- Email: [email protected]
Clinical Spectrum of Choroidal Nevi Based on Age at Presentation in 3422 Consecutive Eyes
Clinical Spectrum of Choroidal Nevi Based on Age at Presentation in 3422 Consecutive Eyes Carol L. Shields, MD, Minoru Furuta, MD, Arman Mashayekhi, MD, Edwina L. Berman, MBBS, Jonathan D. Zahler, DO, Daniel M. Hoberman, BS, Diep H. Dinh, BS, Jerry A. Shields, MD Purpose: To evaluate the clinical features of choroidal nevi based on patient age at presentation and to investigate features of the nevi that are predictive of patient symptoms. Design: Observational case series. Participants: Three thousand four hundred twenty-two consecutive eyes of 3187 patients. Methods: Retrospective clinic-based study of clinical features at referral. Cox proportional hazards regressions were used for evaluation of factors predictive of patient symptoms. Main Outcome Measures: Nevus features as related to patient age group at diagnosis (young [ⱕ20 years], mid-adult [21–50 years], older adult [⬎50 years]) and factors predictive of patient symptoms secondary to the nevus. Results: Of the 3422 eyes with choroidal nevus, 63 (2%) were in young patients, 795 (23%) in mid-adults, and 2564 (75%) in older adults. The following factors showed no substantial increase or decrease by age category (young, mid-adult, older adult) at presentation: symptoms (14%, 12%, 13%), mean nevus base (5.6, 4.7, 5.2 mm), intrinsic nevus pigmentation (89%, 74%, 77%), related subretinal fluid (SRF) (11%, 15%, 9%), overlying orange pigment (6%, 10%, 6%), retinal pigment epithelial hyperplasia (0%, 9%, 7%), and retinal pigment epithelial atrophy (2%, 13%, 10%). The following factors statistically increased with age category: multiple nevi per eye (2%, 8%, 10%) (P ⫽ 0.0001), mean nevus thickness (1.2, 1.5, 1.6 mm) (P⬍0.0001), and overlying drusen (11%, 40%, 58%) (P⬍0.0001). Using multivariate analysis of the entire group, factors predictive of any symptom included nonpigmented nevus (P⬍0.001), location ⱕ 3 mm to foveola (P ⫽ 0.001), subfoveolar fluid (P ⫽ 0.002), any SRF (P ⫽ 0.02), and subfoveolar nevus (P ⫽ 0.027). Conclusions: Choroidal nevi show similar clinical features regardless of age of presentation, with the exception of increasing number of nevi per eye, slightly increasing thickness, and increasing drusen in adults versus younger patients. Symptomatic nevi are more likely to be nonpigmented, beneath the foveola, and with subfoveolar fluid. Ophthalmology 2008;115:546 –552 © 2008 by the American Academy of Ophthalmology.
In clinic-based studies, the prevalence of choroidal nevus has varied from an estimated 0.2% to 30% of patients.1– 8 In population-based studies, choroidal nevus prevalence has ranged from 1.9% of persons older than 13 years to 6.5% of persons over 49.9,10 These and other studies have suggested that choroidal nevus is a fairly common tumor, particularly in Caucasian patients, and carries a small potential for growth into melanoma.3,10 –23 Most previous investigations on choroidal nevi have focused on a select adult population over age 18 years,12,13
over 30,3,5 and over 49.4,10 Some studies have been more exclusive, evaluating middle-aged surgical trauma patients from 18 to 38 years2 and middle-aged pilots and recruits from 18 to 41 years.6 Data collection has varied from direct ophthalmoscopic evaluation to indirect funduscopy to retrospective examination of fundus photographs to obtain information on clinical features of the nevus and surrounding tissue.1,2,6,8,10 Review of color fundus photography, as performed in the Blue Mountains Eye Study (BMES),10 can provide valuable unbiased information on gross features of
Originally received: March 8, 2007. Final revision: July 3, 2007. Accepted: July 6, 2007. Available online: December 6, 2007. Manuscript no. 2007-325. From the Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania. Presented at: International Congress of Ocular Oncology, June 2007, Siena, Italy (CLS), and American Academy of Ophthalmology meeting (as a poster), November 2007, New Orleans, Louisiana (CLS). Support provided by the Retina Research Foundation, Retina Society, Cape Town, South Africa (CLS); Paul Kayser International Award of Merit in
Retina Research, Houston, Texas (JAS); Michael, Bruce, and Ellen Ratner, New York, New York (JAS, CLS); Mellon Charitable Giving from the Martha W. Rogers Charitable Trust, Philadelphia, Pennsylvania (CLS); LuEsther Mertz Retina Research Foundation, New York, New York (CLS); and Eye Tumor Research Foundation, Philadelphia, Pennsylvania (CLS, JAS). The sponsors or funding organizations have had no role in the design or conduct of the research. No conflicting relationship exists for any author. Correspondence to Carol L. Shields, MD, Ocular Oncology Service, Suite 1440, Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107. E-mail: [email protected].
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© 2008 by the American Academy of Ophthalmology Published by Elsevier Inc.
ISSN 0161-6420/08/$–see front matter doi:10.1016/j.ophtha.2007.07.009
Shields et al 䡠 Clinical Spectrum of Choroidal Nevi Table 1. Choroidal Nevus in 3422 Eyes: Tumor Features Based on Patient Age at Initial Examination Feature Involved eye [n⫽3187 patients] Right eye Left eye Both eyes Symptoms [n⫽3422 eyes] Decrease in visual acuity Flashes/floaters Visual field defect No symptoms No. of nevi [median (mean, range)] Per patient (n ⫽ 3187) Per eye (n ⫽ 3422) 1 2 3 ⬎3 Quadrantic location (n ⫽ 3422 eyes) Macula Inferior Temporal Superior Nasal Anteroposterior location (n ⫽ 3422 eyes) Macula Macula–equator Equator–ora serrata Location relative to foveola (n ⫽ 3422 eyes) Subfoveolar Extrafoveolar Proximity to optic disc (mm) (n ⫽ 3422 eyes) [median (mean, range)] Proximity to foveola (mm) (n ⫽ 3422 eyes) [median (mean, range)] Basal diameter (mm) [median (mean, range)] Thickness (mm) [median (mean, range)] Ultrasound acoustic quality (n ⫽ 2505) Flat Hollow Solid Color (n ⫽ 3422 eyes) Pigmented Nonpigmented Mixed Halo nevus (n ⫽ 3422 eyes) Nevus change (n ⫽ 2514 eyes)* Slight enlargement Growth into melanoma
Age < 20 yrs (n ⴝ 63) [n (%)]
Age 21–50 yrs (n ⴝ 795) [n (%)]
Age > 50 yrs (n ⴝ 2564) [n (%)]
36 (57) 25 (41) 1 (2)
371 (49) 334 (45) 45 (6)
1146 (48) 1040 (44) 189 (8)
8 (14) 0 (0) 0 (0) 54 (86)
50 (7) 11 (1) 31 (4) 658 (88)
157 (7) 26 (1) 117 (5) 2075 (87)
1 (1.0,1–2) 1 (1.0,1–2) 62 (98) 1 (2) 0 (0) 0 (0)
1 (1.2,1–10) 1 (1.1,1–10) 731 (92) 55 (7) 6 (1) 3 (⬍1)
1 (1.2,1–7) 1 (1.1,1–6) 2312 (90) 215 (8) 32 (1) 5 (⬍1)
22 (35) 7 (11) 11 (17) 8 (13) 15 (23)
186 (23) 140 (18) 162 (20) 116 (15) 191 (24)
504 (20) 460 (18) 631 (25) 410 (16) 559 (22)
22 (35) 40 (63) 1 (2)
186 (23) 548 (69) 61 (8)
504 (20) 1821 (71) 239 (9)
9 (14) 54 (86) 3.0 (3.7,0–13)
53 (7) 742 (93) 5 (5.1,0–21)
143 (6) 2421 (94) 5 (5.6,0–20)
3 (3.4,0–15)
4 (5.0,0–21)
4.5 (5.3,0–18)
5.0 (5.6,0.75–24) 1 (1.2,0.6–2.2)
4.5 (4.7,0.5–14) 1.5 (1.5,0.7–3.7)
15 (38) 5 (12) 20 (50)
77 (14) 149 (27) 329 (59)
215 (11) 429 (22) 1266 (66)
56 (89) 4 (6) 3 (5) 1 (2) n ⫽ 37 1 (3) 5 (14)
591 (74) 83 (10) 121 (15) 64 (8) n ⫽ 595 19 (3) 53 (9)
1981 (77) 269 (10) 313 (12) 97 (4) n ⫽ 1882 70 (4) 122 (6)
5 (5.2,0.4–20) 1.5 (1.6,0.7–4.5)
RPE ⫽ retinal pigment epithelium. *There were a total of 3422 eyes in this analysis, and follow-up was achieved in 2514 (including those that evolved into melanoma) and 2334 (excluding those that evolved into melanoma).
the nevus but might not be completely revealing of the fine details of the nevus or related retinal information such as subretinal fluid (SRF), retinal edema, or retinal pigment epithelial alterations that could be transparent or subtle on photography. In addition, this approach would not be useful for children who could not cooperate for fundus photography and might not be revealing of peripheral nevi, as most fundus photographic techniques allow for only a view of the postequatorial fundus. In an effort to provide a complete
detailed clinic-based study on choroidal nevus in patients of all ages, we analyzed our experience with 3422 choroidal nevi over 3 decades. In this analysis, we describe detailed clinical features of choroidal nevus and related retinal and retinal pigment epithelial changes in each age group as recorded by experienced examiners using modern techniques of indirect ophthalmoscopy of the entire fundus and high-resolution magnification ophthalmoscopy of the nevus or macula in addition to large detailed fundus drawings and
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Ophthalmology Volume 115, Number 3, March 2008 standard and/or wide-angle fundus photography in all patients. These features were then evaluated for their relationship to patient’s symptoms.
