Myxomatous Corneal Degeneration: A Clinicopathological Study of Six Cases and a Review of the Literature

Myxomatous Corneal Degeneration: A Clinicopathological Study of Six Cases and a Review of the Literature

SURVEY OF OPHTHALMOLOGY VOLUME 57  NUMBER 3  MAY–JUNE 2012 CLINICAL PATHOLOGIC REVIEWS STEFAN SEREGARD AND MILTON BONIUK, EDITORS Myxomatous Corn...

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SURVEY OF OPHTHALMOLOGY

VOLUME 57  NUMBER 3  MAY–JUNE 2012

CLINICAL PATHOLOGIC REVIEWS STEFAN SEREGARD AND MILTON BONIUK, EDITORS

Myxomatous Corneal Degeneration: A Clinicopathological Study of Six Cases and a Review of the Literature Michel J. Belliveau, MD,1,2 Walter N. Liao, MD,1,2 Seymour Brownstein, MD,1,2 Joshua S. Manusow, MD,1,2 David R. Jordan, MD,1 Steven Gilberg, MD,1 and George Mintsioulis, MD1 1

Department of Ophthalmology, University of Ottawa Eye Institute and The Ottawa Hospital, Ottawa, Ontario, Canada; and 2Department of Pathology and Laboratory Medicine, University of Ottawa and The Ottawa Hospital, Ottawa, Ontario, Canada

Abstract. Thirteen cases with myxomatous changes of the corneal stroma have been reported to date. We report six additional cases with clinical, histopathological, and immunohistochemical data. The clinical appearance is most often a gelatinous, whitish elevation with insidious onset. Histopathologically, there are inconspicuous spindle- and stellate-shaped cells in a loose, myxoid matrix. The typical location is in the anterior cornea beneath the epithelium, with varying degrees of extension into the stroma. Vimentin and smooth-muscle actin immunohistochemical stains are characteristically positive, and staining occasionally may be seen with muscle-specific actin, whereas CD34 staining usually is negative. In most cases, myxomatous changes are a degenerative process involving transformation of stromal keratocytes into cells with prominent secretory activity and myofibroblastic differentiation. Most occur in corneas with a history of ocular disease or trauma that disrupts Bowman’s layer. We suggest labelling lesions with these features as ‘‘myxomatous corneal degeneration.’’ So-called ‘‘primary corneal myxomas’’ also exist where there is no significant history. It remains unclear whether the myxomatous changes in such lesions are neoplastic or degenerative. Myxomatous corneal changes are likely under-recognized and under-diagnosed. (Surv Ophthalmol 57:264--271, 2012. Ó 2012 Elsevier Inc. All rights reserved.) microscopy  histopathology  immunohistochemistry Key words. cornea  electron myofibroblast  myxoma  myxomatous degeneration  trauma

Myxomas are benign lesions, occurring most often as intramuscular tumors, and are characterized histopathologically by an abundant myxoid matrix with sparse collagen, scattered stellate- or spindleshaped cells, and a poorly developed vasculature.33 The cells are modified fibroblasts and myofibroblasts capable of producing excessive amounts of



glycosaminoglycans rich in hyaluronic acid. Whether myxoma represents a benign neoplasm or reactive proliferation of hypersecretory fibroblasts and myofibroblasts is still uncertain. A similar histopathological phenotype of stellate- and spindleshaped cells within a glycosaminoglycan-rich myxoid matrix may be seen as a degenerative process, 264

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particularly in heart valves. In mitral valves with myxomatous degeneration, the valvular interstitial cells have features of activated myofibroblasts and express excessive levels of catabolic enzymes, leading to matrix degradation and remodeling.27 Thirteen cases displaying myxomatous features in the cornea have appeared in the literature (Table 1), mostly within the past decade, each of which was labeled a ‘‘myxoma.’’1,3,9,15,18-21,25,26,28,29,34 The majority have followed either a corneal disease that compromised Bowman’s layer, or accidental or iatrogenic trauma. So-called ‘‘primary corneal myxomas’’ also have been reported.9,18,20,25,29 It remains unclear whether the primary myxomatous changes in these corneas are neoplastic, reactive, or degenerative. We report a further six cases of myxomatous corneal degeneration with their histopathological, immunohistochemical, and, in two cases, ultrastructural features. Myxomatous corneal degeneration is considered to be a rare lesion, but we believe that it is under-recognized and under-reported. Our six cases were seen over a period of three years (2008--2010).

