pages. Illustrated. Price $40.00plus $2.50for postage and handling. Check or purchase order mustaccompany all order. (Payment in U.S. funds only.)

SPECIAL OFFER!Buy Radiopharmaceuticals/Ifor$40.OoandgetRadiopharmaceutica!sforonly$10.O0more.(Please add $2.50each for postage and handling.)

Copiesareavailablenow. Orderfrom: Book Order Department Societyof NuclearMedicine 475 Park Avenue South New York, NY 10016

Volume 21, Number 8 737