Materials and Methods A retrospective chart review was performed on all patients with the clinical diagnosis of choroidal nevus managed on the ocular oncology service at Wills Eye Institute between April 1974 and June 2006. Institutional review board approval was obtained for this retrospective study. The initial 1329 patients were included in 2 previous studies.21,23 All patients were examined by one of the senior authors (CLS, JAS) using modern techniques of indirect ophthalmoscopy of the entire fundus and high-resolution magnification ophthalmoscopy (Goldmann or 60-diopter lens with slitlamp biomicroscopy) of the nevus or macula when necessary and possible. Details of the choroidal nevus were recorded on large fundus drawings in all patients. Fundus photography was performed on patients over age 6. Clinical data were collected at initial examination regarding patient age, race, gender, medical history (dysplastic nevus syndrome; cutaneous, choroidal, or conjunctival melanoma; neurofibromatosis), ocular melanocytosis, symptoms, and best-corrected visual acuity (BCVA) by Snellen charts. Other recorded data included quadrantic location of the tumor epicenter (inferior, temporal, superior, nasal, macula), anteroposterior location of the tumor epicenter (macula, macula to equator, equator to ora serrata), distance of nearest tumor margin to optic disc margin and foveola (millimeters), largest tumor basal dimension and thickness (millimeters), tumor color (pigmented, mixed, nonpigmented), and presence of amelanotic halo. If an eye had more than one nevus, then the largest nevus was included in the analysis. Other related data included SRF, orange pigment, drusen, retinal pigment epithelial alterations (hyperplasia, detachment, fibrosis, atrophy), and choroidal neovascular membrane. The status of the foveola (involvement with underlying choroidal nevus, subfoveolar fluid, foveolar edema) was recorded. The final BCVA at date last seen was recorded. The nevus and related features were then analyzed based on patient age at presentation (young [ⱕ20 years], mid-adult [21–50 years], older adult [⬎50 years]). Statistical analysis was performed on the entire group regarding factors predictive of symptoms at presentation.
Statistical Analysis A series of 1-way analyses were performed for each major clinical feature listed in Tables 1 and 2 (the latter available at http:// aaojournal.org) per increasing age group (young, mid-adult, older adult) using the chi-square test and analysis of variance. Contingency analyses of clinical feature per age group were evaluated in a table format. A series of univariate logistic regressions assessed the degree of relationship of all of the variables listed above to any symptom and, specifically, symptoms of decreased visual acuity (VA), visual field (VF) defect, and flashes/floaters. All of the variables were analyzed as discrete variables except for patient age at presentation, tumor basal dimension, tumor thickness, and distance of tumor to optic disc margin and foveola, which were evaluated as continuous variables. Subsequent multivariate models included variables that were significant on a univariate level (P⬍0.05) to identify the combination of factors best related to the 3 outcomes.
Results There were 3422 eyes of 3187 patients with choroidal nevus. The mean patient age at referral was 60 years (median, 62; range, 1–97). Demographic features at initial presentation are listed in Table 3 (available at http://aaojournal.org). When separately evaluating young (ⱕ20 years), mid-adult (21–50), and older adult (⬎50) patients, the race was Caucasian in 95%, 98%, and 99%; gender female in 63%, 65%, and 63%; and skin melanoma was found in 2%, 3%, and 3%. The choroidal nevus features are listed in Table 1. When separately evaluating young, mid-adult, and older adult patients, related symptoms were present in 14%, 12%, and 13%; tumor anteroposterior location was the macula in 34%, 23%, and 20%; median tumor base was 5.0 mm, 4.5 mm, and 5.0 mm; and median tumor thickness was 1.0 mm, 1.5 mm, and 1.5 mm (Figs 1–3). In each age category, the tumor quadrantic location was more often nasal or temporal than inferior or superior. The nevus was located posterior to the equator in 91% of cases. Slight tumor enlargement without melanoma development was found in 3%, 3%, and 4% (Fig 4 [available at http://aaojournal.org]), whereas growth into melanoma was found in 14%, 9%, and 6%. Related retinal and retinal pigment epithelial features are listed in Table 2 (available at http://aaojournal.org). When
™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™3 Figure 1. Choroidal nevi in young (⬍20 years) patients. A, Small pigmented choroidal nevus in an 18-year-old girl. B, Pigmented juxtapapillary choroidal nevus in a 17-year-old boy. C, Pigmented submacular choroidal nevus in a 12-year-old girl. D, Pigmented juxtapapillary choroidal nevus with mild overlying retinal pigment epithelial changes in an 11-year-old girl. E, Nonpigmented choroidal nevus with overlying retinal pigment epithelial alterations in an 11-year-old girl. F, Peripheral choroidal nevus with fine overlying drusen in an 18-year-old girl. Figure 2. Choroidal nevi in mid-adult (20 –50 years) patients. A, Multifocal choroidal nevis in a 35-year-old woman. B, Pigmented choroidal nevus with overlying drusen in a 44-year-old woman. C, Fibrous metaplasia of the retinal pigment epithelium overlying choroidal nevus in a 38-year-old woman. D, Retinal pigment epithelium alterations of detachment, hyperplasia, and fibrous metaplasia overlying choroidal nevus in a 49-year-old woman. E, Amelanotic choroidal nevus with overlying drusen in a 32-year-old woman. F, Extensive retinal pigment epithelial atrophy and hyperplasia overlying variably pigmented choroidal nevus in a 48-year-old woman. Figure 3. epithelial epithelial choroidal woman.
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Choroidal nevi in older (⬎50 years) adult patients. A, Drusen overlying a pigmented choroidal nevus in a 60-year-old man. B, Retinal pigment thinning and drusen overlying choroidal nevus in a 60-year-old woman. C, Halo choroidal nevus in a 64-year-old woman. D, Small pigment detachment overlying choroidal nevus in a 51-year-old woman. E, Retinal pigment epithelial alterations and subretinal fluid (SRF) overlying nevus in a 69-year-old man. F, Choroidal nevascular membrane overlying choroidal nevus and producing SRF and exudation in a 61 year-old
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Ophthalmology Volume 115, Number 3, March 2008 Table 4. Choroidal Nevus in 3422 Eyes: Factors at Initial Presentation Predictive of Symptoms Secondary to the Nevus Using Multivariable Analysis Variable Decreased vision (n ⫽ 222/3422) Proximity of nevus to foveola (ⱕ3 mm vs. ⬎3 mm*) Nevus pigmentation Mixed versus pigmented* Nonpigmented versus pigmented* Subfoveolar fluid (present vs. absent*) Subfoveolar nevus (present vs. absent*) Visual field loss (n ⫽ 38/3422) Quadrantic location of nevus (macula vs. inferior*) Proximity of nevus to foveola (ⱕ3mm vs. ⬎3 mm*) RPE fibrous metaplasia overlying nevus (present vs. absent*) Flashes/floaters (n ⫽ 151/3422) Race (Hispanic vs. white*) Nevus pigmentation (nonpigmented vs. pigmented*) RPE atrophy (present vs. absent*) Any symptom (n ⫽ 411/3011) Proximity of nevus to foveola (ⱕ3 mm vs. ⬎3 mm*) Nevus pigmentation (nonpigmented vs. pigmented*) Subretinal fluid Mild versus none* Moderate versus none* Subfoveolar fluid (present vs. absent*) Subfoveolar nevus (present vs. absent*)
P Value
OR
95% CI
⬍0.001
2.28
1.52–3.42
0.036 0.008 ⬍0.001 0.002
1.65 1.97 6.24 4.16
1.03–2.64 1.19–3.26 2.89–13.48 1.69–10.25
0.022 0.006 0.005
6.33 2.92 3.32
1.31–30.55 1.36–6.25 1.43–7.70
0.025 0.016 0.016
4.16 1.75 1.73
1.20–14.45 1.11–2.76 1.11–2.70
0.001 ⬍0.001
1.53 2.14
1.18–1.98 1.54–2.99
0.020 0.047 0.002 0.027
1.79 3.22 3.87 2.73
1.10–2.91 1.02–10.15 1.65–9.08 1.12–6.63
CI ⫽ confidence interval; OR ⫽ odds ratio. *Reference variable.
