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Absence of Change in Choroidal Nevi Across 5 Years in an Older Population
Sureka Thiagalingam, MBChB, MPH;
Jie Jin Wang, MMed, PhD;
Paul Mitchell, MD, PhD, FRANZCO
Arch Ophthalmol. 2004;122:89-93.
ABSTRACT
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Objective To determine the proportion of choroidal nevi that were previously identified in a population cross section and that showed evidence of growth or progression during a 5-year period.
Methods The Blue Mountains Eye Study was a cohort study of residents 49 years and older living in an area west of Sydney, Australia. Retinal photographs were used to identify choroidal nevi. Repeat photographs were obtained 5 years later and graded side-by-side to ascertain clinical growth or progression of all identified nevi. The greatest diameter and surface area of each nevus were measured. Nevus growth was defined as an increase in size of at least 33%.
Results There were 160 choroidal nevi identified in the 128 subjects with nevi who participated in both eye examinations. Only 1 nevus (0.6%) exhibited clinical growth during the 5 years. No nevi developed other indicators of progression, such as subretinal fluid or orange pigment accumulation.
Conclusions Findings from this study indicate that benign nevi in older persons rarely progress. Regular eye examinations may be unnecessary for clearly defined small nonsuspicious choroidal nevi. This information could relieve patient anxiety and reduce costs associated with regular monitoring of nevi.
INTRODUCTION
CHOROIDAL NEVI ARE A RELAtively common finding, with reported prevalence rates ranging between 1% and 30%.1-8 Although most are generally considered benign, the possibility that some nevi may transform into malignant melanomas has led many ophthalmologists to recommend regular surveillance of choroidal nevi.9-11
A number of investigators have reported on the proportions and characteristics of nevi that across time were confirmed as malignant melanomas, but these nevi were generally regarded as suspicious in that it was difficult to differentiate them from melanoma at initial examination.12-15 Few population-based studies, however, have been performed to characterize and quantify the proportion of initially nonsuspicious nevi that show evidence of malignant transformation. Naumann et al16 followed 124 choroidal nevi for 2 years, none of which grew during that time. Tamler17 showed that in 28 patients, no nevi progressed during 9.5 years.
Findings in the Blue Mountains Eye Study1 indicated that choroidal nevi were present in 6.5% of this older, largely white population. The purpose of the current article is to quantify the number of these nevi that progressed during 5 years. If the growth rate of clearly defined benign nevi was substantially lower than that of suspicious nevi, as suggested by some study results, there may be no need to recommend surveillance of these lesions, with the benefits of reducing patient anxiety and costs.
METHODS
The Blue Mountains Eye Study18 is a population-based study involving residents of an area west of Sydney, Australia. Noninstitutionalized permanent residents 49 years and older were eligible to participate. The first examinations, including a detailed medical and ocular history and eye examination, were performed from 1992 through 1993, with a participation rate of 82.4%. After 5 years, of the 3654 initial participants, 543 persons had died (14.9%), and 2335 (63.9%) underwent a second examination from 1997 through 1999. Details of the study methods have been described elsewhere.18-19
A fundus camera (Zeiss FF3; Carl Zeiss, Oberkochen, Germany) was used at both eye examinations to obtain 30° stereoscopic retinal photographs of the macula and optic disc. Nonstereoscopic photographs were obtained in the upper and lower temporal arcades and nasal retina, with a total field of approximately 70°.19 A nonsuspicious nevus was defined as an unequivocal pigmented choroidal lesion with an elevation up to 1 mm and was slate blue. Partially depigmented and amelanotic nevi were also included. Other pigmented lesions such as pigment clumps and pigmented scars were excluded. No melanomas or melanocytomas were identified in this population.
Subjects with a nevus identified in the first study1 formed the population of interest. Slide transparencies from both examinations were viewed with a fluorescent viewing box and a Donaldson stereo viewer (total magnification, x15). Nevi were assessed for changes in size, shape, or color; an increase in number of overlying drusen, pigment clumping, or subretinal fluid accumulation; and the presence of orange pigment. Clear plastic grids containing 3 concentric circles with radii of 500, 1500, and 3000 µm, initially developed for grading age-related maculopathy,19-20 were placed over the nevus baseline and follow-up photographs to enable side-by-side grading of clinical change in size and other features. In addition, the photographs were digitally scanned, and the surface area and greatest diameter of each nevus at baseline and follow-up were measured (Scion Image Beta 4.02; Scion Corp, Frederick, Md). Nevus growth was defined as an increase in size of at least 33% in the follow-up photograph. All measurements were obtained by 1 grader (S.T.). A random selection of 50 nevi were regraded and tested for intragrader reliability.