Case Reports CASE 1

A 45-year-old man was referred for assessment of his blind, painful right eye. He had had two penetrating traumas to his right cornea at ages 12 and 28. Their management included a pars plana lensectomy with intraocular lens (IOL) insertion, followed by a penetrating keratoplasty with exchange for an anterior chamber IOL, and then a trabeculectomy. The visual acuity (VA) gradually declined to no light perception. A dense leukoma was present in the keratoplasty graft (Fig. 1A). He underwent evisceration of the right ocular contents for pain. Light microscopy of the right cornea revealed a thick pannus of myxoid-appearing material containing spindle and stellate cells between the epithelium and Bowman’s layer (Figs. 1E, 1F). The pannus was predominantly loosely arranged, with more dense fibrous tissue seen adjacent to and focally extending through breaks in Bowman’s layer. Scattered islands of epithelium were present in the pannus. There was a moderate chronic inflammatory cell infiltrate and vascularization in the deeper areas of the myxoid tissue and in the corneal stroma. Descemet’s membrane was focally fragmented, and the endothelium was severely attenuated, with less than one cell present per high power field. A dense fibrovascular ingrowth extended along most of the posterior surface, and this was adherent to the anterior iris surface on one side.

Staining with colloidal iron and Alcian blue confirmed the presence of glycosaminoglycans in the myxoid-appearing pannus (Fig. 1G). The spindle and stellate cells stained positive for vimentin, muscle-specific actin (MSA), and focally for smooth muscle actin (SMA) and S-100 (Table 1). Epithelial markers (AE1/AE3, CK903, and CK8.18), desmin, CD68, glial fibrillary acidic protein, and neuron-specific enolase were negative. The cells in the corneal stroma stained positive with CD34, but this was negative in the cells within the myxoid pannus. Electron microscopy disclosed stellate- and spindle-shaped cells with prominent nucleoli and nuclear membrane invaginations (Figs. 2A, 2B). The cytoplasm contained abundant rough endoplasmic reticulum and Golgi apparatus. Sparse clusters of collagen were present extracellularly. CASE 2

A 76-year-old man was referred for decreasing vision in his left eye from a cataract. He had injured both eyes 10 years previously in a motor vehicle accident with a corneal perforation in his right eye. His past ocular history included a right cataract extraction and lens implant. VA was counting fingers (CF) in both eyes. A hazy, scarred cornea with areas of severe thinning was noted in the right eye (Fig. 1B). The left eye had a dense cataract and a corneal scar. The intraocular pressure was 10 mm Hg bilaterally. He underwent a left cataract extraction, but postoperatively the vision remained CF. Nine months later, he had a right penetrating keratoplasty. The visual acuity was CF on postoperative day 1, and he did not return for further follow-up. Light microscopic examination of the right penetrating keratoplasty specimen showed an irregular epithelium and absent Bowman’s layer in most of the specimen. Myxomatous degeneration was present subepithelially. Some of the constituent cells were multinucleated and contained intranuclear vacuoles. This area blended with the adjacent scarred stroma, which showed a moderate chronic inflammatory cell infiltrate, and vascularization of the deep layers. An area of severe stromal thinning was evident. Descemet’s membrane was disrupted centrally and the endothelium showed moderate attenuation with five cells present on average per 400 high power field. Fibrous ingrowth was present along the posterior corneal surface in the vicinity of the disruption. The immunohistochemical findings were similar to those described for Case 1 (Table 1) except staining for S-100 was negative.

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Clinical and Immunohistochemical Features of All Reported Cases of Corneas with Myxomatous Features Reference

Age (years)

Sex

Case 1 Case 2 Case 3

45 76 69

M M M

Case 4 Case 5 Case 6 Previously reported by our lab; Robinson et al28 Mitvalksy21

63 73 80 55

History

Appearance

Source of Specimen

Vimentin

SMA

MSA

White, gelatinous elevation Glistening, whitish elevation Opaque cornea, central thinning White, gelatinous Whitish opacity White, gelatinous Gelatinous, whitish

Evisceration PK Evisceration

þ þ þ

Focal þ þ

þ Focal þ

M M M M

Trauma, PK Trauma, cataract surgery Trauma, cataract surgery, scleral buckle Trauma Trauma, PK, cataract surgery PK Trauma, multiple PTK

