Receivingthyroidhormonesuppr

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ThERAPEUTIC NUCLEAR MEDICINE

SerumThyroglobulin,A Monitorof DifferentiatedThyroidCarcinomain Patients ReceivingThyroidHormoneSuppressionTherapy:ConciseCommunication

WilliamH.Blahd,MyraV. Drickman,Charles W. Porter, VirginiaA. Hill,and Werner A. Baumgartner

VeteransAdministration Medical Center, WadsworthDivision, and University of California at Los Angeles, (t.@LA) Schoolof Medicine,LosAngeles,California

Serum thyroglobulin levels were obtained in 86 patients who had undergonethy roldectomyand1-131ablationfor dIfferentiatedthyroidcancer,andwhowerere celvlngor hadrecentlydiscontinuedthyroidhormonesuppressiontherapy.Excel lent correlation was observed between serum thyroglobulln levels In patIents re celving thyroid hormonesuppressiontherapy and 1-131 imagIngstudies.Serum thyroglobullnlevelsequalto or below20ng/mlIndicatetheabsenceofthyroidcar cinoma,and valuesexceeding60 ng/mi were IndIcatIveof active thyroidcancer but may Includesome patientswithoutclinical evidenceof dIsease.Intermediate serum thyroglobulin levels were observed In a small number of patients with post surgicalthyroidremnantsor activedisease.Serumthyroglobulinlevelsareof con siderablevalueIn monitoringthe actlvftyof thyroidcancerIn patientswhoare re celvlng thyroid hormone suppression therapy.

J Nuci Med 25: 673—676,1984

The determination of serum thyroglobulin (Tg) 1ev undergone thyroidectomy for papillary, follicular, or els represents an important advance in monitoring the mixed papillary-follicular thyroid carcinoma. All pa course of patients with differentiated thyroid carcinoma. tients also received 1-131ablation therapy in accord with Serial monitoring of serum Tg after complete thyroid our previously reported protocol (1). After obtaining ectomy for thyroid cancer can detect residual tumor written consent, blood samples for serum Tg and serum tissue, metastases, or the recurrence ofdisease. However, levels of thyroid-stimulating hormone (TSH) were ob the value of Tg as a tumor marker in thyroid-cancer tamed. Bloodsamples were taken from patients who were patients may be influenced by thyroid hormone sup receiving thyroid hormone suppression therapy, and pression therapy. Ifserum Tg levels are to be of clinical again at least 1 mo after such therapy had been discon value in the follow-up of thyroid-cancer patients, it is tinued. Scans of the neck and thorax, and whole-body desirable to use the assay while patients are receiving radioactivity surveys, were performed on all patients at thyroid-suppression therapy. This study has been Un 48—72hr afteranoraldoseof 5mCi1-131,usingarec dertaken to evaluate those factors that may be influential tilinear scanner and high-energy focused collimator. Ten in the application of serum Tg as a tumor marker for patients who had abnormal concentrations of I-I 31 differentiated thyroid cancer in patients receiving thy outside the thyroid bed, or had I-I 31 concentration in roid-hormone therapy. Serum thyroglobulin levels were distant metastases, were considered to have active disease obtained with a new thyroglobulin radioimmunoassay and were studied before and after radioiodine ablation kit. therapy.

PATIENTS METHODS We studied 86 patients (49 F and 37 M) who had Serum thyroglobulin was determined by radioim Received Oct. 6, 1983; revision accepted Jan. 19, 1984. For reprints contact: W. H. Blahd,MD (WI 15),Chief,Nuclear munoassay using a commercial thyroglobulin RIA kit.― Medicine Ultrasound Svc., VA Medical Center, Wadsworth Division, The method is a noncompetitiveradioimmunoassay Los Angeles, CA 90073. procedure (delayed addition method). Rabbit anti-hTg

Volume 25, Number 6 673 BLAHD, DRICKMAN, PORTER, HILL, AND BAUMGARTNER

TABLE1. SERUMThYROGLOBULIN TABLE2. EFFECTOF DISCONTiNUATiONOF DETERMINATIONS(rig/mI) PATIENTS ThYROID-SUPPRESSION ThERAPY RECEIVINGAND NOT RECEIVINGThYROID HORMONE 28 Patients without disease Average L@Tg 1.5 ng/ml @20 21 — 60 >60 AverageL@TSH39 sU/ml Active4(13)Nodiseasedisease 0 (0) 0 (4) Patientswithactivedisease 1(1). 96(61) 13(14) Onst@pression Offsuppression Tg/TSH TgITSH patientsnotNumbersinparenthesesaredeterminationson MB 112/4.8 230/37 receivingthyroidhormone. PM 461/12.3 >1000/98 LS 105/5.6 100/4.7 Pz 110/3.5 144/40

