Choroidal Nevi in Children: Size, Growth, and Topographic Distribution.

PURPOSE: To explore size, growth, and topographic distribution of choroidal nevi in children to gain insights into choroidal nevogenesis. DESIGN: Retrospective consecutive case series using pediatric clinic - and population-study data, comparing to adult data. METHODS: Clinical data from Cole Eye Institute (CEI) database (December 2005-January 2023) was derived from a retrospective consecutive case series of 20 children (< 20 years) with choroidal nevi. For population data, 48 children from previously reported pooled data of the participants of the Sydney Pediatric Eye Disease Study, Sydney Myopia Study, Sydney Childhood Eye Study, and Sydney Adolescent Vascular and Eye Disease Study were included. Fundus photographs were reviewed and the locations of 18 choroidal nevi seen at CEI with widefield imaging were mapped on a radial scatter plot. For comparison, 100 consecutive adults with choroidal nevi were identified from CEI database. Main outcomes were size, growth, and topographic distribution of choroidal nevi. RESULTS: The median largest basal diameter was 1.6 mm (range 0.4-4.2) in children. Most choroidal nevi (75%) remained stable, and 16% demonstrated growth at follow-up. The mean growth rate was calculated as 0.12 mm/year (range 0.10-0.15). Malignant transformation was not noted during childhood. All secondary changes (drusen, orange pigment, and subretinal fluid) associated with choroidal nevi in children were less common than those in adults (p < .05). Choroidal nevi in children were located significantly more posterior than in adults. The median distance to fovea was 2.1 mm (range 0.5-8.5) in children and 5.1 mm (range 0.4-16) in adults (p < .0001). CONCLUSIONS: The onset and growth of choroidal nevi in children suggest active choroidal nevogenesis in childhood. A posterior topographic distribution may support the developmental framework for migration and maturation of choroidal melanoblasts.

Uveal melanoma in African Americans: Diagnostic challenges.

Uveal melanoma (UM) is uncommon in African Americans. Owing to its rarity, UM may not be suspected in African Americans leading to delayed diagnosis. In addition, socioeconomic factors may also play a role in delayed diagnosis. Clinical and ultrasonographic features may be atypical due to racial pigmentation, necessitating diagnostic fine needle aspiration biopsy. Herein, we report an illustrative case series of 12 African Americans with UM highlighting clinical features and diagnostic challenges.

Surveillance for Metastasis in High-Risk Uveal Melanoma Patients: Standard versus Enhanced Protocols.

PURPOSE: to evaluate the effectiveness of enhanced surveillance protocols (EP) utilizing high frequency (HF) or enhanced modality (EM) compared to the standard protocol (SP) in detecting metastasis and determining their impact on overall survival (OS) in high-risk uveal melanoma (UM) patients. METHODS: A total of 87 consecutive patients with Class 2 (high risk) primary UM were enrolled, with negative baseline systemic staging. The patients underwent systemic surveillance with either SP (hepatic ultrasonography [US] every 6 months) or EP (either HF [US every 3 months] or EM [incorporation hepatic computed tomography/magnetic resonance imaging]) following informed discussion. The main outcome measures were largest diameter of largest hepatic metastasis (LDLM), number of hepatic metastatic lesions, time to detection of metastasis (TDM), and OS. RESULTS: This study revealed significant differences in LDLM between surveillance protocols, with the use of EP detecting smaller metastatic lesions (HF, EM, and SP were 1.5 cm, 1.6 cm, and 6.1 cm, respectively). Patients on the EM protocol had a lower 24-month cumulative incidence of >3 cm metastasis (3.5% EM vs. 39% SP; p = 0.021), while those on the HF protocol had a higher 24-month cumulative incidence of ≤3 cm metastasis compared to SP (31% HF vs. 10% SP; p = 0.017). Hazard of death following metastasis was significantly reduced in the EP (HR: 0.25; 95% CI: 0.07, 0.84), HF (HR: 0.23; 95% CI: 0.06, 0.84), and EM (HR: 0.11; 95% CI: 0.02, 0.5) groups compared to SP. However, TDM and OS did not significantly differ between protocols. CONCLUSIONS: Enhanced surveillance protocols improved early detection of hepatic metastasis in UM patients but did not translate into a survival advantage in our study cohort. However, early detection of metastasis in patients receiving liver-directed therapies may lead to improved overall survival.