separately evaluating young, mid-adult, and older adult patients, overlying SRF was found in 11%, 15%, and 9% and orange pigment in 6%, 10%, and 6%. Overlying drusen were noted in 11%, 40%, and 58% and retinal pigment epithelial atrophy in 2%, 13%, and 10%. The youngest patient to manifest drusen was an 11-year-old with fine homogeneous drusen overlying a peripheral choroidal nevus. Treatment of the choroidal nevus included observation in 3396 eyes (99%); delimiting laser photocoagulation (n ⫽ 15 eyes) or transpupillary thermotherapy (n ⫽ 4 eyes) for SRF; and laser photocoagulation (n ⫽ 3), transpupillary thermotherapy (n ⫽ 1), or photodynamic therapy (n ⫽ 3) for choroidal neovascular membrane. One-way analyses revealed an increasing number of nevi per patient (P ⫽ 0.003), increasing tumor thickness (P⬍0.0001), and increasing presence of drusen (P⬍0.0001) per increasing age category. Pearson analysis revealed that multiple nevi per eye increased with age (P ⫽ 0.0001). Clinical factors related to the presence of any symptom at presentation included proximity of nevus to foveola (relative risk [odds ratio (OR)], 1.5), subfoveolar nevus (OR, 2.73), nonpigmented nevus (OR, 2.14), moderate SRF (OR, 3.22), and subfoveolar fluid (OR, 3.87) (Table 4).
Discussion Choroidal nevus appears as a pigmented or nonpigmented lesion deep to the retina, typically ⬍2 mm in thickness.14,15 In our cohort, choroidal nevus was completely nonpigmented in 6% of young patients and 10% of adults. Pigmentation within choroidal nevus is an important clue to the diagnosis, but other conditions such as choroidal melanoma, especially small melanoma, pig-
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mented choroidal metastasis, subretinal or choroidal hemorrhage, and retinal pigment epithelial tumors should be excluded. Lack of pigmentation within a choroidal nevus leads to more diagnostic uncertainty, and conditions such as amelanotic melanoma, choroidal metastasis, choroidal hemangioma, choroidal granuloma, choroidal osteoma, posterior scleritis, and sclerochoroidal calcification should be considered before labeling an amelanotic mass as a benign nevus.16 The 2 main concerns of choroidal nevus are its risk for inducing VA loss and risk for transformation into melanoma. Regarding VA loss, Gonder et al found that 22 (11%) of 206 patients with choroidal nevus posterior to the equator of the eye showed related VA loss.17 Shields et al reported 15-year Kaplan–Meier estimates for VA loss in 2334 eyes with choroidal nevus to be 2% for those with extrafoveolar nevus and 26% for those with subfoveolar nevus.18 However, VA at presentation was relatively undisturbed in the population-based BMES of 232 eyes and in the clinic-based study by Shields et al of 3244 eyes, as the median VA at referral was 20/20.10,18 Regarding transformation into melanoma, Ganley and Comstock estimated that 1 in 4800 choroidal nevi would transform into melanoma, and Singh et al estimated transformation at 1 in 8845 in the Caucasian population.3,11 Several reports have identified clinical risk factors for nevus transformation into melanoma, including thickness over 2 mm, SRF, symptoms, orange pigment, location near the optic disc, lack of overlying drusen, fluorescein angiographic hot spots over the tumor, and hollowness on ultrasonography.19 –23
Shields et al 䡠 Clinical Spectrum of Choroidal Nevi The BMES was based on evaluation of dilated fundus photography of 6 standard retinal fields that encompassed a total field of approximately 70°.10 The subjects were fully examined, but data for the choroidal nevus study were gathered from fundus photography. Detailed measurements of nevus diameter and overlying drusen were made based on photographs. Ultrasonography was not performed. Of the 3583 participants, 232 (6.5%) had one or more choroidal nevi. Of the 232 affected patients, 1 nevus was found in 93% of patients, 2 nevi in 4%, and ⬎2 nevi in 1%. In our series, one choroidal nevus per eye was found in 98% of young patients, 92% of mid-adults, and 90% of older adults. Multiplicity of choroidal nevi per eye increased with age. More than 1 nevus per eye was found in 2% of young patients, 8% of mid-adults, and 10% of older adults. In the BMES, a population was screened for choroidal nevus, the mean nevus diameter was 1.25 mm, and the largest nevus was 4.5 mm.10 In our clinic-based study on all ages from a tertiary referral center, the mean nevus diameter was much larger: 5.6 mm in young patients, 4.7 mm in mid-adults, and 5.2 mm in older adults. The largest nevus diameter in our series was 20 mm, a stable giant choroidal nevus with overlying drusen and retinal pigment epithelial alterations. The differences in tumor size in these 2 studies emanate from the study design, as in the population-based study, asymptomatic subjects were screened, and in our clinic-based tertiary referral study, all patients were referred for a suspicious mass in the fundus. Our clinic-based analysis represents the spectrum of choroidal nevus that might prompt a consultation in an ocular oncology center, as many of the nevi exhibited orange pigment and SRF and produced related symptoms. The information from the BMES has contributed important data from another perspective, representing smaller, flatter choroidal nevi detected on high-resolution photography. The detailed images allowed for the detection of drusen overlying choroidal nevus in 98% of cases, some of which were quite subtle and not seen clinically.10 The authors admitted that drusen were recognized on ophthalmoscopy in only 41% of cases. In our series, overlying drusen were detected in 11% of young patients, 40% of mid-adults, and 58% of older adults. Additionally, drusen were found statistically to increase in frequency per increasing age category. Our older adult group (⬎50) correlated best with the subjects in the BMES (⬎49 years), and both groups showed similar frequencies of drusen clinically. It has been found that increasing nevus size correlates with increasing frequency of overlying drusen.10 The importance of drusen overlying choroidal nevus should be underscored, as this chronic finding generally implies a longstanding lesion, visible more often in older rather than younger patients (Figs 1–3). The importance of overlying drusen and chronic retinal pigment epithelial changes was also recognized in the Collaborative Ocular Melanoma Study, as the lack of these findings with small tumors was a risk for tumor growth into melanoma.22 As seen in Table 1, the majority of eyes with choroidal nevis were asymptomatic, with only 12% of patients having symptoms related to the nevus. These included VA loss, VF defect, and flashes and floaters. In a previous analysis of VA
outcome of eyes with choroidal nevus, Shields et al found that one of the most important factors for poor final VA of 20/200 or worse was subfoveal location of the nevus.18 They warned that vision loss over many years should be anticipated in patients with subfoveolar choroidal nevus, particularly those with overlying retinal pigment epithelial detachment, orange pigment, and foveal edema. In this analysis, we specifically evaluated the factors predictive of any symptom and found subfoveolar nevus as well as related SRF to be important. We anticipate that further evaluation of these patients with optical coherence tomography (OCT) and autofluorescence might provide more information regarding the etiology and onset of related symptoms. In our series, SRF overlying or adjacent to choroidal nevus was found in 11% of young patients, 15% of midadults, and 9% of older adults. Subretinal fluid should prompt close follow-up, because it is a risk for VA loss and, more importantly, a risk for ultimate transformation into melanoma.21,23 Shields et al have previously shown that the presence of SRF overlying a small melanocytic choroidal tumor (presumably nevus) imparts a 1.6 relative risk for transformation into melanoma as compared to one without fluid.21,23 Espinoza et al evaluated the role of OCT in assessing small choroidal melanocytic tumors and found that active SRF (retinal separation with normal retinal appearance) was a feature associated with tumor growth into melanoma, whereas inactive SRF (retinal separation with retinal atrophy or intraretinal cysts) was more often found with stable nevi.24 Shields et al further explored OCT findings overlying choroidal nevi in 120 eyes and found chronic features that implied stability such as photoreceptor loss in 51% and retinal edema in 15%. However, overlying active or chronic SRF was noted in 26%.25 Subretinal fluid is judged to be active when outer retinal layers are intact and photoreceptors are preserved, whereas SRF is judged chronic when outer retinal atrophy, photoreceptor loss, and retinal thinning are found. In addition, active SRF is typically more extensive than chronic SRF, which might appear as a focal area of retinal elevation overlying a nevus. Slight enlargement of choroidal nevus without evolution into melanoma was found in 3% to 4% of patients (Fig 4 [available at http://aaojournal.org]). This slight change could be related to many factors, including slight alteration in nevus pigmentation, overlying alterations in the retinal pigment epithelium camouflaging nevus margins, or true slight enlargement of the nevus without continued progression into melanoma. It is well recognized that even photographic artifacts can produce difficulty in interpreting nevus margins.26 Over the 3 decades of this study, nevus growth into melanoma was found in 14% of young patients, 9% of mid-adults, and 6% of older adults. These rates are greater than expected, but in a tertiary referral practice, many patients are sent for consultation of a mass suspicious for a nevus or small melanoma. Unless the mass is an obvious melanoma, a period of cautious observation is often warranted to document activity of the tumor. In the populationbased BMES of subjects older than 49, only 1 of 160 (⬍1%) choroidal nevi showed growth on follow-up.27 They suggested that “regular eye examinations in older patients may
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Ophthalmology Volume 115, Number 3, March 2008 be unnecessary for clearly defined small nonsuspicious choroidal nevi,” based on the lack of tumor progression.27 On the contrary, we continue to recommend regular eye examinations for all patients with choroidal nevi, as our clinicbased study has found tumor progression, even in children who might appear to have an innocent nevus. We hope to analyze further factors predictive of growth of choroidal nevi into melanoma in a future report. Use of clinical risk factors to identify those at highest risk for tumor growth might be helpful for patient monitoring. In summary, choroidal nevi show similar sizes, locations, and related symptoms in young, mid-adult, and older adult patients. Overlying features such as retinal pigment epithelial alterations and drusen appear to increase with time. With new technology such as autofluorescence and OCT, these subtle findings may be more common than previously realized and may prove to be important features in establishing the stability or growth potential of a choroidal nevus. Acknowledgments. Statistical analysis provided by Rishita Nutheti, International Centre for Advancement of Rural Eye Care, L. V. Prasad Institute, Hyderabad, India.