(100 @l)is mixed with 200 @i1serum. After 5 hr of incu bation at 37°C, 100 @l1-125 hTg is added, and the RBC-agglutination technique. Since Tg antibodies in reactants mixed and left at room temperature overnight. terfere with the assay, sera containing antibodies were Buffer ( 100 @s1)is then added and mixed before addition excluded from the study. In the patient population of second antibody (200 @ulof goat anti-rabbit antibody). studied, five individuals had Tg serum antibodies. After 1 hr of incubation at room temperature, the tubes are centrifuged at 5-10°Cfor 15 mm at 2000 g. Su RESULTS pernatants are decanted by inversion and blotting of Patients were separated into two groups depending on tubes. Precision is improved by resuspending the pre whether or not they were receiving thyroid hormone cipitates in 2.0 ml of 6% polyethylene glycol in normal suppression therapy. Serum thyroglobulin levels were saline, then recentrifuging and decanting. Precipitates segregated in three empirically defined groups as sug are counted in a gamma spectrometer. The range of the gested by Echenique et al. (3): serum values equal to or assay is 5-500 ng/ml, with sensitivity of 2 ng/ml. None less than 20 ng/mI; an intermediate group with serum of the following proteins showed any significant cross Tg between 21 and 60 ng/ml: and values exceeding 60 reaction with the anti-human Tg rabbit serum: human ng/ml. AFP, hCG, hPL, hFSH, hPAP, myoglobin. Normal Table 1 lists the results of thyroglobulin determina human serum Tg levels do not exceed 60 ng/ml. Thy tions in patients receiving thyroid suppression and in roid-stimulating hormone was determined by radioim those who were not receiving thyroid hormone. In both munoassay using a commerical kit.@Normal range does groups, thyroglobulin levels usually exceeded 60 ng/ml not exceed 10@sU/ml.All blood samples were tested for if the patient had I-I 3 1 scan findings indicative of ac circulating endogenous anti-Tg antibodies by the tanned tive disease. Patients in both groups who did not have

,@ p I f I

FIG. 1. ChangesIn Tg and TSHwith time indisease-freepatientafterwithdrawalof @YsOFFTHVR@MDSUPPRESSiON thyroid-suppression therapy.

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FiG. 2. changesinTgandTSHwithtime in patientwithactivedisease after with I drawal of thyroid-suppression therapy. I

‘5 20 25 30 35 DAYSOFFTHVROIDSUPPRESSION

positive I- 131 scans had thyroglobulin levels 20 The presence of postsurgical thyroid-bed remnants ng/ml except for a small number whose thyroglobulin measuring 1—3cm in diameter did not correlate with levels were in the intermediate range (21—60ng/ml). thyroglobulin levels. Figure 3, A and B shows postop Included in the intermediate range were six patients with erative scans from two patients. In both cases Tg levels remnants, but also included were four patients with ac were less than 21 ng/ml. tive disease.

There were no false-negative results in either group. DISCUSSION However, two patients gave false-positive results (>60 ng/ml) in spite of concurrently negative 1-131 images Our study confirms the reports that serum thyro and no clinical evidence of disease. globulin levelsreflect tumor activity in thyroidectomized, Table 2 demonstrates the effect of discontinuation of 1-131-ablated thyroid-cancer patients with differentiated thyroid-suppression therapy on serum thyroglobulin and tumor-cell types (2—15).The data indicate that tumor thyroid-stimulating hormone levels in 25 patients activity may be detected readily in patients who are re without evidence of disease. An insignificant rise in ceiving thyroid hormone suppression therapy. Our data thyroglobulin levels was observed in these patients de also support the concept that serum thyroglobulin levels spite a significant rise in TSH levels (Fig. 1). Table 2 also are under the influence of the pituitary (7—9,12—14). shows the effect of discontinuation of thyroid-suppres However, the discontinuation of thyroid-hormone re sion therapy in four patients with active disease. In all placement with concomitant endogenous TSH stimu but one there was a significant rise in both serum Tg and lation appears to enhance serum thyroglobulin levels, TSH levels (Fig. 2). primarily in patients with active disease who have high The correlations between serum thyroglobulin and Tg levels (>60 ng/ml). Similar findings have been re 1-131 scan findings in thyroid-cancer patients—both on and off thyroid hormone suppression therapy—are shown in Table 3. @ ..! ,•.--.

@ TABLE 3. CORRELATIONSBETWEENSERUM ..- ,UJ4t: @ ThYROGLOBUUN AND 1-131 IMAGES IN ./: ..@ @ PATIENTS BOTh ON AND OFF ThYROID •.:‘ HORMONESUPPRESSIONThERAPY @ Onoffsuppressionsuppression @*:.‘•@

.. SSN; @ .. .. : @ Sensrnvfty 1.00 1.00 *, .@ Specificity 0.87 0.80 @ Accuracy 0.88 0.84 . :@:•. A •- .. . Tg >20 was considered positive for statistical anal ysis. FiG. 3. A, B: 1-131Imagesobtainedontwo patientswithpostop erative thyroid remnants. In both patients thyrogIobuIk@levels were 20 ng/ml.