Angiographic Features of Iris Melanocytic Tumors: Nevus versus Melanoma.

Introduction: Determining the nature of iris melanocytic tumors based on clinical exam alone remains challenging. Tumor-associated vasculature of iris melanocytic lesions may facilitate the ability to discern between iris nevus and melanoma. Methods: In a single-institution, retrospective, observational study of 45 patients with pathologically confirmed iris melanoma and 15 patients with iris nevi that were either clinically stable or pathologically confirmed were included. Tumor characteristics and associated vasculature were identified on clinical exam and slit-lamp photographs. Fluorescein angiographic parameters including feeder vessels, intrinsic vessels, leakage, masking, and angiographic silence were assessed. Results: Feeder vessels were present in 17 (43%) melanomas and were absent in the nevus group (p = 0.002). Thirty-three (83%) iris melanomas and 5 (33%) iris nevi were observed to have intrinsic vessels, and a statistically significant association of intrinsic vessels with malignancy (p = 0.001) was noted. Fluorescein leakage was also observed more frequently in iris melanoma 39 (98%) than in nevi 9 (60) with a significant difference (p = 0.001). Angiographic silence occurred in 3 nevi (20%) and was not observed in any melanoma (p = 0.017). Overall, the presence of intrinsic vessels +/- feeder vessels had high sensitivity (0.85) and high positive predictive value (0.87) for diagnosis of iris melanoma. Conclusions: Anterior segment fluorescein angiography allows for the assessment of tumor-associated vascular patterns and demonstrates utility in differentiating iris nevi from melanoma. Feeder vessels were only observed in iris melanoma and were absent in iris nevi. The intrinsic vessels were present more frequently in melanomas and are thus associated with malignancy. Angiographic silence is indicative of iris nevi.

Peripheral Hemorrhagic Chorioretinopathy: Differentiating Features from Choroidal Melanoma.

Introduction: Peripheral exudative hemorrhagic chorioretinopathy (PEHCR) is one of the leading mimickers of choroidal melanoma because of overlapping features with choroidal melanoma that make the distinction between these two entities difficult. Methods: To identify nonoverlapping diagnostic features between PEHCR and choroidal melanoma, a retrospective study of 80 patients (80 eyes); 40 patients (40 eyes) with PEHCR; and 40 patients (40 eyes) with choroidal melanoma was conducted. Ophthalmoscopic and imaging features of PEHCR and choroidal melanoma were compared. Sensitivity and specificity for identifying PEHCR and choroidal melanoma were calculated. Youden's J statistic was assessed for each diagnostic feature. Results: The most frequent clinical features of PEHCR were presence of druse (100%), hemorrhagic PED (93%), dome-shaped mass (B-scan) (90%), and subretinal/intraretinal hemorrhage (78%). Statistical analysis confirmed high sensitivity of hemorrhagic PED (0.93; 95% CI 0.80-0.98) and high specificity of clot retraction cleft, presence of lipid exudation, and bilaterality (1.00; 95% CI 0.91-1.00) as diagnostic features of PEHCR. Statistical analysis revealed presence of subretinal fluid 0.80 (95% CI 0.54-0.91) was most sensitive and presence of orange pigment, mushroom shape on B-scan, ciliary body extension, and choroidal excavation were most specific (1.00; 95% CI 0.91-1.00) for choroidal melanoma. Nonoverlapping diagnostic features of PEHCR were hemorrhagic PED, clot retraction cleft, presence of lipid exudation, and bilaterality. All PEHCR patients (100%) had at least one of these nonoverlapping diagnostic features. Nonoverlapping diagnostic features of choroidal melanoma were the presence of orange pigment, choroidal excavation, mushroom-shaped mass, and ciliary body extension (the latter 3 detected on B-scan). Youden's J statistic was highest for hemorrhagic PED and lowest for dome-shape appearance on B-scan (0.075). Conclusion: PEHCR and choroidal melanoma can be differentiated by identifying diagnostic features that are exclusive to each entity. The presence of hemorrhagic PED strongly supports a diagnosis of PEHCR. B-scan ultrasonography is required to detect a mushroom-shaped mass, choroidal excavation, or ciliary body extension to exclude underlying choroidal melanoma.

