PSEUDOMELANOMAS OF THEPOSTERIOR UVEAL TRACTThe 2006 Taylor R. Smith LectureJERRY A. SHIELDS, MD, ARMAN MASHAYEKHI, MD, SEONG RA, BS,CAROL L. SHIELDS, MD

Purpose: To determine the types and frequency of lesions that clinically simulatechoroidal or ciliary body melanoma (posterior uveal melanoma; PUM).

Patients and Methods: A review was conducted on cases of patients referred to theocular oncology service from October 1978 through September 2003 with the diagnosis ofpossible PUM but who were subsequently diagnosed by the authors to have a simulatinglesion rather than PUM. The type and percent of pseudomelanomas were tabulated andcompared with findings of a similar study from our service on data collected before 1978.

Results: There were �12,000 patients referred because of a lesion believed to be aPUM during the 25 years included in the data collection. Of these patients, 1,739 (14%)were found to have a simulating condition. There were 54 different conditions that simu-lated melanoma. The most frequent condition was choroidal nevus, accounting for 851cases (49%) of the pseudomelanomas. This was followed by peripheral exudative hem-orrhagic chorioretinopathy (139 cases; 8%), congenital hypertrophy of the retinal pigmentepithelium (108 cases; 6%), hemorrhagic detachment of the retina or pigment epithelium(86 cases; 5%), circumscribed choroidal hemangioma (79 cases; 5%) and age-relatedmacular degeneration (76 cases; 4%). Compared with the 1980 report, the rate ofpseudomelanomas diagnosed as choroidal nevus increased from 26% to 49%.

Conclusion: A variety of lesions can simulate PUM. Suspicious choroidal nevus is still thelesion most difficult to differentiate from PUM. Most other pseudomelanomas account for alower percent compared with findings from the prior study, suggesting that clinicians are nowmore familiar with the other pseudomelanomas and less likely to refer them to rule out PUM.

RETINA 25:767–771, 2005

Several lesions can clinically simulate ciliary bodyor choroidal melanoma (posterior uveal melano-

ma; PUM).1–4 Historically, many eyes with simulating

lesions were enucleated because PUM was highlysuspected.5–7 With increased awareness of the clin-ical features of these pseudomelanomas combinedwith selective ancillary studies and more conserva-tive treatments, the problem of erroneous enucle-ation has been alleviated.8 However, there are stillmany patients referred to an ocular oncology centerwith the diagnosis of PUM who are subsequentlydiagnosed to have a simulating condition. We reportour experience with these simulating lesions overthe last 25 years and compare the results with thoseof an earlier study of pseudomelanomas from thesame facility.

From the Oncology Service, Wills Eye Hospital, Thomas Jef-ferson University, Philadelphia, Pennsylvania.

Supported by the Eye Tumor Research Foundation, Philadel-phia, PA (Drs. C. Shields and J. Shields), the Award of Merit inRetina Research, Houston, TX (Dr. J. Shields), the Macula Foun-dation, New York, NY (Dr. C. Shields), and the Rosenthal Awardof the Macula Society (Dr. C. Shields).

To be presented as the 2006 Taylor R. Smith Lecture, AspenRetinal Detachment Society, Aspen, Colorado, March 8, 2006.

Reprint requests: Jerry A. Shields, MD, Ocular Oncology Ser-vice, Wills Eye Hospital, 840 Walnut Street, Philadelphia, PA19107; e-mail: jerry.shields@shieldsoncology.com

767

Patients and Methods

Since 1974, we have recorded the referral diagnosisof all new patients seen at the oncology service. If thepatient had a referral diagnosis of ciliary body orchoroidal melanoma but proved by examination tohave a different diagnosis, the case was also coded asa pseudomelanoma. We included only those patientswho were referred because of legitimate concern overPUM. In this study, we reviewed our files from Oc-tober 1978 through September 2003 to determine thetype and frequency of pseudomelanomas. Data werecollected regarding patient age, race, and sex. Theexact tissue affected and the final diagnoses wererecorded. We compared the incidence of the specificpseudomelanomas with those from a prior study fromour service in which data collection included the 5years before October 1978.4

