blood serum. A diagnosis of GO was ment on radiologic imaging (Figure, tient did not show signs of GO. To made. After resolution of inflamma- F). Antithyroid antibodies were the best of our knowledge, this is the tory symptoms, the retrac- found in his blood serum, but thy- first report to describe GO and IOI tion was surgically corrected. roid function test results were nor- that occurred in the same patients. Case 2. A 35-year-old woman with mal. A diagnosis of euthyroid GO In summary, we have described primary , had sub- was made. After resolution of in- 4 patients with both IOI and GO acute eyelid swelling, proptosis, eye- flammatory signs, his left was separated in both time of onset and ball motility restriction, and pain. On surgically decompressed. orbital localization. Idiopathic or- CT, the right lacrimal gland ap- bital inflammation and GO can be peared enlarged; biopsy of the gland Comment. In this article, 4 pa- differentiated by upper eyelid re- revealed lymphoid cells. She was tients with both GO and IOI sepa- traction, pain, and orbital localiza- treated for IOI () with rated in time of onset and localiza- tion inside or outside the extraocu- intravenous, high-dose methylpred- tion in the orbit are described. Both lar muscles. Therefore, the theory nisolone sodium succinate. Four GO and IOI share characteristics of that GO automatically rules out IOI years later she was treated for dac- proptosis and motility distur- is not necessarily true. ryoadenitis on the left side (Figure, bances, thus they are considered or- C) with intravenous steroids. bital inflammatory diseases. How- Ward R. Bijlsma, MD Four months after that treat- ever, some features differentiate GO Rachel Kalmann, MD, PhD ment, she had developed and from IOI. Upper eyelid retraction Correspondence: Dr Bijlsma, left upper eyelid retraction. Com- and enlargement of the bellies of the Department of , puted tomography revealed left- are considered University Medical Center Utrecht, sided extraocular muscle enlarge- pathognomonic for GO. Further- Heidelberglaan 100, 3584 CX ment (Figure, D). Thyroid antibodies more, in Graves disease, thyroid dys- Utrecht, the Netherlands (w.r.bijlsma were found in her blood serum, and function and antibodies against the @umcutrecht.nl). she was diagnosed as having unilat- thyroid are often, but not necessar- Financial Disclosure: None re- eral GO. To improve eyeball motil- ily, found. Idiopathic orbital inflam- ported. ity, she was treated with radiotherapy. mation can manifest itself with in- Funding/Support: This research was Case 3. A 30-year-old man with flammation of any orbital structure facilitated by an unrestricted grant diabetes mellitus, Crohn disease, and often with pain. In the patients from the F.P. Fischer Foundation. and , had bilateral described in this report, the local- painless proptosis, eyeball motility ization of orbital inflammation that 1. Yuen SJ, Rubin PA. Idiopathic orbital inflam- mation: distribution, clinical features, and treat- disturbances, and upper eyelid does not involve the muscles distin- ment outcome. Arch Ophthalmol. 2003;121(4): retraction. The extraocular muscles guished IOI from GO. Idiopathic or- 491-499. appeared enlarged on CT, and thy- bital inflammation of extraocular 2. Kennerdell JS, Dresner SC. The nonspecific or- bital inflammatory syndromes. Surv Ophthalmol. roid antibodies were found in his muscles, a condition known as myo- 1984;29(2):93-103. blood serum, which yielded a diag- sitis, is different from GO in that it 3. Gerlach M, Ferbert A. Pure eye muscle involve- nosis of GO. The disease resolved also affects the muscular tendon and ment in endocrine orbitopathy. Eur Neurol. 2008; 60(2):67-72. itself without therapy. not only the belly of the muscle, as 4. Cankurtaran M, Oyan B, Kilic¸kap S, Yavuz BB, At the age of 39 years, the patient is found in GO. However, this dis- Batman F. Idiopathic fibrosclerosis of bilateral orbits, bilateral ureters, thyroid: a case report and developed proptosis on the left side tinction can be difficult to make on review of the literature. Int Urol Nephrol. 2004; with eyeball motility disturbances. radiologic images, especially in the 36(4):495-498. Two months later the right side had case of pure eye muscle GO.3 become involved as well. Computed In 3 of the 4 patients, multiple au- tomography revealed lacrimal gland toimmune diseases were found. The enlargement, and a biopsy specimen finding of both GO and IOI in the showed chronic inflammation. A di- same patients could be explained by Delayed Diagnosis agnosis of IOI (dacryoadenitis) was the tendency of autoimmune dis- of Microcystic Adnexal made, and the patient was treated eases to occur together, but given the Carcinoma in Progressive with oral prednisone. low incidence rate of GO and IOI, it Eyelid Distortion Case 4. A 22-year-old man, had is more likely that both diseases share left-sided proptosis, eyeball motil- a yet-unknown common pathogen- Microcystic adnexal carcinoma ity disturbances, and pain. Com- esis. Remarkably, 2 of the 4 patients (MAC) is a rare, insidious, and highly puted tomography revealed a mass had hypothyroidism compared with infiltrative cutaneous malignant neo- in the medial superior orbit (Figure, the general population with GO, most plasm1 that mainly affects the facial E). The lesion was biopsied twice, of whom have hyperthyroidism. This region. Eyelid involvement has been which revealed fibrosis with some observation may point to a thyrotro- described in at least 50 cases, in- lymphocytes. He was diagnosed as pin-binding inhibitory antibody in cluding 8 with orbital extension. We having IOI and treated with radio- the pathogenesis. describe 3 patients with MAC in- therapy and oral prednisone. Cankurtaran et al4 described a pa- vading the orbit or cranium, all re- At the age of 27 years, he devel- tient with thyroid dysfunction and ferred very late after several years oped progressive proptosis of the left IOI that occurred together as part of of unexplained progressive eyelid eye and extraocular muscle enlarge- Riedel thyroiditis. However, their pa- distortion.