References 1. Albers EC. Benign melanomas of the choroid and their malignant transformation. Am J Ophthalmol 1940;23:779 – 83. 2. Wilder HC. Intraocular tumors in soldiers: World War II. Mil Surg 1946;99:459 –90. 3. Ganley JP, Comstock GW. Benign nevi and malignant melanomas of the choroid. Am J Ophthalmol 1973;76:19 –25. 4. Gass JD. Problems in the differential diagnosis of choroidal nevi and malignant melanoma: XXXIII Edward Jackson Memorial lecture. Trans Sect Ophthalmol Am Acad Ophthalmol Otolaryngol 1977;83:19 – 48. 5. Albert DM, Robinson NL, Fulton AB, et al. Epidemiological investigation of increased incidence of choroidal melanoma in a single population of chemical workers. Int Ophthalmol Clin 1980;20(2):71–92. 6. Lang GK, Daumann FJ. Peripheral fundus changes in subjects with healthy eyes (pilots) [in German]. Klin Monatsbl Augenheilkd 1982;181:493–5. 7. Albert DM, Searl SS, Forget B, et al. Uveal findings in patients with cutaneous melanoma. Am J Ophthalmol 1983; 95:474 –9. 8. Rodriguez-Sains RS. Ocular findings in patients with dysplastic nevus syndrome. Ophthalmology 1986;93:661–5. 9. Smith RE, Ganley JP. Ophthalmic survey of a community. 1. Abnormalities of the ocular fundus. Am J Ophthalmol 1972; 74:1126 –30.
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10. Sumich P, Mitchell P, Wang JJ. Choroidal nevi in a white population: the Blue Mountains Eye Study. Arch Ophthalmol 1998;116:645–50. 11. Singh AD, Kalyani P, Topham A. Estimating the risk of malignant transformation of a choroidal nevus. Ophthalmology 2005;112:1784 –9. 12. Naumann G, Yanoff M, Zimmerman LE. Histogenesis of malignant melanomas of the uvea I: histopathologic characteristics of nevi of the choroid and ciliary body. Arch Ophthalmol 1966;76:784 –96. 13. Hale PN, Allen RA, Straatsma BR. Benign melanomas (nevi) of the choroid and ciliary body. Arch Ophthalmol 1965;74: 532– 8. 14. Shields JA, Shields CL. Intraocular Tumors: A Text and Atlas. Philadelphia: Saunders; 1992:85–100. 15. Shields JA, Shields CL. Atlas of Intraocular Tumors. Philadelphia: Lippincott Williams and Wilkins; 1999:53–9. 16. Shields JA, Mashayekhi A, Ra S, Shields CL. Pseudomelanomas of the posterior uveal tract. The 2006 Taylor R. Smith Lecture. Retina 2005;25:767–71. 17. Gonder JR, Augsburger JJ, McCarthy EF, Shields JA. Visual loss associated with choroidal nevi. Ophthalmology 1982;89: 961–5. 18. Shields CL, Furuta M, Mashayekhi A, et al. Visual acuity in 3422 consecutive eyes with choroidal nevus. Arch Ophthalmol. In press. 19. Mims JL III, Shields JA. Follow-up studies of suspicious choroidal nevi. Ophthalmology 1978;85:929 – 43. 20. Butler P, Char DH, Zarbin M, Kroll S. Natural history of indeterminate pigmented choroidal tumors. Ophthalmology 1994;101:710 – 6. 21. Shields CL, Shields JA, Kiratli H, et al. Risk factors for growth and metastasis of small choroidal melanocytic lesions. Ophthalmology 1995;102:1351– 61. 22. Collaborative Ocular Melanoma Study Group. Factors predictive of growth and treatment of small choroidal melanoma: COMS report no. 5. Arch Ophthalmol 1997;115:1537– 44. 23. Shields CL, Cater JC, Shields JA, et al. Combination of clinical factors predictive of growth of small choroidal melanocytic tumors. Arch Ophthalmol 2000;118:360 – 4. 24. Espinoza G, Rosenblatt B, Harbour JW. Optical coherence tomography in the evaluation of retinal changes associated with suspicious choroidal melanocytic tumors. Am J Ophthalmol 2004;137:90 –5. 25. Shields CL, Mashayekhi A, Materin MA, et al. Optical coherence tomography of choroidal nevus in 120 patients. Retina 2005;25:243–52. 26. Johnson RN, McDonald HR, Jumper JM. Camera artifacts producing the false impression of growth of choroidal melanocytic lesions. Am J Ophthalmol 2003;135:711–3. 27. Thiagalingam S, Wang JJ, Mitchell P. Absence of change in choroidal nevi across 5 years in an older population. Arch Ophthalmol 2004;122:89 –93.
Shields et al 䡠 Clinical Spectrum of Choroidal Nevi Table 2. Choroidal Nevus in 3422 Eyes: Related Retinal and Retinal Pigment Epithelium (RPE) Features Based on Patient Age at Initial Examination Feature Retina (n ⫽ 3422 eyes) SRF Overlying nevus ⬍3 mm at margin 3–6 mm at margin ⬎6 mm at margin Retinal invasion RPE (n ⫽ 3422 eyes) Orange pigment Drusen RPE atrophy RPE hyperplasia RPE fibrous metaplasia RPE trough RPE detachment Choroidal neovascularization Foveolar status (n ⫽ 3422 eyes) Subfoveolar nevus With SRF at foveola With edema at foveola Extrafoveolar nevus With SRF at foveola With edema at foveola
Age < 20 yrs (n ⴝ 63) [n (%)]
Age 21–50 yrs (n ⴝ 795) [n (%)]
Age > 50 yrs (n ⴝ 2564) [n (%)]
7 (11) 2 (3) 4 (6) 1 (2) 0 (0) 0 (0)
115 (15) 41 (5) 51 (6) 12 (2) 1 (⬍1) 0 (0)
232 (9) 107 (4) 109 (4) 11 (⬍1) 5 (⬍1) 6 (⬍1)
4 (6) 7 (11) 1 (2) 0 (0) 4 (6) 0 (0) 0 (0) 1 (2)
79 (10) 321 (40) 106 (13) 71 (9) 69 (9) 24 (3) 8 (1) 2 (⬍1)
155 (6) 1491 (58) 261 (10) 178 (7) 190 (7) 35 (1) 34 (1) 17 (1)
9 (14) 1 (2) 0 (0) 55 (87) 5 (8) 0 (0)
53 (7) 12 (2) 4 (1) 742 (93) 22 (3) 0 (0)
143 (6) 24 (1) 10 (⬍1) 2420 (94) 30 (1) 11 (⬍1)
SRF ⫽ subretinal fluid.
