R

meaulld©

M

A

warIOta©

K

mwTfidTt

0d

Annales d’Endocrinologie 72 (2011) 42–44

Clinical case

Graves’ ophthalmopathy after total thyroidectomy for papillary carcinoma

Orbitopathie basedowienne après une thyroïdectomie totale pour un carcinome papillaire

L. Giovansili a,∗, G. Cayrolle a, G. Belange a, G. Clavel a, M.-L. Herdan b

a Service de médecine interne, fondation ophtalmologique A de Rothschild, 25-29, rue Manin, 75019 Paris, Franceb Département d’ophtalmologie, fondation ophtalmologique A de Rothschild, 25-29, rue Manin, 75019 Paris, France

Available online 31 December 2010

ésumé

Nous rapportons le cas d’une femme de 53 ans qui a subi une thyroïdectomie totale en deux temps (juin et décembre 2001) pour un goitreultinodulaire avec découverte fortuite lors du premier temps opératoire d’un carcinome papillaire multifocal du lobe droit. La thyroïdectomie

st suivie d’un traitement par l’iode 131 en raison de la présence d’un petit reliquat cervical. Les différents éléments du suivi sont rassurants :ucun reliquat détecté à l’échographie, thyroglobuline indétectable en l’absence d’anticorps anti-thyroglobuline. En avril 2006, elle développene orbitopathie basedowienne unilatérale avec positivité des anticorps anti-récepteurs de la TSH (TRAb). Sous traitement symptomatique,’orbitopathie s’améliore progressivement, parallèlement à la diminution des TRAb. Le parallélisme entre le titre des TRAb et l’orbitopathie appuiee rôle majeur des TRAb dans la pathogénie de l’ophtalmopathie dysthyroïdienne. Cette observation montre également la possibilité de développeres anticorps en l’absence de tissu thyroïdien détectable.

2010 Elsevier Masson SAS. Tous droits réservés.

ots clés : Ophtalmopathie basedowienne ; Maladie de Basedow ; Carcinome papillaire

bstract

We report the case of a 53-year-old woman who underwent two-phase total thyroidectomy (June and December 2001) for a multinodular goiterith incidental discovery at the first procedure of a multicentric papillary carcinoma of the right thyroid lobe. Thyroidectomy was followed by an

blative dose of 131-radioiodine because of the presence of residual tissue in the neck. The various elements of the follow-up are reassuring: noesidual tissue was detected at the ultrasonography of the neck and thyroglobulin was undetectable in the absence of antithyroglobulin autoantibodies.

n April 2006, the patient developed unilateral Graves’ ophthalmopathy with the appearance of antithyrotropin receptor autoantibodies (TRAb).phthalmopathy progressively improved, in parallel to the decrease of TRAb. The parallel trend of TRAb and the ophthalmopathy supports

he major role of TRAb in the pathogenesis of thyroid-associated ophthalmopathy. This observation also shows the possibility of developingutoantibodies in the absence of detectable thyroid tissue.

2010 Elsevier Masson SAS. All rights reserved.

t

1

eywords: Graves’ophthalmopathy; Graves’disease; Papillary carcinoma

The pathophysiological mechanisms of Graves’ ophthal-opathy remain unclear. The main element is the TSH receptor,hich remains the most likely candidate as an autoantigen.SH receptors should be present on the surface of the orbitalbroblasts like in the thyroid cells. A number of studies have

emonstrated a significant correlation between the level ofRAb, and the occurrence and severity of Graves’ ophthalmopa-

hy (GO) [1].

∗ Corresponding author.E-mail address: lamaendoc@hotmail.com (L. Giovansili).

totr

G

003-4266/$ – see front matter © 2010 Elsevier Masson SAS. All rights reserved.oi:10.1016/j.ando.2010.11.001

We report the case of a patient who developed GO after totalhyroidectomy for papillary thyroid cancer.

. Case report

A non-smoking 53-year-old woman with no family history ofhyroid disease or personal history of Graves’ disease attendedur unit in December 2000 for examination of a voluminous

hyroid nodule, which had been discovered fortuitously in theight lobe.

