Author Affiliations: Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University (Drs C. L. Shields, Say, and J. A. Shields and Mss Shields, Viloria, and Pearlstein), and College of Arts and Sciences, University of Pennsylvania (Ms Pearlstein), Philadelphia, and Biology Department, Franklin and Marshall College, Lancaster (Ms Shields), Pennsylvania; and College of Science, University of Notre Dame, Notre Dame, Indiana (Ms Viloria).
Objective To describe the clinical features of iridocorneal endothelial (ICE) syndrome in a group of patients referred because of suspected iris melanoma.
Methods In a noncomparative case series, we performed medical record review for clinical features of ICE syndrome in 71 patients.
Results At presentation, the median patient age was 54 years. All patients were referred for evaluation of a pigmented iris mass, suspected to be a melanoma. The iris color was blue or green in 51 (72%) and brown in 20 (28%). The mass proved to be a combination of iris stromal atrophy in 41 cases (58%) with exposure or loss of the underlying iris pigment epithelium; ectropion iridis in 24 (34%), imparting a disfigured iris with dark-brown color; iris nodules in 5 (7%); traction elevation with iris distortion from peripheral anterior synechia in 57 (80%); and corectopia in 53 (75%), a feature commonly found with iris melanoma. The mean extent of iris atrophy was 2 clock hours. Ectropion iridis was unidirectional in 10 and multidirectional in 14. Additional features of ICE included corneal endothelial guttata-like changes in 33 (46%), corneal edema in 7 (10%), iris pigment epithelial transillumination defects in 12 (17%), polycoria in 1 (1%), and secondary glaucoma with intraocular pressure higher than 22 mm Hg in 7 (10%).
Conclusions Iridocorneal endothelial syndrome can simulate iris melanoma. Features more suggestive of ICE syndrome include corneal endothelial guttata-like changes and edema, peripheral anterior synechia, multidirectional ectropion iridis, and iris atrophy.
Iridocorneal endothelial (ICE) syndrome is a spectrum of diseases that display common features of corneal endothelial abnormality leading to broad-based peripheral anterior synechiae, iris stromal nodules, and traction-related iris stromal atrophy and iris hole formation.1- 4 The end result of this condition is secondary angle-closure glaucoma.1- 8 This condition is often divided into essential (progressive) iris atrophy, Chandler syndrome, and Cogan-Reese syndrome. Corneal edema and glaucoma are the leading causes of visual loss in this syndrome. In a series of 37 patients with ICE syndrome, Wilson and Shields5 classified 8 (22%) with essential iris atrophy, 21 (57%) with Chandler syndrome, and 8 (22%) with Cogan-Reese syndrome. End-stage glaucomatous cupping of the optic disc was noted in 8 (22%). They commented that eyes with Chandler syndrome manifested more severe corneal edema whereas those with essential iris atrophy and Cogan-Reese syndrome showed more advanced secondary glaucoma.
The diagnosis of ICE syndrome is based on the presence of clinical abnormalities involving the corneal endothelium, anterior chamber angle, and iris, often confirmed with imaging modalities of specular microscopy, confocal microscopy, ultrasound biomicroscopy, and anterior segment optical coherence tomography.9- 12 Occasionally, the features are subtle and this condition is overlooked. Laganowski and coworkers6 evaluated 33 patients with ICE syndrome–related secondary glaucoma and noted that the underlying diagnosis of ICE syndrome was initially overlooked in 17 (68%).
Because of the broad phenotype of ICE syndrome, the differential diagnosis encompasses many conditions including Fuchs endothelial dystrophy, posterior polymorphous dystrophy, iris stromal hypoplasia, Rieger syndrome, aniridia, iridoschisis, ectopia lentis et pupillae, inflammatory nodules, Lisch nodules, iris flocculi (pigment epithelial cysts), and iris melanoma.2 The ICE syndrome features of corectopia, ectropion iridis, dark iris mass from iris stromal atrophy uncovering darker pigment epithelium, iris nodules from endothelial growth on the iris stroma, and synechia-related distortion of the iris could lead to the mistaken diagnosis of iris melanoma. In this report, we describe 71 patients referred with the presumed diagnosis of iris melanoma who ultimately proved to have ICE syndrome.
The computer-coded records of all patients evaluated on the Ocular Oncology Service at Wills Eye Institute were reviewed for codes for iris pseudomelanoma and iridocorneal endothelial syndrome between July 1974 and August 2010. Each record was evaluated for patient age at detection of ocular abnormality, race, sex, medical conditions, ocular conditions, ocular trauma, and family history of eye disease. The referral diagnosis was listed. Each eye was evaluated for symptoms, laterality, visual acuity, intraocular pressure, iris color, and anterior segment features including heterochromia; sentinel vessels; corneal edema, scarring, or endothelial changes; corectopia; polycoria; ectropion iridis; iris nodularity, atrophy, or synechia; and iris pigment epithelial defects.