Table 3. Choroidal Nevus in 3422 eyes of 3187 Patients: Demographics Based on Patient Age at Initial Examination Feature Race (n ⫽ 3187) Caucasian African American Hispanic Asian Indian Gender (n ⫽ 3187) Male Female Extraocular disease (n ⫽ 3187) Dysplastic nevus syndrome Skin melanoma Neurofibromatosis Ocular history (n ⫽ 3187) Ocular melanocytosis Uveal melanoma* (fellow eye) Conjunctival melanoma/PAM with atypia
Age < 20 yrs (n ⴝ 62) [n (%)]
Age 21–50 yrs (n ⴝ 750) [n (%)]
Age > 50 yrs (n ⴝ 2375) [n (%)]
59 (95) 2 (3) 0 (0) 0 (0) 1 (2)
738 (98) 4 (1) 7 (1) 1 (⬍1) 0 (0)
2344 (99) 15 (1) 11 (⬍1) 5 (⬍1) 0 (0)
23 (37) 39 (63)
264 (35) 486 (65)
884 (37) 1491 (63)
2 (3) 1 (2) 0 (0)
13 (2) 22 (3) 2 (⬍1)
11 (⬍1) 82 (3) 1 (⬍1)
3 (5) 0 (0) 0 (0)
32 (4) 25 (3) 5 (1)
87 (4) 84 (4) 7 (⬍1)
PAM ⫽ primary acquired melanosis. *Its presence in 3% to 4% of our cases is a referral bias. These patients were referred to us for evaluation and management of uveal melanoma and, during initial evaluation at the oncology service, were found to have a choroidal nevus in the opposite eye.
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Figure 4. Choroidal nevus followed for 35 years. A, In 1970, an 18-year-old boy was found to have a submacular choroidal nevus. B, In 2005, the mass had shown gradual minimal enlargement of ⬍1 mm. Overlying chronic retinal pigment epithelial changes, with a dried trough of subretinal fluid, were noted.
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In clinic-based studies, the prevalence of choroidal nevus has varied from an estimated 0.2% to 30% of patients.1– 8 In population-based studies, choroidal nevus prevalence has ranged from 1.9% of persons older than 13 years to 6.5% of persons over 49.9,10 These and other studies have suggested that choroidal nevus is a fairly common tumor, particularly in Caucasian patients, and carries a small potential for growth into melanoma.3,10 –23 Most previous investigations on choroidal nevi have focused on a select adult population over age 18 years,12,13
over 30,3,5 and over 49.4,10 Some studies have been more exclusive, evaluating middle-aged surgical trauma patients from 18 to 38 years2 and middle-aged pilots and recruits from 18 to 41 years.6 Data collection has varied from direct ophthalmoscopic evaluation to indirect funduscopy to retrospective examination of fundus photographs to obtain information on clinical features of the nevus and surrounding tissue.1,2,6,8,10 Review of color fundus photography, as performed in the Blue Mountains Eye Study (BMES),10 can provide valuable unbiased information on gross features of
Originally received: March 8, 2007. Final revision: July 3, 2007. Accepted: July 6, 2007. Available online: December 6, 2007. Manuscript no. 2007-325. From the Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania. Presented at: International Congress of Ocular Oncology, June 2007, Siena, Italy (CLS), and American Academy of Ophthalmology meeting (as a poster), November 2007, New Orleans, Louisiana (CLS). Support provided by the Retina Research Foundation, Retina Society, Cape Town, South Africa (CLS); Paul Kayser International Award of Merit in
Retina Research, Houston, Texas (JAS); Michael, Bruce, and Ellen Ratner, New York, New York (JAS, CLS); Mellon Charitable Giving from the Martha W. Rogers Charitable Trust, Philadelphia, Pennsylvania (CLS); LuEsther Mertz Retina Research Foundation, New York, New York (CLS); and Eye Tumor Research Foundation, Philadelphia, Pennsylvania (CLS, JAS). The sponsors or funding organizations have had no role in the design or conduct of the research. No conflicting relationship exists for any author. Correspondence to Carol L. Shields, MD, Ocular Oncology Service, Suite 1440, Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107. E-mail: [email protected].
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© 2008 by the American Academy of Ophthalmology Published by Elsevier Inc.
ISSN 0161-6420/08/$–see front matter doi:10.1016/j.ophtha.2007.07.009
Shields et al 䡠 Clinical Spectrum of Choroidal Nevi Table 1. Choroidal Nevus in 3422 Eyes: Tumor Features Based on Patient Age at Initial Examination Feature Involved eye [n⫽3187 patients] Right eye Left eye Both eyes Symptoms [n⫽3422 eyes] Decrease in visual acuity Flashes/floaters Visual field defect No symptoms No. of nevi [median (mean, range)] Per patient (n ⫽ 3187) Per eye (n ⫽ 3422) 1 2 3 ⬎3 Quadrantic location (n ⫽ 3422 eyes) Macula Inferior Temporal Superior Nasal Anteroposterior location (n ⫽ 3422 eyes) Macula Macula–equator Equator–ora serrata Location relative to foveola (n ⫽ 3422 eyes) Subfoveolar Extrafoveolar Proximity to optic disc (mm) (n ⫽ 3422 eyes) [median (mean, range)] Proximity to foveola (mm) (n ⫽ 3422 eyes) [median (mean, range)] Basal diameter (mm) [median (mean, range)] Thickness (mm) [median (mean, range)] Ultrasound acoustic quality (n ⫽ 2505) Flat Hollow Solid Color (n ⫽ 3422 eyes) Pigmented Nonpigmented Mixed Halo nevus (n ⫽ 3422 eyes) Nevus change (n ⫽ 2514 eyes)* Slight enlargement Growth into melanoma
Age < 20 yrs (n ⴝ 63) [n (%)]
Age 21–50 yrs (n ⴝ 795) [n (%)]
Age > 50 yrs (n ⴝ 2564) [n (%)]
36 (57) 25 (41) 1 (2)
371 (49) 334 (45) 45 (6)
1146 (48) 1040 (44) 189 (8)
8 (14) 0 (0) 0 (0) 54 (86)
50 (7) 11 (1) 31 (4) 658 (88)
157 (7) 26 (1) 117 (5) 2075 (87)
1 (1.0,1–2) 1 (1.0,1–2) 62 (98) 1 (2) 0 (0) 0 (0)
1 (1.2,1–10) 1 (1.1,1–10) 731 (92) 55 (7) 6 (1) 3 (⬍1)
1 (1.2,1–7) 1 (1.1,1–6) 2312 (90) 215 (8) 32 (1) 5 (⬍1)
22 (35) 7 (11) 11 (17) 8 (13) 15 (23)
186 (23) 140 (18) 162 (20) 116 (15) 191 (24)
504 (20) 460 (18) 631 (25) 410 (16) 559 (22)
22 (35) 40 (63) 1 (2)
186 (23) 548 (69) 61 (8)
504 (20) 1821 (71) 239 (9)
9 (14) 54 (86) 3.0 (3.7,0–13)
53 (7) 742 (93) 5 (5.1,0–21)
143 (6) 2421 (94) 5 (5.6,0–20)
3 (3.4,0–15)
4 (5.0,0–21)
4.5 (5.3,0–18)
5.0 (5.6,0.75–24) 1 (1.2,0.6–2.2)
4.5 (4.7,0.5–14) 1.5 (1.5,0.7–3.7)
15 (38) 5 (12) 20 (50)
77 (14) 149 (27) 329 (59)
215 (11) 429 (22) 1266 (66)
56 (89) 4 (6) 3 (5) 1 (2) n ⫽ 37 1 (3) 5 (14)
591 (74) 83 (10) 121 (15) 64 (8) n ⫽ 595 19 (3) 53 (9)
1981 (77) 269 (10) 313 (12) 97 (4) n ⫽ 1882 70 (4) 122 (6)
5 (5.2,0.4–20) 1.5 (1.6,0.7–4.5)
RPE ⫽ retinal pigment epithelium. *There were a total of 3422 eyes in this analysis, and follow-up was achieved in 2514 (including those that evolved into melanoma) and 2334 (excluding those that evolved into melanoma).
the nevus but might not be completely revealing of the fine details of the nevus or related retinal information such as subretinal fluid (SRF), retinal edema, or retinal pigment epithelial alterations that could be transparent or subtle on photography. In addition, this approach would not be useful for children who could not cooperate for fundus photography and might not be revealing of peripheral nevi, as most fundus photographic techniques allow for only a view of the postequatorial fundus. In an effort to provide a complete
detailed clinic-based study on choroidal nevus in patients of all ages, we analyzed our experience with 3422 choroidal nevi over 3 decades. In this analysis, we describe detailed clinical features of choroidal nevus and related retinal and retinal pigment epithelial changes in each age group as recorded by experienced examiners using modern techniques of indirect ophthalmoscopy of the entire fundus and high-resolution magnification ophthalmoscopy of the nevus or macula in addition to large detailed fundus drawings and
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Ophthalmology Volume 115, Number 3, March 2008 standard and/or wide-angle fundus photography in all patients. These features were then evaluated for their relationship to patient’s symptoms.