Evisceration Lamellar biopsy Lamellar biopsy PK

þ þ þ þ

Focal Focal Focal þ

Focal þ -

26

F

Keratitis, staphyloma resection

Enucleation

NR

NR

NR

Bussy3

66

M

Ulcer

Enucleation

NR

NR

NR

Pe´rez-Grosmann et al26 Le´ger et al19 Wollensak et al34

57 26 48

M F M

Evisceration PK Superficial keratectomy

NR þ þ

NR NR -

NR NR

4 months 58

F M

Hazy cornea, focal elevation Whitish, elevated lesion

PK Lamellar keratectomy

NR NR

þ NR

NR NR

44 36 65 56 70

F F M F M

Ulcer Keratoconus Trauma, scleral buckle, lensectomy, bullous keratopathy Peters’ anomaly Cataract surgery, pterygium removal No ocular disease or trauma Strabismus surgery No ocular disease or trauma No ocular disease or trauma No ocular disease or trauma

Soft, pedunculated, reddish mass Opaque and firm cornea, stromal vessels White nodule Translucent, whitish mass Whitish elevation

Gelatinous, whitish mass Whitish, fleshy opacity White gelatinous Gelatinous, raised lesion Whitish nodule

Superficial Superficial Superficial Superficial Superficial

NR þ NR NR þ

NR þ þ NR -

NR þ NR NR NR

Khan et al15 Alkatan et al1 Lo et al20,a Hansen et al9,a Soong et al29,a Lang et al18,a Peralta et al25,a

keratectomy keratectomy keratectomy keratectomy keratectomy

BELLIVEAU ET AL

M 5 male; F 5 female; MSA 5 muscle-specific actin; NR 5 not reported; PK 5 penetrating keratoplasty; PTK 5 phototherapeutic keratectomy; SMA 5 smooth muscle actin. a These five cases were reported as ‘‘primary corneal myxoma.’’

Surv Ophthalmol 57 (3) May--June 2012

TABLE 1

MYXOMATOUS CORNEAL DEGENERATION

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Fig. 1. Clinical photographs showing the characteristic elevated, whitish, gelatinous appearance of myxomatous corneal degeneration (A, Case 1; B, Case 2; C, Case 4; D, Case 6). The texture is soft and indentation of the lesion can often be performed clinically with an object such as a cotton swab. Case 6 had a preoperative diagnosis of myxomatous corneal degeneration. E: Case 1: Subepithelial, hypocellular lesion of the cornea (hematoxylin and eosin, original magnification 25). F: Case 1: Spindle- and stellate-shaped cells in a loose, myxoid matrix (hematoxylin and eosin, original magnification 640). G: Case 1: Abundant glycosaminoglycans in the myxoid matrix (colloidal iron, 200). H: Case 4: The spindle and stellate cells in the myxoid matrix stain positive for vimentin (vimentin immunoperoxidase, 640).

Electron microscopic examination of the right corneal button showed similar findings as in Case 1, except there was more extracellular collagen. CASE 3

A 69-year-old man described 2 years of pain in his blind left eye. He had injured his left eye in a motor vehicle accident. He subsequently had a left cataract

extraction and a scleral buckle for a retinal detachment without much improvement in his vision. He lost his remaining vision shortly thereafter. On examination, he had a phthisical left eye with no light perception (NLP), an intraocular pressure (IOP) of !1 mm Hg, and severe central corneal thinning. An evisceration was performed. Histopathological examination showed a severely thinned cornea centrally, including an area where

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Surv Ophthalmol 57 (3) May--June 2012

BELLIVEAU ET AL CASE 4

A 63-year-old man was referred for assessment of a blind, painful right eye. He had suffered a pellet gun injury at age 12 that ultimately left this eye NLP. His cornea was opaque, vascularized, and ectatic (Fig. 1C). Evisceration was performed. Light microscopic examination of the right cornea revealed myxomatous degeneration. There were numerous blood vessels and lymphatic vessels that stained with D2-40, and a moderate chronic inflammatory cell infiltrate within the connective tissue matrix and remaining stroma. There was acanthosis of the epithelium, and Bowman’s layer was only focally present in the adjacent fibrovascular pannus. A dense fibrous ingrowth was present on the posterior surface. Immunohistochemical studies were similar to those of the previous cases (Table 1), except some of the spindle cells in the periphery of the myxoma stained positive with CD34. CASE 5