Descriptive analyses of the nevi and scatterplots of baseline vs follow-up measurements, including linear regression lines, were obtained (Statistics Package for the Social Sciences version 10.0; SPSS Inc, Chicago, Ill). Confidence intervals (CIs) for the proportion of nevi showing growth were calculated by using the exact method (EXACTPCI, a macro function in Statistical Analysis System, version 6.2; SAS Institute Inc, Cary, NC). Intragrader reliability was measured by using Pearson correlation analysis (R2; SPSS Inc) and quadratic weighted  statistic (Stata, release 6; Stata Corp, College Station, Tex). The level of agreement between baseline and follow-up nevus diameter measurements was also assessed with a Bland-Altman plot (Analyse-it, version 1.65; Analyse-It Software Ltd, Leeds, England).
RESULTS
Of the 232 subjects with nevi identified in the first study, 157 returned for the 5-year examinations. Of participants who were not reexamined, 27 had died (11.6%), 20 refused to participate (8.6%), and 28 (12.1%) had either moved from the area or were lost to follow-up. The mortality rate in subjects with nevi (11.6%) was comparable with that in the whole cohort (14.9%), and no deaths were attributed to choroidal melanoma or other melanoma. Of those who returned, 29 (18.5%) did not have adequate 5-year photographs of their nevi, leaving 128 subjects with gradable photographs from both examinations.
This study subset of 128 subjects had a mean ± SD age of 64.5 ± 7.9 years (range, 49-83 years), and 61.7% were women. A total of 160 nevi was found in the 128 subjects. Nevi were found in the right eye in 54 subjects, the left eye in 63 subjects, and both eyes in 11 subjects. Two or more nevi were found in 27 subjects (21.1%), with 1 participant having 4 nevi. The mean ± SD nevus diameter was 1.28 ± 0.55 mm (range, 0.34-4.04 mm), and the mean ± SD surface area was 1.09 ± 1.17 mm2 (range, 0.07-9.49 mm2). Intragrader reliability for these measurements was high for both nevus diameter ( = 0.97, R2 = 0.99) and surface area ( = 0.97, R2 = 0.99).
Table 1 outlines the baseline features of nevi in our study. Most nevi were oval (43.8%), had a distinct edge (46.3%), were slate blue (90.0%), and were located in the posterior pole (68.8%), with almost two thirds (60.6%) located within the macula. Most were found in the temporal region: 42.5% in the upper and 43.8% in the lower temporal region. Drusen were found overlying 76.9% of the nevi. Pigment clumping and subretinal fluid were each associated with 2 nevi. None of the nevi studied had overlying orange pigment. Characteristics of nevi identified at baseline that were not reexamined at 5 years, including nevus location, color, shape, and other features, were similar to those that were reexamined.
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Characteristics of Choroidal Nevi at 5-Year Follow-up
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One nevus (0.6%; 95% CI, 0.01%-3.4%) was clinically noted to have increased in size, with a diameter of 0.49 mm and a surface area of 0.11 mm2 at the initial examination and a diameter of 0.73 mm and a surface area of 0.29 mm2 at follow-up (Figure 1). No other nevi exhibited growth during this period. There was no evidence of orange pigment deposition in any nevi at follow-up. The appearance of 2 nevi that had associated subretinal fluid at the baseline examination was unchanged at the 5-year examination. No new nevi or melanomas were identified.
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Figure 1. A, Baseline appearance of the single nevus (arrow) that demonstrated growth during 5 years. B, After 5 years, the nevus (arrow) is clearly larger, with a change in diameter from 0.49 to 0.73 mm. There are no other features of progression.
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Figure 2 shows a large nevus that was unchanged during follow-up. Figure 3A and B shows scatterplots of baseline vs follow-up measurements of the largest diameter and surface area of each nevus. The linear regression line generated for each of these plots has a slope close to 1.0, which suggests that there was little change in size during the 5 years. Figure 3C displays a Bland-Altman plot of nevus diameter at baseline and follow-up. It demonstrates the level of agreement between the 2 sets of measurements by plotting the difference in nevus size between the examinations against the mean of the 2 values. A similar number of nevi appeared to have either grown slightly or shrunk slightly during the 5 years, which is likely to represent measurement noise; however, on average, there appears to have been little change in nevus size during the 5 years (bias from zero = +0.03 mm; 95% CI, 0.009-0.05).
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Figure 2. A, Baseline photograph of the largest nevus in our study population, with a diameter of 4.04 mm. The nevus has multiple overlying drusen. B, After 5 years, there are no changes other than partial depigmentation and an increasing number of drusen.