Materials and Methods A retrospective chart review was performed on all patients with the clinical diagnosis of choroidal nevus managed on the ocular oncology service at Wills Eye Institute between April 1974 and June 2006. Institutional review board approval was obtained for this retrospective study. The initial 1329 patients were included in 2 previous studies.21,23 All patients were examined by one of the senior authors (CLS, JAS) using modern techniques of indirect ophthalmoscopy of the entire fundus and high-resolution magnification ophthalmoscopy (Goldmann or 60-diopter lens with slitlamp biomicroscopy) of the nevus or macula when necessary and possible. Details of the choroidal nevus were recorded on large fundus drawings in all patients. Fundus photography was performed on patients over age 6. Clinical data were collected at initial examination regarding patient age, race, gender, medical history (dysplastic nevus syndrome; cutaneous, choroidal, or conjunctival melanoma; neurofibromatosis), ocular melanocytosis, symptoms, and best-corrected visual acuity (BCVA) by Snellen charts. Other recorded data included quadrantic location of the tumor epicenter (inferior, temporal, superior, nasal, macula), anteroposterior location of the tumor epicenter (macula, macula to equator, equator to ora serrata), distance of nearest tumor margin to optic disc margin and foveola (millimeters), largest tumor basal dimension and thickness (millimeters), tumor color (pigmented, mixed, nonpigmented), and presence of amelanotic halo. If an eye had more than one nevus, then the largest nevus was included in the analysis. Other related data included SRF, orange pigment, drusen, retinal pigment epithelial alterations (hyperplasia, detachment, fibrosis, atrophy), and choroidal neovascular membrane. The status of the foveola (involvement with underlying choroidal nevus, subfoveolar fluid, foveolar edema) was recorded. The final BCVA at date last seen was recorded. The nevus and related features were then analyzed based on patient age at presentation (young [ⱕ20 years], mid-adult [21–50 years], older adult [⬎50 years]). Statistical analysis was performed on the entire group regarding factors predictive of symptoms at presentation.
Statistical Analysis A series of 1-way analyses were performed for each major clinical feature listed in Tables 1 and 2 (the latter available at http:// aaojournal.org) per increasing age group (young, mid-adult, older adult) using the chi-square test and analysis of variance. Contingency analyses of clinical feature per age group were evaluated in a table format. A series of univariate logistic regressions assessed the degree of relationship of all of the variables listed above to any symptom and, specifically, symptoms of decreased visual acuity (VA), visual field (VF) defect, and flashes/floaters. All of the variables were analyzed as discrete variables except for patient age at presentation, tumor basal dimension, tumor thickness, and distance of tumor to optic disc margin and foveola, which were evaluated as continuous variables. Subsequent multivariate models included variables that were significant on a univariate level (P⬍0.05) to identify the combination of factors best related to the 3 outcomes.
Results There were 3422 eyes of 3187 patients with choroidal nevus. The mean patient age at referral was 60 years (median, 62; range, 1–97). Demographic features at initial presentation are listed in Table 3 (available at http://aaojournal.org). When separately evaluating young (ⱕ20 years), mid-adult (21–50), and older adult (⬎50) patients, the race was Caucasian in 95%, 98%, and 99%; gender female in 63%, 65%, and 63%; and skin melanoma was found in 2%, 3%, and 3%. The choroidal nevus features are listed in Table 1. When separately evaluating young, mid-adult, and older adult patients, related symptoms were present in 14%, 12%, and 13%; tumor anteroposterior location was the macula in 34%, 23%, and 20%; median tumor base was 5.0 mm, 4.5 mm, and 5.0 mm; and median tumor thickness was 1.0 mm, 1.5 mm, and 1.5 mm (Figs 1–3). In each age category, the tumor quadrantic location was more often nasal or temporal than inferior or superior. The nevus was located posterior to the equator in 91% of cases. Slight tumor enlargement without melanoma development was found in 3%, 3%, and 4% (Fig 4 [available at http://aaojournal.org]), whereas growth into melanoma was found in 14%, 9%, and 6%. Related retinal and retinal pigment epithelial features are listed in Table 2 (available at http://aaojournal.org). When
™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™3 Figure 1. Choroidal nevi in young (⬍20 years) patients. A, Small pigmented choroidal nevus in an 18-year-old girl. B, Pigmented juxtapapillary choroidal nevus in a 17-year-old boy. C, Pigmented submacular choroidal nevus in a 12-year-old girl. D, Pigmented juxtapapillary choroidal nevus with mild overlying retinal pigment epithelial changes in an 11-year-old girl. E, Nonpigmented choroidal nevus with overlying retinal pigment epithelial alterations in an 11-year-old girl. F, Peripheral choroidal nevus with fine overlying drusen in an 18-year-old girl. Figure 2. Choroidal nevi in mid-adult (20 –50 years) patients. A, Multifocal choroidal nevis in a 35-year-old woman. B, Pigmented choroidal nevus with overlying drusen in a 44-year-old woman. C, Fibrous metaplasia of the retinal pigment epithelium overlying choroidal nevus in a 38-year-old woman. D, Retinal pigment epithelium alterations of detachment, hyperplasia, and fibrous metaplasia overlying choroidal nevus in a 49-year-old woman. E, Amelanotic choroidal nevus with overlying drusen in a 32-year-old woman. F, Extensive retinal pigment epithelial atrophy and hyperplasia overlying variably pigmented choroidal nevus in a 48-year-old woman. Figure 3. epithelial epithelial choroidal woman.
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Choroidal nevi in older (⬎50 years) adult patients. A, Drusen overlying a pigmented choroidal nevus in a 60-year-old man. B, Retinal pigment thinning and drusen overlying choroidal nevus in a 60-year-old woman. C, Halo choroidal nevus in a 64-year-old woman. D, Small pigment detachment overlying choroidal nevus in a 51-year-old woman. E, Retinal pigment epithelial alterations and subretinal fluid (SRF) overlying nevus in a 69-year-old man. F, Choroidal nevascular membrane overlying choroidal nevus and producing SRF and exudation in a 61 year-old
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Ophthalmology Volume 115, Number 3, March 2008 Table 4. Choroidal Nevus in 3422 Eyes: Factors at Initial Presentation Predictive of Symptoms Secondary to the Nevus Using Multivariable Analysis Variable Decreased vision (n ⫽ 222/3422) Proximity of nevus to foveola (ⱕ3 mm vs. ⬎3 mm*) Nevus pigmentation Mixed versus pigmented* Nonpigmented versus pigmented* Subfoveolar fluid (present vs. absent*) Subfoveolar nevus (present vs. absent*) Visual field loss (n ⫽ 38/3422) Quadrantic location of nevus (macula vs. inferior*) Proximity of nevus to foveola (ⱕ3mm vs. ⬎3 mm*) RPE fibrous metaplasia overlying nevus (present vs. absent*) Flashes/floaters (n ⫽ 151/3422) Race (Hispanic vs. white*) Nevus pigmentation (nonpigmented vs. pigmented*) RPE atrophy (present vs. absent*) Any symptom (n ⫽ 411/3011) Proximity of nevus to foveola (ⱕ3 mm vs. ⬎3 mm*) Nevus pigmentation (nonpigmented vs. pigmented*) Subretinal fluid Mild versus none* Moderate versus none* Subfoveolar fluid (present vs. absent*) Subfoveolar nevus (present vs. absent*)
P Value
OR
95% CI
⬍0.001
2.28
1.52–3.42
0.036 0.008 ⬍0.001 0.002
1.65 1.97 6.24 4.16
1.03–2.64 1.19–3.26 2.89–13.48 1.69–10.25
0.022 0.006 0.005
6.33 2.92 3.32
1.31–30.55 1.36–6.25 1.43–7.70
0.025 0.016 0.016
4.16 1.75 1.73
1.20–14.45 1.11–2.76 1.11–2.70
0.001 ⬍0.001
1.53 2.14
1.18–1.98 1.54–2.99
0.020 0.047 0.002 0.027
1.79 3.22 3.87 2.73
1.10–2.91 1.02–10.15 1.65–9.08 1.12–6.63
CI ⫽ confidence interval; OR ⫽ odds ratio. *Reference variable.
separately evaluating young, mid-adult, and older adult patients, overlying SRF was found in 11%, 15%, and 9% and orange pigment in 6%, 10%, and 6%. Overlying drusen were noted in 11%, 40%, and 58% and retinal pigment epithelial atrophy in 2%, 13%, and 10%. The youngest patient to manifest drusen was an 11-year-old with fine homogeneous drusen overlying a peripheral choroidal nevus. Treatment of the choroidal nevus included observation in 3396 eyes (99%); delimiting laser photocoagulation (n ⫽ 15 eyes) or transpupillary thermotherapy (n ⫽ 4 eyes) for SRF; and laser photocoagulation (n ⫽ 3), transpupillary thermotherapy (n ⫽ 1), or photodynamic therapy (n ⫽ 3) for choroidal neovascular membrane. One-way analyses revealed an increasing number of nevi per patient (P ⫽ 0.003), increasing tumor thickness (P⬍0.0001), and increasing presence of drusen (P⬍0.0001) per increasing age category. Pearson analysis revealed that multiple nevi per eye increased with age (P ⫽ 0.0001). Clinical factors related to the presence of any symptom at presentation included proximity of nevus to foveola (relative risk [odds ratio (OR)], 1.5), subfoveolar nevus (OR, 2.73), nonpigmented nevus (OR, 2.14), moderate SRF (OR, 3.22), and subfoveolar fluid (OR, 3.87) (Table 4).