Fig. 2. A: Case 1: Electron micrograph shows a stellateshaped cell with nuclear indentations and abundant rough endoplasmic reticulum (R) (original magnification 9000). B: Case 2: Electron micrograph of spindle-shaped cells with nuclear indentations, abundant rough endoplasmic reticulum (R) and loosely arranged extracellular collagen (original magnification 9000).

only acanthotic epithelium was seen without underlying stroma or Descemet’s membrane. In the adjacent superficial corneal stroma on one side, myxomatous degeneration was evident. The overlying epithelium also was acanthotic, and there was no Bowman’s layer in this area. Several blood vessels along with scattered macrophages and plasma cells also were present. The remaining Descemet’s membrane and the endothelium were mostly preserved. A focal fibrous ingrowth was identified. The immunohistochemical results were similar to those described for Case 2 (Table 1).

A 73-year-old man was assessed for an intermittently uncomfortable left eye that had no useful vision. His ocular history was significant for trauma sustained during a fall from a tree as a child, damaging the left eye, which was repaired surgically. He underwent a left penetrating keratoplasty and cataract extraction at age 57, followed by a lamellar keratectomy and a Gundersen flap because of graft failure. He had only LP in the left eye, and the IOP was 20 mm Hg. His left cornea was opaque and vascularized. The cause of his discomfort was thought to be recurrent corneal erosions so he was scheduled for phototherapeutic keratectomy. Based on our experience from our previous cases, the preoperative diagnosis was myxomatous corneal degeneration, and a corneal biopsy also was performed. Light microscopic examination disclosed myxomatous corneal degeneration with occasional round, plump cells and tadpole-shaped cells. Immunohistochemical staining was similar to that in our prior cases except for negative staining for MSA (Table 1). CASE 6

An 80-year-old man who was being followed for a right failed graft post-penetrating keratoplasty was evaluated for recurrent erosions. Visual acuity was CF. The cornea was vascularized and the graft was opaque (Fig. 1D). The clinical appearance was suggestive of myxoma so a biopsy was performed in conjunction with phototherapeutic keratectomy for the recurrent erosions.

MYXOMATOUS CORNEAL DEGENERATION

Light microscopy disclosed spindle-shaped cells in a loose myxoid matrix. Immunohistochemical staining was similar to that noted with Case 1 (Table 1).

Discussion Myxomas are uncommon benign tumors characterized by a hypocellular and hypovascular myxoid stroma with abundant glycosaminoglycans rich in hyaluronic acid.33 The constituent cells are modified fibroblasts and myofibroblasts with prominent secretory activity. Systemically, myxomas are found most commonly intramuscularly in the large muscles of the thigh, shoulder, buttocks, and upper arm and also occur in the atria of the heart, usually on the left side.2,33 Less commonly, myxomas arise juxtaarticularly, especially at the knee and the jaw, and cutaneously. Myxomas can be distinguished from low-grade myxoid sarcomas (myxoid liposarcoma, myxoid chondrosarcoma, and myxofibrosarcoma) by their lack of pleomorphism and their inconspicuous vascularity, and in the case of myxoid chondrosarcoma, a hyaluronic acid rather than chondroitin sulfate matrix.33 Other diagnostic considerations include myxoid neural tumors, spindle cell lipoma, and botryoid rhabdomyosarcoma. Whether systemic myxoma represents a benign neoplasm or reactive proliferation of hypersecretory fibroblasts and myofibroblasts is still uncertain. Their benign clinical behavior is compatible with either. Okamoto et al have identified an activating missense mutation in the Arg201 codon of the gene encoding the alpha subunit of the G protein that stimulates cAMP formation (GNAS1) in intramuscular myxoma.22 They also demonstrated that the same mutation is not present in juxta-articular myxoma.23 Enzinger initially suggested that the cells in intramuscular myxoma, instead of going into a proliferative phase as seen in nodular fasciitis, enter a secretory phase and produce vast amounts of extracellular mucoid substance and occasional collagen fibers.6 This hypersecretory activity of the fibroblasts and myofibroblasts is confirmed ultrastructurally by the presence of abundant dilated rough endoplasmic reticulum, Golgi complexes, and pinocytotic vesicles.10 Our electron microscopy of myxomatous corneal degeneration shows similar features. Nodular fasciitis is another benign process composed of fibroblasts and myofibroblasts. The proportion of myxoid and fibrous stroma varies, but this lesion is distinguished from myxoma by the higher density of fibroblasts arranged into bundles and fascicles, a higher mitotic rate, and increased vascularization.33 Myxoma has been described in the conjunctiva, eyelid, and orbit.8,11-14,24 Myxoma or myxomatous