Clustering of uveal melanoma: County wide analysis within Ohio.

PURPOSE: To determine if a greater than expected number of cases (clustering) of uveal melanoma occurred within Ohio for any specific region or time period as compared to others. DESIGN: Analysis of population database. METHODS: Ohio Cancer Incidence Surveillance System (OCISS) database (2000-2019) was accessed for the diagnosis of uveal melanoma using the International Classification of Disease for Oncology codes: C69.3 (choroid), C69.4 (ciliary body and iris). Counties within Ohio were grouped by geographic regions (7) and socioeconomic variables. Age- and race-standardized incidence ratios (SIR) were calculated to determine temporal or geographic clustering. RESULTS: Over the twenty-year period, the total number of uveal melanoma cases reported within Ohio were 1,617 with the overall age-adjusted annual incidence of 6.72 cases per million population (95% CI 6.30-7.16). There was an increase in the incidence of uveal melanoma over 20 years (p<0.001) across seven geographic regions, but no significant difference in incidence rates between the regions. There was no difference in incidence based on county classification by age composition (p = 0.14) or education level (p = 0.11). Counties with a low median household income (p<0.001), those classified as urban (p = 0.004), and those with a greater minority population (p = 0.004) had lower incidence. Less populated counties had a higher incidence of uveal melanoma (p<0.001). CONCLUSIONS: There is no evidence of geographic or temporal clustering of uveal melanoma within Ohio from 2000 to 2019.

Iris melanoma: Prognostication for metastasis.

Uveal melanoma prognostication studies have mainly included posterior uveal melanomas located in the ciliary body and choroid, often excluding iris melanoma. In this study, we report prognostic status and survival outcomes in a series of 35 patients with biopsy-proven iris melanoma. Fluorescence in situ hybridization was performed in 10 (29%) cases and 2 (5%) underwent multiplex ligation-dependent probe amplification. In total, 9 cases demonstrated disomy 3, 2 cases with monosomy 3 (fluorescence in situ hybridization), and 1 had a technical failure. On gene expression profile testing, 20 of the 23 cases (90%) were gene expression profile class 1A, and the remaining 3 (10%) were class 1B. No patient had a Class 2 status. The median follow-up period was 49 months (mean 59, range 2-156 months). No metastasis was reported during follow-up, and metastasis-free survival was 100%. A review of the published literature revealed 47 cases with high-risk status on molecular prediction, of which only 6 (13%) developed metastasis. Ciliary body involvement was reported in 5 cases and was unknown in 2 cases. We conclude that molecular prognostication of iris melanoma demonstrates low-risk prognostic status in the majority of cases irrespective of the technique used. Even those with high-risk status do not develop metastasis unless the tumor involves the ciliary body.

INTRAVITREAL FLUOCINOLONE ACETONIDE IMPLANT FOR RADIATION RETINOPATHY: Report of Preliminary Findings.

PURPOSE: To assess the efficacy of a 0.18 mg intravitreal fluocinolone acetonide (FA) implant (Yutiq, EyePoint Pharmaceuticals, Watertown, MA) as a treatment option for patients with radiation retinopathy-related cystoid macular edema. METHODS: A retrospective review of seven patients treated for uveal melanoma who developed radiation retinopathy-related cystoid macular edema. They were initially treated with intravitreal anti-vascular endothelial growth factor and/or steroid injections and then transitioned to intravitreal FA implant. Primary outcomes include best-corrected visual acuity, central subfield thickness, and number of additional injections. RESULTS: After FA implant insertion, best-corrected visual acuity and central subfield thickness remained stable in all patients. The variance in best-corrected visual acuity decreased from 75.5 ETDRS letters (range 0-199 letters) to 29.8 (range 1.2-134) after FA implant insertion. Mean central subfield thickness was 384 µ m (range 165-641) and 354 µ m (range 282-493) before and after FA implant insertion, resulting in a 30- µ m mean reduction. The number of intravitreal injections (average 4.9, range 2-10) decreased after intravitreal FA implant insertion with only two patients requiring one additional FA implant (average 0.29, range 0-1) over a mean of 12.1 months (range 0.9-18.5) follow-up. CONCLUSION: Intravitreal FA implant is an effective treatment for cystoid macular edema radiation retinopathy. The slow release of steroid allows for sustained control of macular edema, which correlated with stable visual acuity and decreased injection burden for patients.

