Purpose
To quantify potential loss (loss of vision) and gain (freedom from metastasis) in patients with small choroidal melanoma treated after a period of surveillance to document growth.
Methods
A total of 167 patients with small choroidal melanoma (size: 5.0-16.0 mm in largest basal diameter and 1.0-2.5 mm in height) were identified: 42 treated after surveillance (documented growth) and 125 treated immediately. A prediction model was applied to each patient in the immediate treatment group to obtain the predicted risk of melanoma (high risk vs low risk). Potential loss (loss of vision) and gain (freedom from metastasis) were compared between the low-risk immediate treatment group and those treated after surveillance.
Results
By using the optimal cut point (0.60; 95% confidence interval: 0.37-0.61) of predicted risk for small choroidal melanoma (sensitivity: 0.74, specificity: 0.95), we identified 94 (75%) patients as high risk (score: ≥0.6) and the remaining 31 (25%) as having low-risk melanoma (score: <0.6). Over a median follow-up of 34.6 months, 5 developed metastasis (high risk = 4, low risk = 1) compared with 1 patient in the surveillance group. Initial visual acuity and loss of <15-letter visual acuity were not significantly different at 36 months between the low-risk patients immediately treated and those treated after surveillance (81% vs 83%), respectively.
Conclusions
Low-risk choroidal melanoma identified by the prediction model can be labeled as an indeterminate melanocytic tumor. Such patients can be managed by surveillance to document growth before receiving vision-threatening treatment without increased risk of metastatic death. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
D ebate regarding the appropriate management of small choroidal melanoma (SCM) is ongoing because of diagnostic uncertainty in the absence of pathologic confirmation of the clinically suspected diagnosis. Some choroidal melanocytic tumors labeled as SCM are choroidal nevi, a fact that can be established by documenting stable dimensions over a period of 2 or more years. , As such, these tumors are best referred to as indeterminate choroidal melanocytic tumor (IMT) with the need to differentiate choroidal nevus from melanoma. , In the absence of diagnostic biopsy or documented growth, , diagnosis has relied on the presence of externally unvalidated “risk factors” that are predictive of growth in the future. , ,
The estimated maximal predicted risk of growth is not greater than 63%, , implying that prediction based on published “risk factors” is only an approximate guide to the diagnosis of SCM. Moreover, “growth” documented beyond 12 months most likely represents malignant transformation of the nevus rather than growth of incipient melanoma that is observable within the initial 12 months (mean growth rate in basal dimension of 1.8 mm/12 months).
There is a trend toward immediate treatment of SCM rather than a period of surveillance to document growth , to minimize the risk of metastasis. However, the risk of metastasis in patients with SCM seems to be low, ranging from 0% to 3% in a prospective study (Collaborative Ocular Melanoma Study [COMS] report), American Joint Committee on Cancer’s (AJCC) tumor, node, metastasis (TNM) cohort study, and in several retrospective studies. These survival outcomes are not in conflict with the recent understanding of the mutational landscape and prognostic evaluation that has shown that smaller tumors are highly likely (approximately 95%) to have a nonmetastatic (good prognosis) profile, and even if they have a metastatic (bad prognosis) profile, for reasons not fully understood, their survival outcomes are better than larger tumors with bad prognostic profiles. , Although small tumors can be fatal, studies of tumor size and prognostication in large studies have revealed that the only group of patients that did not develop metastasis were small tumors (AJCC classification) with good prognostic profiles.
Given diagnostic uncertainty, it can be hypothesized that some proportion of SCM are in fact nevi that may be amenable to an initial period of surveillance to document growth rather than immediate treatment with vision-threatening interventions. As a corollary, with the tacit aim of reducing the risk of metastasis (potential gain), there may be some cases that need not be treated with the consequent risk of vision loss (potential loss). Using a diagnostic predictive model for SCM, we explored the use of a probabilistic selection for surveillance rather than immediate treatment. We also quantified the potential loss (vision loss) and potential gain (freedom from metastasis) in those who were treated immediately but could have been initially managed by a period of surveillance to document growth before treatment.