269

change of the cornea has been described in 13 cases1,3,9,15,18-21,25,26,28,29,34 (Table 1), mostly within the past decade, and we report a further six cases. Myxomatous corneal degeneration appears to represent a degenerative process involving transformation of stromal keratocytes into cells with prominent secretory activity and myofibroblastic differentiation. The majority of cases occur in corneas with a history of ocular disease or trauma that disrupted the integrity of Bowman’s layer. So-called ‘‘primary corneal myxomas’’ also exist where there is no apparent significant history (Table 1).9,18,20,25,29 The clinical appearance is most often a gelatinous, whitish elevation of the cornea. In some cases clear cornea is evident between the lesion and the limbus, supporting a corneal origin. These are located in the anterior cornea beneath the epithelium, with varying degrees of extension into the stroma. Their onset is typically insidious. The clinical differential diagnosis includes pannus, Salzmann nodular degeneration, keloid, amyloid deposition, dermoid, and squamous cell carcinoma. In 1894, Mitvalsky published the first report of a corneal myxoma.21 He described a 26-year-old woman with childhood tuberculous keratitis who developed a partial corneal staphyloma that was resected at age 16 years. Ten years later, over a 3month period, she developed a pea-sized, lobulated, reddish tumor on her central cornea. There was a decreased corneal diameter of 8--9 mm and peripheral neovascularization. The lesion was soft, shiny, and pedunculated, with a 4-mm diameter stalk fixed to the central corneal surface. It extended well beyond the eyelid margin, ultimately reaching the size of a hazelnut, and symptoms of irritation prompted enucleation of the phthisical eye. The specimen showed stellate- and spindleshaped cells in a mucoid background, as well as cysts within the lesion. Mitvalsky believed that the lesion was idiopathic and primary, but astutely commented that the history of inflammation and surgery could not be ignored and that it was possible that this was a secondary process in a traumatized cornea.21 ‘‘Corneal myxomas’’ with antecedent corneal disease or trauma have been reported in seven more patients.1,3,15,19,26,28,34 The clinical histories and appearance of the lesions are summarized in Table 1. We suggest that all are best considered examples of ‘‘myxomatous corneal degeneration.’’ Of the 13 reported cases of corneal myxoma, 5 were considered primary (Table 1).9,18,20,25,29 In 1990, Lo et al reported the first case of corneal myxoma since 1925 and brought this entity to the attention of the current generation of ophthalmologists and ophthalmic pathologists.20 They described a 44year-old woman with a gelatinous, whitish mass that

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Surv Ophthalmol 57 (3) May--June 2012