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Figure 3. A, Scatterplot of largest nevus diameter at baseline and follow-up. The line of linear regression has a slope close to 1.0, which indicates little change in nevus diameter across 5 years (Pearson correlation coefficient = 0.97). B, Scatterplot of nevus surface area measurements at baseline and follow-up. The slope of the linear regression line is again close to 1.0 (Pearson correlation coefficient = 0.99). C, Bland-Altman plot of nevus diameter measurements displays the level of agreement between baseline and follow-up measurements. Many nevi lie above or below the mean (solid line), which is likely to represent measurement noise. The overall change in size is minimal (+0.03 mm), as shown by the dotted line.
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COMMENT
Choroidal nevi are generally considered a benign finding. A small proportion of nevi may develop into malignant melanomas, which is similar to findings in cutaneous nevi. Evidence supporting this theory has been obtained from a number of histological reports demonstrating features of nevi in established melanomas.21 Yanoff and Zimmerman9 found that 73 of 100 malignant melanomas had benign nevus cells at the periphery and at the scleral edge. Albert et al22 also described nevuslike cell morphology at the base of multiple metastatic choroidal melanomas in 1 patient. Authors of a number of case series have also reported possible transformation of a nevus into a malignant melanoma.7-8,10, 23 Most of these authors, however, agree that transformation is rare, given that choroidal nevi are much more frequent than are choroidal melanomas.4
In our study of 160 benign choroidal nevi, only 1 was judged to have grown during a 5-year interval. The clinical importance of this growth is uncertain given the initial small size of the nevus. Our results support the findings of Naumann et al16 who followed 124 choroidal nevi in 112 patients for an average of 2 years and found that none grew during that time. After follow-up for 5 years in patients referred to an oncology service, Augsburger et al,24 found that 4.5% of 62 benign nevi grew. Tamler17 also observed 28 patients with nevi (most were between one fourth and 2 disc diameters) for 9.5 years and found that none grew. Results of another study11 with a smaller number of subjects also support this finding.
The current recommended management for all nevi is identical to that for small melanomas25 and consists of annual follow-up eye examinations. This approach is recommended because (in addition to potential malignant transformation), in some instances, it may be difficult to differentiate a small melanoma from a large nevus. Sahel and Albert25 described features of these suspicious nevi, including thickness greater than 3 mm, presence of overlying orange pigment, retinal detachment without choroidal neovascularization, and pinpoint leaks at fluorescein angiography. Mims and Shields13 addressed this issue by describing suspicious nevi as being 1 to 2 mm thick and having a largest diameter between 2 and 5 disc diameters, and they also described effects on overlying structures, especially orange pigment. Authors of a number of articles focus on these lesions and features that might predict progression.12, 14, 24
None of these features was present in the nevi followed in our study. The low rate of growth of the nevi in our population suggests that nevi clearly defined as benign on the basis of size (<3-mm diameter and <1 mm thick), with no other suspicious features, may not need any regular surveillance. Patients with small nevi could be reassured that progression is rare. Clinicians can also assume that although a large number of benign nevi go undetected, it is unlikely that these lesions will produce symptoms or be associated with increased mortality. In the rare case of progression, evidence suggests that the mortality rate from small melanomas is low.26-27
A potential limitation of our study is that neither fluorescein angiography nor ultrasonography was performed to further differentiate these lesions from melanomas. A strength of our study is that our findings are likely to be more representative of the general older population, as compared with findings in nevi studies based on referral practices. We were also able to measure nevus size by using multiple techniques to increase accuracy.
In summary, our study of nonsuspicious choroidal nevi in a population-based cohort of older persons showed that fewer than 1% exhibited growth across a 5-year period. These findings suggest that small nonsuspicious nevi rarely progress and may not require routine surveillance.
AUTHOR INFORMATION
Corresponding author: Paul Mitchell, MD, PhD, FRANZCO, Centre for Vision Research, Dept of Ophthalmology, University of Sydney, Westmead Hospital, Hawkesbury Rd, Westmead, New South Wales, Australia 2145 (e-mail: paul_mitchell{at}wmi.usyd.edu.au).
Submitted for publication July 2, 2002; final revision received July 25, 2003; accepted August 15, 2003.
This study was supported by grant 974159 from the National Health and Medical Research Council, Canberra, Australia.
From the Department of Ophthalmology, University of Sydney, and the Westmead Millennium Institute Centre for Vision Research, Westmead Hospital, Westmead, Australia. The authors have no financial interest in this article.
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