Volume 25, Number 6 675 BLAHD, DRICKMAN, PORTER, HILL, AND BAUMGARTNER ported by Schneider, Schiumberger, and Ashcraft and REFERENCES their co-workers (7,8,12). I. KRISHNAMURTHY GT, BLAHD WH: Radioiodine 1-131 Several groups have reported abnormally elevated therapy in the management of thyroid cancer. Cancer 40: serum levels of thyroglobulin in patients with negative 195—202,1977 I-i 31 images (5,8,12—14).In the present study, two 2. LO GERFOP, STILLMAN D, FEINDC: Serum thyroglobulin patients had elevated serum thyroglobulin levels despite and recurrent thyroid cancer. Lancet 1:881—882,1977 3. ECHENIQUERL, KASI L, HAYNIE TP, et al: Critical repeatedly negative 1-131images. Routine determination evaluation of serum thyroglobulin levelsand 1-131scans in of serum thyroglobulin may be of paramount importance post-therapy patients with differentiated thyroid carcinoma: in following the clinical course of such patients, since Concise communication. J Nuc! Med 23:235—240,1982 some investigators believe that serum thyroglobulin may 4. VAN HERLE AJ, ULLER RP: Elevated serum thyroglobulin. be a more sensitive indicator of disease than the I-i 31 A marker of metastases in differentiated thyroid carcinomas. J Clin Invest 56:272—277,1975 image (12). 5. BLACKEG,GIMLETTETMD, MAISEYMN, et al: Serum It is apparent that the most important clinical appli thyroglobulin in thyroid cancer. Lancet 443-445, 1981 cation of the serum Tg assay is to monitor thyroid-cancer 6. TANGFUISCN,HOFFENBERGR, MAISEYMN, et al: patients who are receiving thyroid hormone suppression Serum thyroglobulin concentrations and whole-body ra therapy. If the assay can detect tumor activity reliably dioiodinescanin follow-upofdifferentiatedthyroidcancer after thyroid ablation. Br Med J 2:298-300, 1979 under such conditions, it will obviate the morbidity as 7. PEZZINOV,COZZANIP,FILErrI 5,Ctal: A radioimmu sociated with the prolonged abstinence from replacement noassay for human thyroglobulin: Methodologyand clinical therapy required to perform 1-131 imaging. However, applications. Eur I C/in Invest 7:503—508,1977 to assure this degree of reliability, an assay with sub 8. SCHLUMBERGERM, CHARBORDP,FRAGUP.Ctal: Cir stantial sensitivity and specificity is required. On the culating thyroglobulinand thyroid hormonesin patients with metastases of differentiated thyroid carcinoma: Relationship basis of the present data, the assay used in this investi to serum thyrotropin levels. J C/in Endocrin Metab 51: gation appears to offer these attributes. 513—519,1980 Based on this assay system, and considering thyroid 9. SCHNEIDERAB,LINEBR,GOLDMANJM,etal: Sequen ectomized and I-i 31-ablated patients either on or off @ialserum thyroglobulin determinations, 13h1scans, and 131J thyroid suppression therapy, we conclude that: uptakesafter triiodothyroninewithdrawalin patientswith thyroid cancer. J C/in Endocrin Metab 53:1199-1206, 1. Serum thyroglobulin levels that are less than or I981 equal to 20 ng/ml appear to indicate the absence of 10. Lo GERFO P, COLACCHIO T, COLACCHIO D, et al: Thy thyroid carcinoma. roglobulin in benign and malignant thyroid disease. JAMA 2. Intermediate serum thyroglobulin levels between 241:923—926,1979 20 and60 ng/ml areobservedin patientswith postsur II. BARSANOCP, SKOSEYC, DEGR00T Li, REFETOFF5: Serum thyroglobulin in the management of patients with gical thyroid remnants and a small number of patients thyroid cancer. Arch Intern Med I42:763—767,I982 with active disease. 12. ASHCRAFTMW, VAN HERLEAi: Thecomparativevalue 3. Serum thyroglobulin levels exceeding 60 ng/ml are of serum thyroglobulin measurements and iodine 131 total indicative of active thyroid carcinoma, but may include body scans in the follow-upstudy of patients with treated some patients with latent disease without any clinical differentiated thyroid cancer. Am J Med 71:806—814,1981 13. COLACCHIOTA, Lo GERFO P. COLACCHIODA, et al: manifestations. Such patients require long-term Radioiodinetotal bodyscan versusserum thyroglobulinlevels follow-up. in follow-up of patients with thyroid cancer. Surgery 91: 42-45, 1982 14. SCHLUMBERGERM, FRAGUP, PARMENTIERC, et al: FOOTNOTE Thyroglobulin assay in the follow-upof patients with differ entiatedthyroidcarcinomas:comparisonof its valuein pa * Nuclear Medical Systems, Inc., Newport Beach, CA 92663. tients with or withoutnormalresidualtissue.Ada Endocrino/ 98:215—221,1981 ACKNOWLEDGMENT 15. GALLIGANJP,WINSHIPi, VAN DOORNT, et al: A com parisonof serum thyroglobulinmeasurementsand wholebody Presentedin part at the ThirdWorldCongressof NuclearMedicine 1-I31 scanning in the management of treated differentiated and Biology,Paris, France,August 1982. thyroid carcinoma. Aust NZ J Med I2:248-254, 1982

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