had histopathological and ultrastructural features of myxoma. The patient had no history of ocular disease or trauma. Bowman’s layer was absent in the examined sections, but the specimen was from a superficial keratectomy; thus, their impression was that Bowman’s layer remained in the native cornea. Hansen et al described a primary corneal myxoma in a 36-year-old woman with no history of corneal pathology or trauma, but with a fragmented Bowman’s layer.9 Soong et al reported another primary case with rapid growth over 3 months in a 65-year-old man with no known trauma.29 They demonstrated that corneal ultrasound biomicroscopy can be helpful in planning surgical removal. Their lesion was subepithelial and easily removed by superficial keratectomy over an intact Bowman’s layer. Peralta and colleagues’ case of ‘‘primary corneal myxoma’’ arose in the limbal area over 1 month in a 70-year-old man without a history of ocular disease or trauma.25 This extended over an apparently intact peripheral Bowman’s layer, and had a dense collagenous matrix. Lang et al describe a similar corneal limbal primary myxomatous lesion, but with focal disruption of Bowman’s layer.18 Although in some of these five cases disruption of Bowman’s layer was not observed, a focal disruption missed on pathology cannot be excluded with certainty. Entrapment of keratocytes between the corneal epithelium and Bowman’s layer during embryogenesis has been proposed as an explanation for primary myxoma,29 and it is plausible the keratocytes could remain above Bowman’s layer during stromal differentiation. Furthermore, the primary corneal limbal myxomas may be derived from limbal fibroblasts, rather than from corneal stromal keratocytes.18,25 The immunohistochemical profile of both primary corneal myxoma and myxomatous corneal degeneration characteristically reveals staining with vimentin and may show staining with SMA and, less frequently, with MSA (Table 1). Vimentin is an intermediate filament protein expressed in all mesenchymal cells, including myofibroblasts. SMA isoforms also are expressed by myofibroblasts, and in some cases staining is present only in the peripheral cytoplasm in a ‘‘tram-track’’ pattern corresponding to the peripheral actin filament bundles characteristic of this cell type.7 Actin is expressed by all cell types, and the label ‘‘musclespecific actin’’ is somewhat of a misnomer because the distinction is quantitative rather than qualitative, with muscle cells having far more actin than other cell types.7 Rare cells within myxomas found elsewhere in the body stain for actins, and staining also has been demonstrated in both conjunctival and orbital myxomas.11,12,33 The absence of CD34 staining within most corneal myxomas and corneas

BELLIVEAU ET AL

showing myxomatous degeneration is consistent with previous reports of loss of normal keratocyte CD34 positivity in diseased corneas.32 Carney complex is an autosomal dominant multiple neoplasia syndrome caused by mutations at 17q2 (type1) and 2p16 (type 2) in which myxoma, particularly cutaneous and cardiac, is associated with spotty pigmentation of mucous membranes (including the conjunctiva) and skin, freckles, lentigines, nevi, and endocrine overactivity (e.g., Cushing syndrome and acromegaly).4,16,17,30 It is important to diagnose cardiac myxoma because 24% of affected patients die of its complications, including emboli, heart failure, and dysrhythmia.2 Other manifestations of Carney complex include psammomatous melanotic schwannoma of the gastrointestinal tract, Sertoli cell tumor of the testicle, and pulmonary tumors such as chondroma and leiomyosarcoma.18,31 Myxoma of the eyelid is common in Carney complex, and orbital myxoma also has been reported.8,13,14 Kennedy et al found eyelid myxomas in 10 of 63 patients with Carney complex—along with facial and eyelid lentigines in 70% and pigmented lesions of the caruncle or conjunctival semilunar fold in 27%.13 To our knowledge, myxoma of the cornea or conjunctiva has not been reported with Carney complex. The ‘‘orbital myxoma’’ described in Carney complex by Kennedy et al14 has been cited as an example of ‘‘conjunctival myxoma’’5 but careful review of their description suggests that the authors were correct in labelling this as ‘‘orbital’’. We recommend that patients with a cardiac myxoma be referred for an ophthalmological examination, including the eyelids, conjunctiva, cornea, and orbit, although only eyelid and orbital myxomas are reported in the Carney complex.

Conclusion In conclusion, myxomatous corneal degeneration should be in the ophthalmologist’s and pathologist’s differential diagnosis of an elevated, whitish, gelatinous lesion of the cornea. If there is no history of corneal disease or trauma, the most appropriate description may be ‘‘primary corneal myxoma’’. We prefer the term ‘‘myxomatous corneal degeneration’’ for those corneal lesions with a history of trauma or chronic corneal disease.

Method of Literature Search Searches of the Medline (1948--2010) and Embase (1947--2010) databases were performed using the OVID interface. The search was conducted using

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the following key words: myxoma, myxomatous, cornea, ocular, and eye. Articles cited in the reference lists of the retrieved articles were also reviewed. Articles in languages other than English or French were not included, although none were identified.

Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. This article was presented, in part, at the Annual Meeting of the American Association of Ophthalmic Pathologists, Chicago, Illinois, on 15 October 2010.

17.

18. 19. 20. 21. 22. 23.

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The authors thank Jeffrey McClintock, MSc, for providing his technical expertise to assist with the electron microscopy studies and Andre´ Jastrzebski, MD, for his technical contributions. Reprint address: Seymour Brownstein, MD, University of Ottawa Eye Institute, 501 Smyth Rd, Room W6213, Ottawa, ON, Canada, K1H 8L6. e-mail: [email protected]