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Figure 1. Notched (arrow) and retracted left upper eyelid with no madarosis (A), and axial computed tomography showing a superolateral soft-tissue mass involving the left superior rectus-levator complex and extending into the cavernous sinus through the superior orbital fissure (arrowheads) (B). Report of Cases. Case 1. An other- neoplasm in a desmoplastic stroma, positive for the epithelial markers wise fit 53-year-old man was re- with nests and strands of epithelial BerEP4 and CK7. After Mohs mi- ferred with slowly progressive left cells showing focal perineural infil- crographic excision, the area was re- upper eyelid notching for 9 years, ip- tration (Figure 2A and B). Mild cy- paired with a hard palate mucosal silateral supraorbital hypoesthesia tological atypia and rare mitoses graft and a Mustarde´ cheek rota- for 6 years, and diplopia for 3 years; were present. With a diagnosis of tion flap. Neurogenic devel- the left eye was amblyopic from MAC, the patient was referred for oped 10 months after surgery, with childhood squint. Results from in- palliative radiotherapy. ipsilateral and decreased vestigations for thyroid disease and Case 2. A fit 24-year-old woman eye movements (Figure 3B). Com- myasthenia as well as 2 magnetic was referred with progressive right puted tomography showed patchy resonance imaging scans had been lower eyelid thickening for 7 years, opacification from the right cheek to reported as normal and—ignoring the lesion having been treated as a the orbital apex (Figure 3C) and bi- the eyelid distortion and cranial hy- following uninformative opsies confirmed extensive tumor in- poesthesia— surgery was biopsy 2 years prior to referral. filtration. The patient underwent or- performed. The patient was re- Topical therapy and intralesional bital exenteration and fractionated ferred to Moorfields Eye Hospital steroids were unsuccessful and external beam radiotherapy; tumor when his symptoms failed to resolve. development of eyelid retraction was present at the posterior mar- At his initial visit with us, his vi- prompted referral. gins of resection. sual acuity was 20/20 OU and he had Visual functions, posi- Case 3. A 70-year-old man had no dysfunction or intra- tions, and ocular ductions were slowly progressive right lower eye- ocular disease; 1-mm left relative normal on referral. The right lower lid thickening for several years. proptosis was evident, with ipsilat- eyelid margin was thickened medi- There were 2 firm intradermal nod- eral hyperphoria, reduced vertical ally with pearly changes, telangiec- ules in the medial part of the eyelid ductions, and supraorbital, supra- tasia, and mild distortion. but no madarosis, telangiectasia, ul- trochlear, and nasociliary hypoes- There was a subcutaneous mass ceration, or periocular sensory loss. thesia. The left upper eyelid was overlying the lower eyelid retrac- Right upgaze was reduced and com- peaked and retracted (Figure 1A), tors (Figure 3A) and MAC was fa- puted tomography revealed an en- with localized skin thickening and vored on clinical grounds: eyelid and hancing soft-tissue mass involving distorted tarsus but no madarosis. retractor biopsies revealed a dense the cheek, lower eyelid, and infe- No orbital mass or lymphadenopa- desmoplastic stroma pervaded by rior oblique and rectus muscles. Bi- thy was detected. Computed tomog- numerous small ducts with occa- opsy showed MAC with a slightly raphy revealed an ill-defined supero- sional tadpole-like morphology and hyalinized desmoplastic stroma con- lateral soft-tissue mass involving the accompanied by bland epithelial taining fine sheets and aggregates of superior rectus-levator complex and cells located within the superficial epithelial cells with large, atypical extending into the cavernous sinus dermis (Figure 2C). No cytological nuclei and prominent nucleoli but through the superior orbital fissure atypia or mitotic activity was pres- no mitotic activity; the epithelial (Figure 1B). Excision of the eyelid ent, but there was an infiltrative cells stained with BerEp4 and CK7. notch and deep orbital biopsies growth pattern with early perineu- The patient underwent orbital ex- showed an infiltrative malignant ral involvement; tumor cells were enteration.