There were 71 eyes of 71 patients referred for evaluation of iris melanoma and found to have ICE syndrome. The patient demographics are listed in Table 1. The mean age was 51 years and 54 (76%) were female and 17 (24%), male. Known glaucoma was present in 11 (15%) and herpes keratitis in 5 (7%). A history of ocular trauma was disclosed in 7 and family history of glaucoma in 3 (4%), corneal disease in 2 (3%), and cutaneous melanoma in 2 (3%). Symptoms included abnormal pupil in 33 (46%), decreased vision in 8 (11%), eye pain in 4 (6%), heterochromia in 3 (4%), and eye redness in 2 (3%), and symptoms were absent in 19 (27%).
The ocular features are listed in Table 2. The iris color was blue or green in 51 (72%) and brown in 20 (28%). Intraocular pressure was higher than 22 mm Hg in 7 (10%) and higher than 35 mm Hg in 2 (3%). The most common corneal features were endothelial guttata-like changes in 33 (46%) and edema in 7 (10%). The most common iris features were corectopia in 53 (75%), iris stromal atrophy in 41 (58%), and ectropion iridis in 24 (34%), with ectropion extending in a median of 3 separate directions per iris (Figures 1, 2, and 3). Peripheral anterior synechia were present in 57 (80%) and were broad based (≥2 clock hours) in 46 (65%).
Figure 1. Iridocorneal endothelial syndrome with peripheral anterior synechia and corectopia masquerading as iris melanoma because of iris contraction imparting a darker color at the 4:30 meridian (A), visible darker-colored iris adherence to the cornea in the angle region at the 2:00 meridian (B), iris stromal atrophy exposing a darker iris pigment epithelium at the 2:30 meridian (C), and extensive corectopia with a yellow-white angle mass from iridocorneal adhesion at the 4:30 meridian (D).
Figure 2. Iridocorneal endothelial syndrome simulating iris melanoma with features of dark ectropion iridis (A and B), iridocorneal adhesion from the 1:00 to 5:00 and 6:00 to 10:00 meridians (C), and extensive iris atrophy exposing the underlying iris pigment epithelium (D). Note the subtle multidirectional ectropion/corectopia toward the 12:00, 3:00, and 8:30 meridians (B) and more obvious multidirectional traction toward the 1:30 and 8:00 meridians (D).
Figure 3. Iridocorneal endothelial syndrome simulating iris melanoma in a middle-aged woman with a unilateral brown iris mass (A) that represented iris pigment epithelial adhesion to the corneal endothelium (B and C).
The underlying abnormality in ICE syndrome is the proliferation of corneal endothelial cells and Descemet membrane over the trabecular meshwork and onto the iris.3,4,13,14 Progressive enlargement and contraction of this membrane leads to iris traction with corectopia and ectropion iridis and eventual traction-related iris stromal atrophy and iris pigment epithelial holes. Further involvement of the trabecular meshwork with membrane overgrowth leads to angle-closure glaucoma.2 Studies have demonstrated that “ICE cells” are pleomorphic and large, with features of epithelial cells, including desmosomes, tonofilaments, and microvilli.3,13,14 The ICE cells show a similar profile of differentiation as normal limbal epithelial cells.13 This acquired endotheliopathy is speculated to arise from herpes simplex viral origin.15
Most previously reported clinical series of patients with ICE syndrome have emanated from glaucoma departments.1,2,5- 7 In 1978, Shields and coauthors1 reported 82 patients in their series of “the essential iris atrophies” and noted 56 (68%) were female and 63 (77%) had glaucoma (Table 3). Ocular features included corectopia in 58 (71%), ectropion iridis in 23 (28%), and polycoria in 20 (24%). In 1989, Wilson and Shields5 described the clinical features in 37 patients with ICE syndrome showing features of corneal edema in 14 (38%), peripheral anterior synechia in 34 (92%), corectopia in 27 (73%), ectropion iridis in 10 (27%), iris nodules in 7 (19%), and iris stromal atrophy in 20 (54%). In that series, the main focus was secondary glaucoma and the intraocular pressure was elevated over 22 mm Hg in 21 eyes (57%) and over 35 mm Hg in 6 (16%), with 8 eyes (22%) displaying an advanced cup-disc ratio of 0.9 to 1.0. In 1992, Laganowski and coauthors6 identified 66 patients with ICE syndrome and found 33 (50%) with glaucoma, commenting that the underlying diagnosis of ICE was overlooked in 25 of the 33 with glaucoma. They emphasized that the diagnosis of ICE syndrome should be considered in younger patients with unilateral glaucoma. More recently, Teekhasaenee and Ritch7 described ICE syndrome in 60 Thai patients and noted similarities of female preponderance and middle-age onset compared with white series. They could visualize a translucent membrane (representing endothelial overgrowth) in these Asian eyes, as the membrane contrasted against the dark brown irides.