She was free of any signs of hyperthyroidism orO; the thyroid profile was as follows: TSH = 1.2 �U/mL

’Endocrinologie 72 (2011) 42–44 43

(Twawhwc

nt

dciwinpd

a1Br1

on

aa

ta(nn

tnn

ed1

lwc

ta

ip(

Fig. 1. Orbital MRI, normal aspect of the right orbit. Left orbit: grade II exoph-thalmia. Enlargement of the extraocular muscles and orbital fat. Absence ofanother intra-orbital lesion.Apd

w(

t

twtnr2Ie

2

a

rTt1

i1

L. Giovansili et al. / Annales d

normal range, 0.25–5); T4 = 18 pmol/L (normal range, 10–25),3 = 4.7 pmol/L (normal range, 3.1–6.1). Blood calcitonin levelas in the normal range, and antithyroperoxidase (TPOAb),

ntithyroglobulin (TgAb) and TSHR autoantibodies (TRAb)ere negative. The ultrasonography confirmed the presence of aeterogeneous necrotic right lobe nodule measuring 34 × 25 mmith many microcysts. A fine-needle aspiration biopsy was non-

ontributory.Right lobo-isthmectomy was performed in June 2001: the

odule was benign on the frozen-section analysis, as well as inhe final histological examination.

The final histological assessment resulted in the discovery,istant from this nodule, of a right infiltrating papillary car-inoma measuring 0.2 cm, with seven or eight other zones ofnframillimetric carcinoma. One of these was located in contactith conjunctive tissue of the thyroid capsule without infiltrat-

ng it. The histology of the left lobe was totally negative, witho localization of papillary carcinoma. Total thyroidectomy waserformed in December 2001, without systematic lymph nodeissection.

In March 2002, an ultrasonography showed the presence ofrichly vascularized right laterotracheal formation measuring

5 mm, with an aspect suggestive of residual thyroid tissue.ecause of this image, in June 2002 the patient subsequently

eceived, after levothyroxine withdrawal, an ablative dose of31-radioiodine (131I; 100 mCi).

The post-therapy whole body scan showed a reduction in sizef the residual tissue, measuring 7 mm on ultrasonography witho other uptake.

In March 2003, a new whole body scan (131I, 5 mCi)fter levothyroxine withdrawal, did not show any iodine-ccumulating tissue.

Levothyroxine suppressive therapy at 100 �g was con-inued, the patient was re-evaluated every 6 months, thennnually: TSH levels were between 0.20 and 0.4 �U/mLnormal range, 0.25–5 �U/mL); T4 and T3 remained in theormal range, thyroglobulin was undetectable; TgAb wereegative.

An ultrasonography did not show any residual thyroidissue, nor pathological adenopathy (two non-vascularized,on-specific left jugular micronodules). Neck palpation wasormal.

In April 2006, the patient consulted for left retrobulbar pain,xophthalmia which had developed over 6 months without visualeterioration or diplopia. She was treated with levothyroxine00 �g/day.

Opthalmological examination confirmed the suspected uni-ateral GO: grade II exophthalmia, upper lid retraction, lid lag,ithout any abnormality of the oculomotricity, or any major

linical signs of inflammation.The orbital magnetic resonance imaging (MRI) confirmed

he grade II exophthalmia, with an enlargement of the musclesnd the orbital fat compatible with GO (Fig. 1).

MRI did not show the presence of other lesions in the orbit orn the brain. Measurement of thyroid hormones revealed a sup-ression of TSH < 0.05 �u/mL, an increase of T4 at 2.68 ng/dLNR: 0.8–1.9 ng/dL) and a normal level of T3. TPOAb and TgAb

9ni1

spect normal de l’orbite droit. Orbite gauche : exophtalmie grade II. Hypertro-hie de l’ensemble des muscles oculomoteurs et de la graisse orbitaire. Absence’autre lésion intra-orbitaire.

ere undetectable whereas TRAb was now detectable at 8 IU/LNR < 1 IU/L).

Thyroglobulin was undetectable. Ultrasonography as well ashoraco-abdominal computed tomography were negative.