Discussion Choroidal nevus appears as a pigmented or nonpigmented lesion deep to the retina, typically ⬍2 mm in thickness.14,15 In our cohort, choroidal nevus was completely nonpigmented in 6% of young patients and 10% of adults. Pigmentation within choroidal nevus is an important clue to the diagnosis, but other conditions such as choroidal melanoma, especially small melanoma, pig-
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mented choroidal metastasis, subretinal or choroidal hemorrhage, and retinal pigment epithelial tumors should be excluded. Lack of pigmentation within a choroidal nevus leads to more diagnostic uncertainty, and conditions such as amelanotic melanoma, choroidal metastasis, choroidal hemangioma, choroidal granuloma, choroidal osteoma, posterior scleritis, and sclerochoroidal calcification should be considered before labeling an amelanotic mass as a benign nevus.16 The 2 main concerns of choroidal nevus are its risk for inducing VA loss and risk for transformation into melanoma. Regarding VA loss, Gonder et al found that 22 (11%) of 206 patients with choroidal nevus posterior to the equator of the eye showed related VA loss.17 Shields et al reported 15-year Kaplan–Meier estimates for VA loss in 2334 eyes with choroidal nevus to be 2% for those with extrafoveolar nevus and 26% for those with subfoveolar nevus.18 However, VA at presentation was relatively undisturbed in the population-based BMES of 232 eyes and in the clinic-based study by Shields et al of 3244 eyes, as the median VA at referral was 20/20.10,18 Regarding transformation into melanoma, Ganley and Comstock estimated that 1 in 4800 choroidal nevi would transform into melanoma, and Singh et al estimated transformation at 1 in 8845 in the Caucasian population.3,11 Several reports have identified clinical risk factors for nevus transformation into melanoma, including thickness over 2 mm, SRF, symptoms, orange pigment, location near the optic disc, lack of overlying drusen, fluorescein angiographic hot spots over the tumor, and hollowness on ultrasonography.19 –23
Shields et al 䡠 Clinical Spectrum of Choroidal Nevi The BMES was based on evaluation of dilated fundus photography of 6 standard retinal fields that encompassed a total field of approximately 70°.10 The subjects were fully examined, but data for the choroidal nevus study were gathered from fundus photography. Detailed measurements of nevus diameter and overlying drusen were made based on photographs. Ultrasonography was not performed. Of the 3583 participants, 232 (6.5%) had one or more choroidal nevi. Of the 232 affected patients, 1 nevus was found in 93% of patients, 2 nevi in 4%, and ⬎2 nevi in 1%. In our series, one choroidal nevus per eye was found in 98% of young patients, 92% of mid-adults, and 90% of older adults. Multiplicity of choroidal nevi per eye increased with age. More than 1 nevus per eye was found in 2% of young patients, 8% of mid-adults, and 10% of older adults. In the BMES, a population was screened for choroidal nevus, the mean nevus diameter was 1.25 mm, and the largest nevus was 4.5 mm.10 In our clinic-based study on all ages from a tertiary referral center, the mean nevus diameter was much larger: 5.6 mm in young patients, 4.7 mm in mid-adults, and 5.2 mm in older adults. The largest nevus diameter in our series was 20 mm, a stable giant choroidal nevus with overlying drusen and retinal pigment epithelial alterations. The differences in tumor size in these 2 studies emanate from the study design, as in the population-based study, asymptomatic subjects were screened, and in our clinic-based tertiary referral study, all patients were referred for a suspicious mass in the fundus. Our clinic-based analysis represents the spectrum of choroidal nevus that might prompt a consultation in an ocular oncology center, as many of the nevi exhibited orange pigment and SRF and produced related symptoms. The information from the BMES has contributed important data from another perspective, representing smaller, flatter choroidal nevi detected on high-resolution photography. The detailed images allowed for the detection of drusen overlying choroidal nevus in 98% of cases, some of which were quite subtle and not seen clinically.10 The authors admitted that drusen were recognized on ophthalmoscopy in only 41% of cases. In our series, overlying drusen were detected in 11% of young patients, 40% of mid-adults, and 58% of older adults. Additionally, drusen were found statistically to increase in frequency per increasing age category. Our older adult group (⬎50) correlated best with the subjects in the BMES (⬎49 years), and both groups showed similar frequencies of drusen clinically. It has been found that increasing nevus size correlates with increasing frequency of overlying drusen.10 The importance of drusen overlying choroidal nevus should be underscored, as this chronic finding generally implies a longstanding lesion, visible more often in older rather than younger patients (Figs 1–3). The importance of overlying drusen and chronic retinal pigment epithelial changes was also recognized in the Collaborative Ocular Melanoma Study, as the lack of these findings with small tumors was a risk for tumor growth into melanoma.22 As seen in Table 1, the majority of eyes with choroidal nevis were asymptomatic, with only 12% of patients having symptoms related to the nevus. These included VA loss, VF defect, and flashes and floaters. In a previous analysis of VA
outcome of eyes with choroidal nevus, Shields et al found that one of the most important factors for poor final VA of 20/200 or worse was subfoveal location of the nevus.18 They warned that vision loss over many years should be anticipated in patients with subfoveolar choroidal nevus, particularly those with overlying retinal pigment epithelial detachment, orange pigment, and foveal edema. In this analysis, we specifically evaluated the factors predictive of any symptom and found subfoveolar nevus as well as related SRF to be important. We anticipate that further evaluation of these patients with optical coherence tomography (OCT) and autofluorescence might provide more information regarding the etiology and onset of related symptoms. In our series, SRF overlying or adjacent to choroidal nevus was found in 11% of young patients, 15% of midadults, and 9% of older adults. Subretinal fluid should prompt close follow-up, because it is a risk for VA loss and, more importantly, a risk for ultimate transformation into melanoma.21,23 Shields et al have previously shown that the presence of SRF overlying a small melanocytic choroidal tumor (presumably nevus) imparts a 1.6 relative risk for transformation into melanoma as compared to one without fluid.21,23 Espinoza et al evaluated the role of OCT in assessing small choroidal melanocytic tumors and found that active SRF (retinal separation with normal retinal appearance) was a feature associated with tumor growth into melanoma, whereas inactive SRF (retinal separation with retinal atrophy or intraretinal cysts) was more often found with stable nevi.24 Shields et al further explored OCT findings overlying choroidal nevi in 120 eyes and found chronic features that implied stability such as photoreceptor loss in 51% and retinal edema in 15%. However, overlying active or chronic SRF was noted in 26%.25 Subretinal fluid is judged to be active when outer retinal layers are intact and photoreceptors are preserved, whereas SRF is judged chronic when outer retinal atrophy, photoreceptor loss, and retinal thinning are found. In addition, active SRF is typically more extensive than chronic SRF, which might appear as a focal area of retinal elevation overlying a nevus. Slight enlargement of choroidal nevus without evolution into melanoma was found in 3% to 4% of patients (Fig 4 [available at http://aaojournal.org]). This slight change could be related to many factors, including slight alteration in nevus pigmentation, overlying alterations in the retinal pigment epithelium camouflaging nevus margins, or true slight enlargement of the nevus without continued progression into melanoma. It is well recognized that even photographic artifacts can produce difficulty in interpreting nevus margins.26 Over the 3 decades of this study, nevus growth into melanoma was found in 14% of young patients, 9% of mid-adults, and 6% of older adults. These rates are greater than expected, but in a tertiary referral practice, many patients are sent for consultation of a mass suspicious for a nevus or small melanoma. Unless the mass is an obvious melanoma, a period of cautious observation is often warranted to document activity of the tumor. In the populationbased BMES of subjects older than 49, only 1 of 160 (⬍1%) choroidal nevi showed growth on follow-up.27 They suggested that “regular eye examinations in older patients may
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Ophthalmology Volume 115, Number 3, March 2008 be unnecessary for clearly defined small nonsuspicious choroidal nevi,” based on the lack of tumor progression.27 On the contrary, we continue to recommend regular eye examinations for all patients with choroidal nevi, as our clinicbased study has found tumor progression, even in children who might appear to have an innocent nevus. We hope to analyze further factors predictive of growth of choroidal nevi into melanoma in a future report. Use of clinical risk factors to identify those at highest risk for tumor growth might be helpful for patient monitoring. In summary, choroidal nevi show similar sizes, locations, and related symptoms in young, mid-adult, and older adult patients. Overlying features such as retinal pigment epithelial alterations and drusen appear to increase with time. With new technology such as autofluorescence and OCT, these subtle findings may be more common than previously realized and may prove to be important features in establishing the stability or growth potential of a choroidal nevus. Acknowledgments. Statistical analysis provided by Rishita Nutheti, International Centre for Advancement of Rural Eye Care, L. V. Prasad Institute, Hyderabad, India.
