British Journal ofOphthalmology, 1983, 67, 596-599

Squamous cell carcinoma of the eyelidmasquerading as 'malignant' ophthalmopathyof Graves's diseaseH. C. FORD,' J. W. DELAHUNT,2 AND C. A. TEAGUE'

From the Departments of 'Pathology and 2Medicine, Wellington Clinical School of Medicine,Wellington, New Zealand

SUMMARY A patient with Graves's disease is described in whom the periorbital changes of severeophthalmopathy and iatrogenic Cushing's syndrome delayed the diagnosis of a squamous cellcarcinoma of the eyelid. It is suggested that the immunosuppressive therapy which the patientreceived may have enhanced the growth of a pre-existing malignancy.

Progressive inflammation of the orbital tissue occursin less than 3% of patients with Graves's disease. ' 2 Insevere cases glucocorticoid treatment is indicated,3and immunosuppression with azathioprine47 andcyclophosphamide"9 has also been used by somegroups, with or without plasmapheresis.

In immunosuppressed patients the incidence ofmalignant neoplasms is markedly increased. '0 A largeproportion of these tumours are skin cancers, whichmay develop within 4 months of the initiation of

Correspondence to Dr H. C. Ford, Department of Pathology,Wellington Clinical School of Medicine, Wellington Hospital,Wellington 2, New Zealand.

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immunosuppressive therapy. I" Basal cell car-cinomas are the predominant type of skin cancer inthe general population; however, in the immuno-suppressed patient the majority are squamous cell.We describe a patient with Graves's ophthalmo-

pathy of sufficient severity to warrant treatment withazathioprine and prednisone, in whom the presenceof a squamous cell carcinoma of one lower eyelid wasnot promptly recognised as a factor contributing tothe retraction and inflammation of the lid. Thediagnostic difficulties that were encountered and thepossibility that the high doses of immunosuppressivedrugs that the patient received accelerated tumourgrowth prompted us to offer the following case report.

First ophthalmologicalexamination

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Irregular lid Excisioncontour (Fig 2) Biopsy

I Azathioprine IIF

1979

Fig. 1 Summary ofthe patient's course and treatment.

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Squamous cell carcinoma ofthe eyelid masquerading as 'malignant' ophthalmopathy of Graves's disease

Case report

The patient, a 59-year-old male construction fore-man, was first discovered to be hyperthyroid inAugust 1978 after 2 months of symptoms which didnot include eye complaints. He was initially treatedwith carbimazole and propranolol, and firstreceived '31I (10 mCi) in November 1978. Because ofbiochemical evidence of recurrent hyperthyroidism,further treatment with radioiodine was given in April1980 (10 mCi), October 1980 (15 mCi), and July 1981(2OmCi). During this time thyroid function was main-tained largely within normal biochemical limits withappropriate doses of carbimazole. With occasionalminor exceptions the levels of thyroid stimulatinghormone remained within normal limits.He was admitted to the hospital in February 1979

with a history of progressive exophthalmos associatedwith a painful, gritty sensation of the eyes andphotophobia (Fig. 1). There was moderate proptosis,oedema of the periorbital tissues, especially the lowerlids, chemosis, and slight limitation of upward gaze

bilaterally. The conjunctivae were inflamed and werevery boggy and swollen near the inner canthus. Nospecific abnormalities of the left lower eyelid werenoted. There was no change in visual acuity and no

papilloedema. Prednisone (60 mg/day) was admin-

Fig. 2 The patient, Mav 1980. Swelling of the periorbitaltissue, exophthalmos and chronic inflammatory changes ofthe conjuncti vae are evident. The contour ofthe left lower lidmargin is lost and the surrounding skin has a glistening,irregular appearance.

istered and was followed by a decrease in proptosisbilaterally (23-22 mm right eye and 24-21 mm lefteye, measured with a Hertel ophthalmometer). Overthe next several months the dose of prednisone wasdecreased to 30 mg/day, with little change in the eyes.In May 1980 prednisone was decreased to 20mg daily,but this was associated with an increase in proptosis,conjunctival injection, and eye pain (Fig. 2).

In June 1980 azathioprine therapy was begun at adaily dose of 150 mg/day (17 mg/kg) and wasincreased to 200 mg/day in September 1980;prednisone (20 mg/day) was continued. Because itwas considered that the eye changes were entering amore chronic stage, the prednisone treatment wasgradually discontinued over the ensuing months.There was little change in the eye signs except for adimunition in periorbital fullness associated withdisappearance of the Cushingoid facies. The scleralconjunctivae were thickened and were markedlyinflamed and oedematous at the inner canthusbilaterally. As the Cushingoid facies regressed,asymmetry of lid retraction and irregularity of thecontour of the left lid margin became more apparent.

In September 1981 azathioprine therapy was dis-continued, and the left lower lid was biopsied andsubsequently excised and replaced. Pathologicalexamination showed a moderately differentiated

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H. C. Ford, J. W. Delahunt, and C. A. Teague

Fig. 3 Photomicrograph ofa representative area oftheeyelid biopsy. The surface epithelium (above) is replaced bydisorganised bands ofpleomorphic hyperchromaticsquamous carcinoma cells showing intercellular 'prickles'(small arrow). Islands ofcarcinoma (large arrows) are seenin the adjacent connective tissue. (Haematoxylin andeosin, x300).

nonkeratinising squamous cell carcinoma of thelower lid with invasion of the adjacent connectivetissue (Fig. 3).The patient is currently receiving a replacement

dose of thyroxine. There is moderate exophthalmos,but visual acuity is unchanged, and range ofmotion ofthe eyes is full (Fig. 4). There is no evidence oftumour recurrence.