Levothyroxine was decreased (alternation 100 and 75 mcg),he ophthalmopathy was treated by local care. The patientas followed with serial determination of thyroid hormones,

hyroid autoantibodies, physical and ophthalmological exami-ation. TRAb levels decreased gradually, returned to the normalange in June 2008 until the last consultation in November009. In parallel, the ophthalmopathy improved significantly.n November 2009, the patient had moderate non-progressivexophthalmia.

. Discussion

The appearance of TRAb after 131-radioiodine treatment isknown phenomenon.

Some studies have reported the occurrence of hyperthy-oidism in parallel with positivity of TRAb in previouslyRAb-negative patients treated by 131I for a toxic nodular goi-

er [2,3]. In most cases, TRAb appeared 3 to 12 months after31I therapy and spontaneously disappeared over 12 months.

Several studies have found increased TgAb or TPOAb levelsn patients with thyroid cancer after total thyroidectomy and31I therapy [4–6].

A case of bilateral exophthalmos with TRAb occurring

years after total thyroidectomy for a papillary thyroid carci-oma was reported in the presence of metastasis [7]. Howevern this patient Ab had not been measured before surgery and31I therapy.

4 ’End

ao

T1atti

tatif

Tc

emot

oftiopa

eri

aoGtie[

aTtTb

(dfs

tfi

C

R

[

[

[

[

[

[

4 L. Giovansili et al. / Annales d

Another case of GO with TRAb was reported 40 years aftertotal thyroidectomy for a papillary carcinoma, in the presencef vertebral metastasis [8].

Antonelli et al. reported a case similar to ours, of GO andRAb which occurred 4 years after total thyroidectomy and31I therapy for papillary thyroid carcinoma [9]. In our patientntibodies (TPOAb, TgAb, TRAb) were negative before thehyroidectomy and 131I therapy; TRAb activity and exoph-halmia appeared simultaneously approximately 5 years later,n the absence of recurrence or metastasis of cancer.

Subsequently TRAb progressively decreased, in parallel withhe improvement of ophthalmopathy, and disappeared 6 yearsfter the thyroidectomy and 131I therapy. This delay is similaro that reported in a study showing the disappearance of TRAbn 182 patients, who were treated with thyroidectomy and 131Ior papillary carcinoma and followed for 10 years [10].

Our observation supports previous reports of increases inRAb levels after 131I therapy for nodular goiter, which in mostases spontaneously disappear.

In contrast with published cases of GO in patients with cancer,xcept for the case reported by Antonelli et al., no detectableetastases were present in our patient, proving that the presence

f thyroid tissue (normal or pathological) is not necessary forhe development of thyroid autoantibodies.

It is nevertheless important to underline that TRAb devel-ped several years after 131I therapy, so it is not possible toormally confirm the role of this therapy in the induction of thehyroid autoimmunity. We cannot absolutely exclude the fortu-tous character of the thyroid autoimmunity and the occurrencef an isolated form of GO (euthyroid Graves’ disease), nor theersistence of residual microcarcinoma, potentially functional,t the origin of an increase of Graves’ disease.

Furthermore, the presence of TRAb had no impact on thevolution of thyroid carcinoma, which remained in completeemission according to various clinical, biological and radiolog-cal criteria.

Indeed, a number of studies have suggested an increasedggressiveness of papillary thyroid carcinoma (multifocality,ccurrence of distant and locoregional lymph node metastasis) inraves’ disease patients, despite the suppression of TSH under

reatment. TRAb apparently plays an important stimulating rolen this poor outcome of carcinoma [11–14]. Nevertheless, thisffect is still discussed and with some authors totally disagreeing15].

In our patient treated with thyroidectomy and 131I therapy fornon-metastatic and multicentric papillary thyroid carcinoma,RAb with unilateral GO appeared 5 years later. The parallel

ime course of TRAb and GO reinforces the hypothesis thatRAb plays a causal role in the pathogenesis of GO, supportedy several studies [1,16].

It is of interest to note that the patient developed TRAb

initially absent) when she had no detectable thyroid tissue asemonstrated by the search for serum thyroglobulin (negativerom 2006 to 2009) and various scans. This would appear touggest that the antigen can arise from a tiny fragment of unde-

[

ocrinologie 72 (2011) 42–44

ectable thyroid tissue, or even come from orbital tissue (orbitalbroblasts?).

onflict of interest statement

The authors do not have any conflict of interest.

eferences

[1] Eckstein AK, Plicht M, Lax H, Neuhäuser M, Mann K, Lederbogen S,et al. Thyrotropin receptor autoantibodies are independent risk factors forGraves’ ophthalmopathy and help to predict severity and outcome of thedisease. J Clin Endocrinol Metab 2006;91:3464–70.