Our cohort is different from previous series as our cases emanate from an ocular oncology department and all patients were referred with the presumed diagnosis of iris melanoma. In comparison with those from glaucoma departments1,5- 7 (Table 3), our cases are similar in that there was a female preponderance and the condition occurred in middle-aged white individuals. However, our cases differ in that there was far less glaucoma (15% vs 43%-77%), less corneal edema (10% vs 38%-72%), and less polycoria (1% vs 22%-24%). Additionally, the eyes in our series were more often subclassified with essential iris atrophy (49% vs 13%-33%) than most glaucoma series,1,5,7 except that of Laganowski and coworkers6 (59%).
In our series, the referring diagnosis of iris melanoma was suspected from features of iris nodules, iris elevation and distortion (corectopia, ectropion iridis) from peripheral anterior synechia, iris atrophy with exposure of underlying iris pigment epithelium, and the combined features with the presence of secondary glaucoma (Tables 2 and 4). Iris melanoma classically manifests as a circumscribed or diffuse tumor16- 19 (Table 5) (Figure 4). In a report on 169 eyes with iris melanoma, the tumor was classified as circumscribed in 121 (72%) and diffuse in 47 (28%).16 The circumscribed tumor appears as a solitary, nodular, pigmented mass within the iris stroma, often with intrinsic vessels and feeding vessels and surrounding tumor seeding on the iris stroma or within the angle (Figure 4). The diffuse form appears as a minimally thickened, irregular sheet of pigmented cells on the iris surface, often with secondary glaucoma from angle invasion (Figure 4).16,17,19 There is an unusual variant of diffuse melanoma in which the malignancy arises solely in the trabecular meshwork, producing secondary glaucoma without an obvious mass.20
Figure 4. Spectrum of iris melanoma with corectopia. Pigmented iris melanoma with corectopia (A-F), subtle ectropion iridis (B, D, and E), and prominent episcleral vessels (A, B, and D-F). The melanomas were classified as circumscribed (A-C, E, and F) and diffuse (E). Note the subtle adjacent iris seeding (A) and extensive seeding (D and E).
A comparison of the clinical features of ICE syndrome in this series with iris melanoma16 shows similarities and differences (Table 4) (Figures 1, 2, 3, and 4). The similarities (ICE syndrome vs melanoma) include mean age at presentation (51 years vs 48 years), prominent episcleral blood vessels (8% vs 25%), corectopia (75% vs 62%), ectropion iridis (34% vs 44%), and elevated intraocular pressure (8% vs 30%). Iridocorneal endothelial syndrome–related glaucoma is caused by membrane overgrowth onto the trabecular meshwork often leading to an angle-closure mechanism,6 whereas melanoma-related glaucoma is usually from trabecular meshwork infiltration by tumor.21,22 The differences include features found primarily with ICE syndrome such as corneal guttata-like changes (46% vs 0%), corneal edema (10% vs 0%), peripheral anterior synechiae (80% vs 0%), iris atrophy (58% vs 0%), iris transillumination light transmission (17% vs 0%), and multidirectional ectropion iridis/corectopia (20% vs 0%). Other differences relate to features found primarily with iris melanoma such as solid tumor compressed in angle (0% vs 46%), iris seeding of tumor (0% vs 56%), angle seeding of tumor (0% vs 57%), and extrascleral extension of tumor (0% vs 6%).
The differentiation of ICE syndrome from iris melanoma is important as the main therapeutic strategy for ICE syndrome–related glaucoma involves open surgical procedures,8 and these should be avoided in eyes with melanoma to prevent extraocular tumor spread. The treatment of iris melanoma depends on many factors including tumor size, tumor seeding, and presence of glaucoma. Large iris melanomas, particularly those with seeding and glaucoma, require enucleation or plaque radiotherapy whereas those without seeding or glaucoma can be managed with iridectomy, iridogoniectomy, iridogoniocyclectomy, or plaque radiotherapy, depending on the structures involved.17,23,24
In summary, ICE syndrome can simulate iris melanoma as is shown in our 71 cases. Both can produce corectopia, ectropion iridis, iris distortion, and glaucoma. Distinguishing features of ICE syndrome include corneal endothelial guttata-like changes, peripheral anterior synechia, iris atrophy, and multidirectional corectopia/ectropion iridis. These are rarely found with iris melanoma. Additional endothelial imaging could assist in confirming the benign condition of ICE syndrome from the malignant iris melanoma.
Correspondence: Carol L. Shields, MD, Ocular Oncology Service, Ste 1440, Wills Eye Institute, 840 Walnut St, Philadelphia, PA 19107 (firstname.lastname@example.org).
Submitted for Publication: November 27, 2011; final revision received January 25, 2011; accepted January 27, 2011.
Published Online: April 11, 2011. doi:10.1001/archophthalmol.2011.70
Author Contributions: Dr C. L. Shields has had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Financial Disclosure: None reported.
Funding/Support: Support provided by the Eye Tumor Research Foundation (Dr C. L. Shields).
Disclaimer: The funders had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; and in the preparation, review, or approval of the manuscript.
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