Discussion

Squamous cell carcinoma of the eyelid is an unusualtumour occurring with about one-fortieth thefrequency of basal cell carcinoma.'617 The presence

of the tumour in our patient was not promptlyrecognised-in part because it was infiltrative ratherthan papillomatous. 16 Moreover, the periorbitalchanges were at first attributed to acute and chronicGraves's ophthalmopathy and to Cushing'ssyndrome. Another case of squamous cell carcinomaof the left lower lid in an immunosuppressed patienthas recently been reported. 18

In retrospect there is little doubt that the carcinomaof the eyelid was present in our patient beforeazathioprine therapy was begun (Fig. 2). There is noconvincing evidence, to our knowledge, thatprolonged treatment with pharmacological doses ofglucocorticoid alone increases the risk of thedevelopment of epithelial tumours in man. Whetherimmunosuppression with azathioprine andprednisone combined increased the chance ofunhindered development of the malignant cellsalready present, as has been suggested,"4 remains aworrying possibility.The role of immunosuppressive treatment in

severe Graves's ophthalmopathy is undergoingevaluation at present. ' Although it cannot be decidedwith certainty whether our patient's skin cancer wasenhanced by the therapy he received, we believe it isimportant to remind clinicians of the association ofimmunosuppressive therapy and an increasedincidence of malignant neoplasms.

We thank Mr P. C. Herrick, ophthalmologist, Wellington Hospital.for assistance, and Mrs N. Painton for typing the manuscript.

References

1 Wall JR, Henderson J, Strakosch CR, Joyner DM. Graves' oph-thalmopathy. Can Med Assoc J 1981; 124: 855-66.

2 Hamilton RD, Mayberry WE, McConahey WM, Hanson KC.Ophthalmopathy of Graves' disease: a comparison betweenpatients treated surgically and patients treated with radioiodide.Mayo Clin Proc 1967; 42: 812-8.

3 Werner SC. Prednisone in emergency treatment of malignantexophthalmos. Lancet 1966; i: 1004-7.

4 Burrow GN, Mitchell MS, Howard RO, Morrow LB. Immuno-suppressive therapy for the eye changes of Graves' disease. J ClinEndocrinol Metab 1970; 31: 307-11.

5 Winand R, Mahieu P. Prevention of malignant exophthalmosafter treatment of thyrotoxicosis. Lancet 1973; i: 1196.

6 Dandona P, Marshall N, Bidey S, Nathan AW, Havard CWH.Treatment of acute malignant exophthalmos with plasmaexchange. In: Stockigt JR, Nagataki S, eds. Thyroid researchVIII. Canberra: Australian Academy of Science, 1980: 583.

7 Dandona P, Marshall NJ, Bidey SP, Nathan A, Havard CWH.Successful treatment of exophthalmos and pretibial myxoedemawith plasmapheresis. Br MedJ 1979; i: 374-6.

8 Wall JR, Strakosch CR, Fang SL, Ingbar SH, Braverman LE.Thyroid binding antibodies and other immunological abnor-malities in patients with Graves' ophthalmopathy: effect oftreatment with cyclophosphamide. Clin Endocrinol 1979; 10:79-91.

9 Bigos ST, Nisula BC, Daniels GH, Eastman RC, Johnston HH,Kohler PO. Cyclophosphamide in the management of advancedGraves' ophthalmopathy. Ann Intern Med 1979; 90: 921-3.

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10 Penn 1. Development of cancer as a complication of clinicaltransplantation. Transplant Proc 1977; 9: 1121-7.

11 Walder BK, Robertson MR, Jeremy D. Skin cancer andimmunosuppression. Lancet 1971; il: 1282-3.

12 Westburg SP, Stone OJ. Multiple cutaneous squamous cellcarcinomas during immunosuppressive therapy. Arch Dermatol1973; 107:893-5.

13 Marshall V. Premalignant and malignant skin tumours inimmunosuppressed patients. Transplantation 1974; 17: 272-5.

14 Maize JC. Skin cancer in immunosuppressed patients. JAMA1977; 237: 1857-8.

Fig. 4 The patient, February 1983, 17months after excisionof the tumour and reconstruction ofthe left lower lid.

15 Hoxtell EO, Mandel JS, Murray SS, Schuman LM, Goltz RW.Incidence of skin carcinoma after renal transplantation. ArchDermatol 1977; 113: 436-8.

16 Duke-Elder S, MacFaul PA. The ocular adnexa. In: Duke-ElderS, ed. System of ophthalmology. London: Kimpton, 1974: 13:420.

17 Yanoff M, Fine BS. Ocular pathology: a text and atlas.Hagerstown: Harper and Row, 1975: 214.

18 Stewart WB, Nicholson DH, Hamilton G, Tenzel RR, SpencerWH. Eyelid tumors and renal transplantation. Arch Ophthalmol1980; 98: 1771-2.

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