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Figure 2. Low-power photomicrograph of full-thickness eyelid resection (case 1) showing scattered small islands of tumor set in reasonably well-circumscribed areas of desmoplasia (arrow) (original magnification ϫ40) (A), and medium-power photomicrographs from case 1 showing solid B C elements (box) in a desmoplastic background (B) and from case 2 showing ductlike elements (box) in a desmoplastic background (C) (hematoxylin-eosin, original magnification ϫ100).

Comment. Microcystic adnexal car- the clinician to this diagnosis. Like- resemble commas or tadpoles, and cinoma is a rare skin tumor of pilar wise, progressive multiple cranial perineural invasion is an important and eccrine differentiation1; the eti- nerve deficits over years (as in case diagnostic feature. Although MAC ology is unknown, although cases 1) should always alert a physician to does not have a unique immuno- have been described after radio- the likelihood of an insidious malig- phenotype, staining with BerEP4, therapy or immunosuppression.2 As nant neoplasm such as MAC. CK15, and CK7 helps differentiate in our cases, MAC progresses insidi- Histological confirmation of MAC MAC from desmoplastic trichoepi- ously and is often missed for years is difficult—the minimal cellular theliomas, infiltrative basal cell car- before diagnosis. The tumor may atypia giving it a bland appearance— cinoma, and squamous ductal manifest as yellow or flesh-colored and such tumors may be thought to carcinoma.4 nodules, as ill-defined plaques, or be benign or may be missed en- Treatment options for periocu- with relentless eyelid distortion; skin tirely (as in case 2 before referral). lar MAC include wide local exci- telangiectasia may be present but ul- Inadequate tissue sampling may re- sion, Mohs micrographic surgery, ceration or madarosis is rare.3 Micro- sult in less than 10% diagnostic and radiotherapy. Perhaps reflect- cystic adnexal carcinoma often shows yield.3 Eyelid distortion and retrac- ing the infiltrative nature of MAC, intraneural and perineural infiltra- tion are caused by an eosinophilic small series using Mohs surgery have tion, and eyelid distortion with pain desmoplastic reaction containing ec- shown a lower recurrence rate (0%- or periocular numbness should alert crine ducts or keratinized cysts that 12%) as compared with en bloc ex-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 and its presence in 2 of our patients A must limit their chance of cure (cases 1 and 2). Relentless eyelid retraction (in the absence of thyroid dysfunction) or distortion should always be re- garded as tumor-induced fibrosis un- til proven otherwise. Adequate bi- opsy specimens must be taken and B the histopathologist should be alerted to the diagnosis of MAC. In particu- lar, there should be a specific re- quest to search for sparse epithelial cells within deep tissues or dense fi- brosis—the presence of which is likely to confirm this diagnosis. Sidath E. Liyanage, MRCOphth George M. Saleh, FRCOphth C Geoffrey E. Rose, FRCOphth Philip J. Luthert, FRCPath Michele Beaconsfield, FRCOphth David H. Verity, FRCOphth Correspondence: Dr Rose, Adnexal Service, Moorfields Eye Hospital, City Road, London EC1V 2PD, England ([email protected]). Financial Disclosure: None re- ported.

1. Goldstein DJ, Barr RJ, Santa Cruz DJ. Microcys- tic adnexal carcinoma: a distinct clinicopatho- logic entity. Cancer. 1982;50(3):566-572. 2. Cooper PH, Mills SE. Microcystic adnexal Figure 3. Right lower eyelid margin showing thickening and pearly changes (A), appearance of onset of carcinoma. J Am Acad Dermatol. 1984;10(5, pt right third cranial nerve palsy with a dilated and recurrent ptosis (B), and axial computed 2):908-914. tomography showing patchy opacification throughout the right orbit, extending to the orbital apex (C). 3. Clement CI, Genge J, O’Donnell BA, Lochhead AG. Orbital and periorbital microcystic ad- nexal carcinoma. Ophthal Plast Reconstr Surg. 2005;21(2):97-102. 4. Hoang MP, Dresser KA, Kapur P, High WA, Ma- cision (30%-47%).5 Toluidine blue tive high-dose radiotherapy may be halingam M. Microcystic adnexal carcinoma: an staining during Mohs clearance used. Despite its invasive nature, immunohistochemical reappraisal. Mod Pathol. 2008;21(2):178-185. helps highlight tumor strands and periocular MAC has a fairly good 5. Leibovitch I, Huilgol SC, Richards S, Paver R, perineural invasion. Exenteration is prognosis, with only 7 cases of me- Selva D. Periocular microcystic adnexal carci- noma: management and outcome with Mohs’ mi- advised for perineural or orbital in- tastasis and 1 death reported. Intra- crographic surgery. Ophthalmologica. 2006;220 filtration, and palliative or adjunc- cranial invasion has been reported, (2):109-113.

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