Because we did not have histopathologic confirma-tion that a small melanocytic choroidal lesion was anevus, rather than melanoma, we relied on certaincriteria that we used for years to make a presumptivediagnosis. We generally coded a melanocytic lesion asa nevus if it were �6 mm in diameter and �2.5 mmin thickness and as a melanoma if it were �6 mm indiameter and �2.5 mm in thickness. However, therewas some variability in coding such lesions. For ex-ample, if a lesion were in the nevus size range but hadsurface orange pigment, subretinal fluid, and docu-mented growth, we upgraded it to a melanoma forpurposes of diagnostic coding, and it was not includedwith the pseudomelanoma tabulations. Likewise, if alesion were barely in the melanoma size range but hadsurface drusen, had no subretinal fluid, and had notbeen documented to, it was coded as a nevus and wasincluded in the study as a pseudomelanoma. All pa-tients were observed by us or by referring physicians,and in the rare instance where a presumed nevusshowed subsequent growth, it was reclassified as amelanoma and was not included in the pseudomela-noma statistics.

Results

During the 25 years included in the data collection,there were �12,000 patients referred to the oncologyservice because of a lesion suspected to be a possiblePUM. General ophthalmologists or retinal specialistsreferred most patients. Demographic information isincluded in Table 1. Most patients were adult whites.Pseudomelanomas occurred in middle-aged or olderpatients, similar to the age distribution for PUM. Thenumber and percent of the various pseudomelanomasare shown in Table 2. There were 1,739 patientswhose cases were coded as pseudomelanomas, repre-

senting 14% of all patients referred with the diagnosisof possible PUM. Thus, 86% of patients referred witha diagnosis of PUM had a correct diagnosis. The mostfrequent pseudomelanoma was choroidal nevus,which accounted for 851 cases or 49% of the totalnumber of simulating lesions. Other conditions thatwere referred to rule out PUM are shown in Table 2.

Discussion

The conditions that can simulate PUM and thefeatures that help distinguish them from PUM are welldescribed in the literature.1–4 In our series, choroidalnevus was the most frequent pseudomelanoma, ac-counting for 49% of cases. This represents a sharpincrease since the 1980 report,4 in which choroidalnevus represented 27% of cases. We realize that byusing the criteria for differentiating nevus from mel-anoma as described under Patients and Methods wecould have made a few errors in the diagnosis ofborderline lesions. However, based on our clinicalexperience and on publications in the literature, suchcategorization should separate nevus from melanomain most cases. A lesion with two or more risk factorsfor metastasis was generally classified as melanoma,depending on all of the clinical circumstances.9–11

There are possible explanations why choroidal ne-vus accounted for a higher percent of pseudomela-noma in this series as compared with prior studies.First, ophthalmologists have become more familiarwith the clinical features of the various lesions thatsimulate melanoma, like disciform macular degener-ation, congenital hypertrophy of the retinal pigmentepithelium (RPE), choroidal hemangioma, and choroi-

Table 1. Demographic Features of Pseudomelanoma in1,739 Consecutive Patients

Feature Value

AgeMean 61 yMedian 64 yRange 8 wk to 97 y

Race, no. (%)*White 1,643 (94)African American 52 (3)Hispanic 15 (1)Asian 29 (2)

Sex, no. (%)Male 717 (40)Female 1,022 (60)

Follow-up (mo)Mean 21Median 5Range 6–299

* Information on race was not available for 56 patients.

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dal metastasis, and are less likely to refer them assuspected melanoma. Second, our group in recentyears has propagated treatment of selected borderlinelesions that possess reported risk factors for growthand metastasis, thus stimulating more referrals forborderline lesions.