[2] Rubio IG, Perone BH, Silva MN, Knobel M, Medeiros-Neto G. Humanrecombinant TSH preceding a therapeutic dose of radioiodine for multin-odular goiter has no significant effect in the surge of TSH-receptor andTPO antibodies. Thyroid 2005;15:134–9.

[3] Dunkelmann S, Wolf R, Koch A, Kittner C, Groth P, Schuemichen C.Incidence of radiation–induced Graves’ disease in patients treated withradioiodine for thyroid autonomy before and after introduction of a high-sensitivity TSH receptor antibody assay. Eur J Nucl Med Mol Imaging2004;31:1428–34.

[4] Görges R, Maniecki M, Jentzen W, Sheu SN, Mann K, Bockisch A, et al.Development and clinical impact of thyroglobulin antibodies in patientswith differentiated thyroid carcinoma during of the first 3 years after thy-roidectomy. Eur J Endocrinol 2005;153:49–55.

[5] Kumar A, Shah DH, Shrihari U, Dandekar SR, Vijayan U, Sharma SM.Significance of antithyroglobulin antibodies in differentiated thyroid car-cinoma. Thyroid 1994;4:199–202.

[6] Franke WG, Zöphel K, Wunderlich G, Kühne A, Schimming C, KroppJ, et al. Thyroid peroxidase (TPO) as a tumor marker in the follow-upof differentiated thyroid carcinomas with surgical and ablative radioio-dine therapy. An assessment after evaluation. Anticancer Res 1999;19:2711–6.

[7] Katz SB, Garcia AJ, Niepomniszcze H. Development of Graves’ diseasenine years after total thyroidectomy due to follicular carcinoma of thethyroid. Thyroid 1997;7:909–11.

[8] Rogers PB, Gupta N, Rose GE, Plowman PN. Thyroid eye disease associ-ated with athyria. Br J Ophthalmol 2000;84:439.

[9] Antonelli A, Fallahi P, Tolari S, Ferrari SM, Ferrannini E. Thyroid-associated ophthalmopathy and TSH receptor auto antibodies in nonmetastatic thyroid cancer after total throidectomy. Am J Med Sci2008;336(3):288–90.

10] Chiovato L, Latrofa F, Braverman LE, Pacini F, Capezzone M, MasseriniL, et al. Disappearance of humoral thyroid autoimmunity after completeremoval of thyroid antigens. Ann Intern Med 2003;139:346–51.

11] Belfiore A, Garofalo MB, Giuffrida D, Runello F, Filetti S, Fiumara A,et al. Increased aggressiveness of thyroid cancer in patients with Graves’disease. J Clin Endocrinol 1990;70:830–5.

12] Pellegriti G, Belfior A, Giuffrida D, Lupo L, Vigneri R. Outcome of dif-ferentiated thyroid cancer in Graves’ patients. J Clin Endocrinol Metab1998;83:2805–9.

13] Filetti S, Belfior A, Amir SM, Daniels GH, Ippolito O, Vigneri R, et al. Therole of thyroid-stimulating antibodies of Grave’s disease in differentiatedthyroid cancer. N Eng J Med 1988;318:753–9.

14] Mazzaferri EL. Thyroid cancer and Graves’ disease. J Clin EndocrinolMetab 1990;70:826–9.

15] Yukiko Y, Hiroshi S, Wataru K, Mitsuji N, Kiminori S, Kunihiko I, et al.Recent outcome of Graves’ disease patients with papillary thyroid cancer.

Eur J Endocrinol 2007;157:325–9.

16] Gerding MN, Vander Meer JW, Broenink M, Bakker O, WiersingaWM, Prummel MF. Association of thyrotropin receptor antibodies withthe clinical features of Graves’ ophthalmopathy. Clin Endocrinol (Oxf)2000;52:267–71.