METHODS
The study adhered to the Declaration of Helsinki. This retrospective study included 167 patients with a clinical diagnosis of SCM (COMS criteria) defined as a pigmented choroidal melanocytic lesion of size 5.0 to 16.0 mm in largest basal diameter and 1.0 to 2.5 mm in thickness, who were treated with primary enucleation, plaque brachytherapy, or transpupillary thermotherapy from January 2010 to January 2019. For the analysis of the institutional deidentified dataset, Institutional Review Board approval was obtained.
data collection
All patients were evaluated using a standard slitlamp and fundus examination to make a clinical diagnosis of SCM. Detailed fundus drawing depicting the entire extent of the lesion along with color fundus photography was performed for all the patients. The clinical records were reviewed for the following variables at the initial examination: patient age and sex, laterality, visual symptoms, presenting best-corrected VA (recorded in Snellen notation was converted to Early Treatment Diabetic Retinopathy Study VA letter score), quadratic distribution (superotemporal, superonasal, inferotemporal, inferonasal, juxtapapillary, or macular), posterior tumor margin in relation to optic disc and foveola (<3 mm or ≥3 mm), and tumor dimensions. The largest tumor basal diameter (BD) was estimated in millimeters by ophthalmoscopy, and the greatest tumor height in millimeters was measured by ultrasonography. Specific tumor features, such as the presence of subretinal fluid, surface orange pigment, drusen, and retinal pigment epithelial atrophy, were also assessed by 90D ophthalmoscopic examination and supplemented by ancillary studies such as optical coherence tomography and autofluorescence. The record of each patient was reviewed to establish if there was documented evidence of growth at any time before treatment. Growth was judged by an increase in BD of at least 0.5 mm by meticulous comparison of serial fundus photographs or by an increase in thickness of 0.3 mm by serial ultrasonograms. The interval time between the last stable examination and the documentation of tumor growth was recorded.
study groups
Immediate treatment group (N = 125)
In this retrospective study, all included patients had been treated based on clinical criteria without a period of surveillance (observation). A prediction model was applied to each patient to obtain the predicted risk of melanoma. Using the data used to build the prediction model, we identified the optimal cut point of predicted risk for defining high- vs low-risk melanoma. A total of 1000 bootstrap samples were used to assess the performance, and the 95% confidence interval (CI) for the cut point was calculated using the percentile method, by identifying the 0.025 and 0.975 percentiles of the bootstrapped cut point values.
Surveillance (growth confirmed) group (N = 42)
A total of 42 cases who were treated after documented growth, judged by an increase in BD of at least 0.5 mm by meticulous comparison of serial fundus photographs or by an increase in thickness of 0.3 mm by serial ultrasonograms. The interval time between the last stable examination and the documentation of tumor growth was recorded. In our previous work, such growth was observed to be consistent with histopathologic confirmation of SCM.
statistical analysis
Patient and disease characteristics were summarized as the median and interquartile range for continuous variables and the frequency and percentage for categorical variables. Comparisons of patient and disease characteristics between groups were made using the Wilcoxon rank-sum test for continuous variables, and either the Fisher exact test or the χ 2 test, as appropriate based on expected cell counts, for categorical variables. Time to metastasis was defined as the time from when the patient was first seen to the date of first documented metastasis. Visual acuity outcomes were reported as loss of <15 letters, mean loss of VA letters, and Snellen equivalent of 20/40 or better and 20/200 or worse over time (12, 24, and 36 months).
Time to metastasis was defined as the time from uveal melanoma diagnosis to date of first documented metastasis. Overall survival was defined as the time from when the patient was first seen to date of death from any cause. Patients without the event were censored at the date they were last seen. The Kaplan-Meier method was used to estimate the metastasis-free probability (MFS) and overall survival probability. Because of the small number of events, no statistical comparisons were conducted.