The second most frequent pseudomelanoma was

peripheral exudative hemorrhagic chorioretinopathy(peripheral diskiform degeneration), which accountedfor 139 cases (8%). It accounted for 11% of cases inour prior series and still represents a lesion that oftenprompts referral for a possible PUM.2,4 However, theclassic appearance of subretinal blood in variousstages of resolution is different from a comparable-sized peripheral choroidal melanoma that would beunlikely to cause appreciable subretinal hemorrhage.We acknowledge that there could be some overlapamong the lesions that we called peripheral exudativehemorrhagic chorioretinopathy, hemorrhagic detach-ment of the retina or RPE, and age-related maculardegeneration. However, we coded a lesion as periph-eral exudative hemorrhagic chorioretinopathy if it oc-curred as a hemorrhagic and/or exudative lesion in theequatorial region in an older person in the setting ofperipheral drusen. We coded any other cause of hem-orrhage besides peripheral exudative hemorrhagic chori-oretinopathy and age-related macular degeneration ashemorrhagic detachment of the retina or RPE. Causes ofsuch bleeding included hemorrhage from retinal macroa-neurysm, polypoidal choroidopathy, trauma, anticoagu-lant use, and several other conditions.

The third most frequent pseudomelanoma was sol-itary congenital hypertrophy of the RPE, accountingfor 108 cases (6%).12–14 Larger congenital hypertro-phy of the RPE lesions that are located in the periph-eral fundus can frequently give the illusion of greaterelevation. However, the sharp border, distinct black orgray color, depigmented or pigmented halo, and de-pigmented lacunae in the lesion should differentiate itfrom melanoma. Although congenital hypertrophy ofthe RPE was traditionally believed to be a stationarylesion, it is now known to gradually enlarge in mostcases.12,14 In addition, congenital hypertrophy of theRPE can rarely spawn an elevated component that webelieve represents an adenoma of the RPE.15 In onesuch case in which histopathologic examination wasperformed, the lesion proved to be an adenocarcinomaof the RPE.16

Other lesions that can resemble PUM are listed inTable 2. Hemorrhagic detachment of the retina or RPEaccounted for 86 pseudomelanomas (5%). This wasdifferent from typical age-related macular degenera-tion or peripheral exudative hemorrhagic chorioreti-nopathy by virtue of its parafoveal or postequatoriallocation and could have been due to a number ofunclear causes, as mentioned above. Choroidal metas-tasis can resemble amelanotic choroidal melanoma.The ophthalmoscopic features that differentiate cho-roidal melanoma from choroidal metastasis have beenreported.1–4,5,17 In addition, ancillary studies like flu-orescein angiography and ultrasonography can be

Table 2. Diagnoses of Pseudomelanoma in 1,739Consecutive Patients

DiagnosisNo. (%) ofPatients

Choroidal nevus 851 (49)Peripheral exudative hemorrhagic

chorioretinopathy139 (8)

Congenital hypertrophy of RPE 108 (6)Hemorrhagic detachment retina or

pigment epithelium86 (5)

Circumscribed choroidal hemangioma 79 (5)Age-related macular degeneration 76 (4)Hyperplasia of RPE 42 (2)Optic disk melanocytoma 37 (2)Choroidal metastasis 34 (2)Hemorrhagic choroidal detachment 29 (2)Vasoproliferative tumor 20 (1)Rhegmatogenous retinal detachment 18 (1)Choroidal detachment 17 (1)Uveal effusion syndrome 17 (1)Choroidal or disk granuloma 14 (1)Adenoma of RPE or CPE 13 (�1)Sclerochoroidal calcification 12 (1)Staphyloma 12 (1)Cataract 10 (1)Retinal capillary hemangioma (capillary

or cavernous)10 (1)

Adenoma of nonpigmented CPE 10 (�1)Leiomyoma, ciliary body 10 (�1)Degenerative retinoschisis 8 (�1)Retinal cavernous hemangioma 7 (�1)Chorioretinal scar 7 (�1)Vortex vein varix 7 (�1)Vitreous hemorrhage 7 (�1)Choroidal osteoma 5 (�1)Preretinal macular gliosis 5 (�1)Scleritis 5 (�1)Combined hamartoma of retina and RPE 4 (�1)Ocular melanocytosis (choroidal) 4 (�1)Subluxated lens 4 (�1)Compression by orbital tumor 3 (�1)Central retinal vein obstruction 3 (�1)Retinal foreign body 3 (�1)Lens fragments/remnants 3 (�1)Neurilemoma 3 (�1)Limited choroidal hemorrhage 3 (�1)Coloboma 2 (�1)Pars plana cyst 2 (�1)Hazy media with suspicious ultrasound

findings2 (�1)

White without pressure 2 (�1)Familial exudative vitreoretinopathy 1 (�1)Lattice degeneration of retina 1 (�1)Choroidal lymphoma 1 (�1)Myelinated nerve fibers 1 (�1)Neurofibroma 1 (�1)Optic disk/retina astrocytic hamartoma 1 (�1)

RPE, retinal pigment epithelium; CPE, ciliary body epithelium.