References 1. Albers EC. Benign melanomas of the choroid and their malignant transformation. Am J Ophthalmol 1940;23:779 – 83. 2. Wilder HC. Intraocular tumors in soldiers: World War II. Mil Surg 1946;99:459 –90. 3. Ganley JP, Comstock GW. Benign nevi and malignant melanomas of the choroid. Am J Ophthalmol 1973;76:19 –25. 4. Gass JD. Problems in the differential diagnosis of choroidal nevi and malignant melanoma: XXXIII Edward Jackson Memorial lecture. Trans Sect Ophthalmol Am Acad Ophthalmol Otolaryngol 1977;83:19 – 48. 5. Albert DM, Robinson NL, Fulton AB, et al. Epidemiological investigation of increased incidence of choroidal melanoma in a single population of chemical workers. Int Ophthalmol Clin 1980;20(2):71–92. 6. Lang GK, Daumann FJ. Peripheral fundus changes in subjects with healthy eyes (pilots) [in German]. Klin Monatsbl Augenheilkd 1982;181:493–5. 7. Albert DM, Searl SS, Forget B, et al. Uveal findings in patients with cutaneous melanoma. Am J Ophthalmol 1983; 95:474 –9. 8. Rodriguez-Sains RS. Ocular findings in patients with dysplastic nevus syndrome. Ophthalmology 1986;93:661–5. 9. Smith RE, Ganley JP. Ophthalmic survey of a community. 1. Abnormalities of the ocular fundus. Am J Ophthalmol 1972; 74:1126 –30.
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10. Sumich P, Mitchell P, Wang JJ. Choroidal nevi in a white population: the Blue Mountains Eye Study. Arch Ophthalmol 1998;116:645–50. 11. Singh AD, Kalyani P, Topham A. Estimating the risk of malignant transformation of a choroidal nevus. Ophthalmology 2005;112:1784 –9. 12. Naumann G, Yanoff M, Zimmerman LE. Histogenesis of malignant melanomas of the uvea I: histopathologic characteristics of nevi of the choroid and ciliary body. Arch Ophthalmol 1966;76:784 –96. 13. Hale PN, Allen RA, Straatsma BR. Benign melanomas (nevi) of the choroid and ciliary body. Arch Ophthalmol 1965;74: 532– 8. 14. Shields JA, Shields CL. Intraocular Tumors: A Text and Atlas. Philadelphia: Saunders; 1992:85–100. 15. Shields JA, Shields CL. Atlas of Intraocular Tumors. Philadelphia: Lippincott Williams and Wilkins; 1999:53–9. 16. Shields JA, Mashayekhi A, Ra S, Shields CL. Pseudomelanomas of the posterior uveal tract. The 2006 Taylor R. Smith Lecture. Retina 2005;25:767–71. 17. Gonder JR, Augsburger JJ, McCarthy EF, Shields JA. Visual loss associated with choroidal nevi. Ophthalmology 1982;89: 961–5. 18. Shields CL, Furuta M, Mashayekhi A, et al. Visual acuity in 3422 consecutive eyes with choroidal nevus. Arch Ophthalmol. In press. 19. Mims JL III, Shields JA. Follow-up studies of suspicious choroidal nevi. Ophthalmology 1978;85:929 – 43. 20. Butler P, Char DH, Zarbin M, Kroll S. Natural history of indeterminate pigmented choroidal tumors. Ophthalmology 1994;101:710 – 6. 21. Shields CL, Shields JA, Kiratli H, et al. Risk factors for growth and metastasis of small choroidal melanocytic lesions. Ophthalmology 1995;102:1351– 61. 22. Collaborative Ocular Melanoma Study Group. Factors predictive of growth and treatment of small choroidal melanoma: COMS report no. 5. Arch Ophthalmol 1997;115:1537– 44. 23. Shields CL, Cater JC, Shields JA, et al. Combination of clinical factors predictive of growth of small choroidal melanocytic tumors. Arch Ophthalmol 2000;118:360 – 4. 24. Espinoza G, Rosenblatt B, Harbour JW. Optical coherence tomography in the evaluation of retinal changes associated with suspicious choroidal melanocytic tumors. Am J Ophthalmol 2004;137:90 –5. 25. Shields CL, Mashayekhi A, Materin MA, et al. Optical coherence tomography of choroidal nevus in 120 patients. Retina 2005;25:243–52. 26. Johnson RN, McDonald HR, Jumper JM. Camera artifacts producing the false impression of growth of choroidal melanocytic lesions. Am J Ophthalmol 2003;135:711–3. 27. Thiagalingam S, Wang JJ, Mitchell P. Absence of change in choroidal nevi across 5 years in an older population. Arch Ophthalmol 2004;122:89 –93.
Shields et al 䡠 Clinical Spectrum of Choroidal Nevi Table 2. Choroidal Nevus in 3422 Eyes: Related Retinal and Retinal Pigment Epithelium (RPE) Features Based on Patient Age at Initial Examination Feature Retina (n ⫽ 3422 eyes) SRF Overlying nevus ⬍3 mm at margin 3–6 mm at margin ⬎6 mm at margin Retinal invasion RPE (n ⫽ 3422 eyes) Orange pigment Drusen RPE atrophy RPE hyperplasia RPE fibrous metaplasia RPE trough RPE detachment Choroidal neovascularization Foveolar status (n ⫽ 3422 eyes) Subfoveolar nevus With SRF at foveola With edema at foveola Extrafoveolar nevus With SRF at foveola With edema at foveola
Age < 20 yrs (n ⴝ 63) [n (%)]
Age 21–50 yrs (n ⴝ 795) [n (%)]
Age > 50 yrs (n ⴝ 2564) [n (%)]
7 (11) 2 (3) 4 (6) 1 (2) 0 (0) 0 (0)
115 (15) 41 (5) 51 (6) 12 (2) 1 (⬍1) 0 (0)
232 (9) 107 (4) 109 (4) 11 (⬍1) 5 (⬍1) 6 (⬍1)
4 (6) 7 (11) 1 (2) 0 (0) 4 (6) 0 (0) 0 (0) 1 (2)
79 (10) 321 (40) 106 (13) 71 (9) 69 (9) 24 (3) 8 (1) 2 (⬍1)
155 (6) 1491 (58) 261 (10) 178 (7) 190 (7) 35 (1) 34 (1) 17 (1)
9 (14) 1 (2) 0 (0) 55 (87) 5 (8) 0 (0)
53 (7) 12 (2) 4 (1) 742 (93) 22 (3) 0 (0)
143 (6) 24 (1) 10 (⬍1) 2420 (94) 30 (1) 11 (⬍1)
SRF ⫽ subretinal fluid.
Table 3. Choroidal Nevus in 3422 eyes of 3187 Patients: Demographics Based on Patient Age at Initial Examination Feature Race (n ⫽ 3187) Caucasian African American Hispanic Asian Indian Gender (n ⫽ 3187) Male Female Extraocular disease (n ⫽ 3187) Dysplastic nevus syndrome Skin melanoma Neurofibromatosis Ocular history (n ⫽ 3187) Ocular melanocytosis Uveal melanoma* (fellow eye) Conjunctival melanoma/PAM with atypia
Age < 20 yrs (n ⴝ 62) [n (%)]
Age 21–50 yrs (n ⴝ 750) [n (%)]
Age > 50 yrs (n ⴝ 2375) [n (%)]
59 (95) 2 (3) 0 (0) 0 (0) 1 (2)
738 (98) 4 (1) 7 (1) 1 (⬍1) 0 (0)
2344 (99) 15 (1) 11 (⬍1) 5 (⬍1) 0 (0)
23 (37) 39 (63)
264 (35) 486 (65)
884 (37) 1491 (63)
2 (3) 1 (2) 0 (0)
13 (2) 22 (3) 2 (⬍1)
11 (⬍1) 82 (3) 1 (⬍1)
3 (5) 0 (0) 0 (0)
32 (4) 25 (3) 5 (1)
87 (4) 84 (4) 7 (⬍1)
PAM ⫽ primary acquired melanosis. *Its presence in 3% to 4% of our cases is a referral bias. These patients were referred to us for evaluation and management of uveal melanoma and, during initial evaluation at the oncology service, were found to have a choroidal nevus in the opposite eye.
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Figure 4. Choroidal nevus followed for 35 years. A, In 1970, an 18-year-old boy was found to have a submacular choroidal nevus. B, In 2005, the mass had shown gradual minimal enlargement of ⬍1 mm. Overlying chronic retinal pigment epithelial changes, with a dried trough of subretinal fluid, were noted.
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