All statistical analyses were performed using R software version 4.0 (R Core Development Team). A P value of <.05 was considered statistically significant.
RESULTS
We identified 167 patients with SCM who could be classified into those treated after a period of surveillance with documented growth (n = 42) and those treated immediately without a period of surveillance (n = 125). The latter group was further divided into low-risk melanoma (31) and high-risk melanoma (94) (Supplemental Figure 1).
immediate treatment group ( n = 125)
The optimal cut point of predicted risk for defining melanoma was 0.60 (95% CI: 0.37-0.61). This cut point was associated with a sensitivity of 0.74 and a specificity of 0.95 (Supplemental Figure 2). The prediction model when applied to the immediate treatment group identified 94 (75%) of treated patients as high risk of melanoma (score: ≥0.6) and the remaining 31 (25%) as having low risk of melanoma (score: <0.6) (Supplemental Figure 3).
The high-risk melanomas were more likely to be <3.0 mm from optic disc (64% vs 16%, P < .001) and fovea (64% vs 32%, P = .002), thicker (2.0 vs 1.6 mm, P = .036) and had associated subretinal fluid (98% vs 32%, P < .001), and orange pigment (94% vs 55%, P < .001) as compared with low-risk melanoma ( Figure 1 ). Among these patients treated immediately without a period of surveillance, over a median follow-up of 34.6 months, 5 patients died from any cause (high risk = 3, low risk = 2) and 5 developed metastasis (high risk = 4, low risk = 1). The Kaplan-Meier estimate of MFS (at 3 years) for high- and low-risk group was 93% (95% CI: 86%, 100%) and 96% (95% CI: 89%, 100%), respectively.
surveillance (growth confirmed) group (n = 42)
Patient and tumor characteristics were partially described previously. , The interval time between the last stable examination and the documentation of tumor growth (increase in either BD of at least 0.5 mm or an increase in thickness of 0.3 mm) was recorded. The median time to growth was 9.0 months (mean: 10.1 months, range: 3-24 months) ( Figure 2 ). The change in BD and height ranged from 0 to 5.5 mm (median: 1.6 mm) and 0 to 1 mm (median: 0.4 mm), respectively. The mean growth rate (BD) was 1.8 mm/12 months (range: 0-7.4 mm; [95% CI: 1.32-2.28]). As comparable growth rate is observed in pathologically confirmed SCM, tumors exhibiting such growth rates can be clinically diagnosed as SCM without a need for biopsy.
comparison: low-risk immediate treatment and surveillance group
Potential loss (loss of vision) and gain (freedom from metastasis) were assessed by comparing these outcomes between the low-risk immediate treatment group and those treated after surveillance (documented growth) with an assumption that patients with low-risk melanoma could have been observed to document growth by surveillance before treatment rather than immediately treated. Patients who underwent a period of surveillance to document growth before treatment were older (median: 60 years vs 54 years; P = .024), were more frequently <3 mm from the optic nerve (43% vs 16%; P = .015), and more frequently had subretinal fluid (62% vs 32%; P = .012) and drusen (57% vs 29%; P = .017) vs those receiving immediate treatment (Supplemental Table 1).
visual outcomes
Initial VA letter (median 82 vs 85; P = .3) and letters ≥65 (95% vs 94%; P = 1.00) were not significantly different between patients who were observed to document growth before treatment vs those receiving immediate treatment. Loss of <15-letter VA was not significantly different at 12, 24, and 36 months between those treated after documented growth and the low-risk immediately treated patients (94% vs 100%, 97% vs 92%, 83% vs 81%), respectively. Other visual outcomes reported as a mean change in VA letters and Snellen equivalent of 20/40 or better and 20/200 or worse over time (12, 24, and 36 months) also did not differ between these groups of patients ( Figure 3 ).