769PSEUDOMELANOMAS OF POSTERIOR UVEA • SHIELDS ET AL

helpful in the differentiation.1–5 In some cases, fine-needle aspiration biopsy of the intraocular mass maybe necessary to establish the diagnosis.18 Circum-scribed choroidal hemangioma is another conditionthat can mimic choroidal melanoma,2,3,19,20 account-ing for 5% of pseudomelanomas in our series. It has atypical red orange color, shows early hyperfluores-cence with angiography, and has high internal reflec-tivity with ultrasonography.2,3,20

Lesions like combined hamartoma of the retina andRPE,21,22 reactive hyperplasia of the RPE, optic diskmelanocytoma,23–26 retinal vasoproliferative tumor,27

and choroidal osteoma28,29 usually have rather distinc-tive features that should serve to differentiate themfrom melanoma.21–29 Some intraocular tumors, likeciliary body leiomyoma,2,3,30 neoplasms of the pig-ment epithelium,2,3,31,32 and nonpigmented ciliary ep-ithelium,33 were once believed to be indistinguishablefrom PUM and may still be difficult in certain cases.However, recent studies have addressed their differ-ences from melanoma.30–33

There are other tumors that may be impossibleclinically to differentiate from melanoma. These in-clude benign peripheral nerve sheath tumors such aschoroidal neurofibroma and neurilemoma (schwanno-ma).2,3,34 These rare spindle cell uveal tumors can beidentical to amelanotic melanoma with regard to oph-thalmoscopic features and ancillary studies. We haveseen two patients with schwannoma who underwentenucleation after failure of plaque radiotherapy forsuspected melanoma, and the diagnosis of neurilem-oma was first realized by histopathologic examination.One case of pigmented schwannoma was impossibleto differentiate from melanoma.35

Some inflammatory conditions can also simulateposterior uveal melanoma. Solitary choroiditis forwhich no specific etiology has been determined alsoprompts referral because of suspected amelanoticPUM.36 In addition, nodular posterior scleritis can besimilar to amelanotic melanoma but has different fea-tures.37,38 In borderline cases, a short course of cortico-steroid treatment may help make the correct diagnosis.

There are several other unusual and fascinatinglesions that can simulate melanoma and have receivedlittle or attention in prior reports of pseudomelanoma.Limited choroidal hemorrhage that sometimes occursafter cataract surgery can resemble PUM.39 We haveseen patients who had fundus photographs and ultra-sonograms reported to be typical of melanoma, andthe transient choroidal hemorrhage had resolved bythe time the patient arrived for consultation. Sclero-choroidal calcification has received attention in therecent literature, and its association with certain sys-temic diseases has been discussed.40,41 This nodular

yellow lesion, usually found along the retinal vasculararcades, can resemble a amelanotic melanoma. Varixof a vortex vein ampulla can dilate in certain fields ofgaze and appear as an elevated choroidal mass.42,43

However, it flattens or collapses in other fields of gazeor when slight pressure is applied to the globe. Otherunusual examples of pseudomelanoma included staph-yloma (12 cases), dense cortical cataract that wasbelieved to be a pigmented ciliary body melanoma(10), totally dislocated lens in the posterior fundus (4),fundus foreign body for which the patient recalled noocular trauma (3), and others.

In summary, we reviewed the diagnoses and fre-quency of lesions that prompted referral to our oncol-ogy service because of suspected PUM and comparedtheir frequency with findings from an older study.Choroidal nevus still accounts for most pseudomela-nomas, and its differentiation from small PUM re-mains a clinical dilemma. Other lesions that weremore difficult to differentiate from melanoma a fewyears ago, like congenital hypertrophy of the RPE,choroidal hemangioma, and age-related macular de-generation, are now being diagnosed more accuratelyand account for a lower percent of pseudomelanomas.The salient features that differentiate some of theselesions from PUM have been elucidated.

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