Predicted vs Observed Metastasis-Free Survival in Individuals With Uveal Melanoma.

Importance: Accuracy of the predicted metastasis-free survival (MFS) by a commercially available gene expression profiling (GEP) test is not known. Objective: To compare the predicted MFS with the observed MFS in patients in this cohort and with those in published studies (published MFS, meta-analysis). Design, Setting, and Participants: This cohort study included consecutive patients from the University of Iowa and Cleveland Clinic who were diagnosed with uveal melanoma who underwent prognostic fine-needle aspiration biopsy at the time of primary treatment. Patients were recruited from December 2012 to December 2020. The predicted MFS for patients was extracted from the GEP report. The observed MFS was defined as time to metastasis. Cox proportional hazards models were fit to identify tumor variables impacting MFS in patients with class 2 tumors. The overall estimate of the published MFS was obtained by performing meta-analysis of data from published series. Analysis took place in August 2021. Main Outcomes and Measures: MFS. Results: There were 92 patients from the University of Iowa and 255 patients from the Cleveland Clinic. The mean (SD) age at diagnosis was 59.4 (13.0) years. The median (IQR) follow-up interval was 38.0 (19.0-57.0) months. The observed MFS for patients with class 2 tumor in this cohort (3 years: 67% [95% CI, 59%-77%]; 5 years: 47% [95% CI, 37%-61%]) and in published studies (3 years: 62% [95% CI, 57%-66%]; 5 years: 40% [95% CI, 34%-46%]) were better than those predicted (50% and 28% for 3 and 5 years, respectively). Within patients with class 2 tumor, those with metastasis had larger tumors compared with nonmetastatic tumors (mean largest basal diameter difference, 1.7 [95% CI, 0.5-3.0] mm; P = .01; mean thickness ratio, 1.3 [95% CI, 1.04-1.5]; P = .01, respectively). An increasing tumor size was significantly associated with increased hazard ratio (1.16 [95% CI, 1.06-1.27]; P < .001) of metastasis. Conclusions and Relevance: These findings suggest the predicted MFS for metastatic tumors (class 2) appears to be worse than that observed here and reported by others. Incorporation of tumor size in the prediction model may enhance its accuracy. Adjuvant therapy trials may not be able to rely on predicted MFS to calculate efficacy with a high degree of confidence.

Aqueous humor as a surrogate biomarker for retinoblastoma tumor tissue.

PURPOSE: To demonstrate the feasibility of identifying a germline RB1 pathogenic variant in retinoblastoma (RB) from an aqueous humor (AH) sample. METHODS: In this pilot case series, peripheral blood, fresh tumor tissue, and AH were obtained from 3 eyes of 3 RB patients who underwent enucleation at a tertiary eye care institute. After isolation of the cell-free DNA (cfDNA), sequence analysis of the RB1 core promoter and of exons 1 through 27, including nearby flanking intronic regions, was performed using a custom targeted hybridization protocol, followed by high-throughput sequencing. RESULTS: The study cohort included 3 enucleated eyes with advanced RB (group E [n = 2], group D [n = 1]). In case 1, deletion of the RB1 promoter to exon 23 (delP->23) on both alleles was identified from tumor as well as AH samples and absent in the blood sample, indicative of absence of a germline RB1 pathogenic variant. In case 2, two heterozygous RB1 nonsense variants, c.610G>T p.(Glu204Ter) and c.751C>T p.(Arg251Ter), were identified in tumor and AH samples (allele frequency of 49% and 45%, resp.) and were absent in the blood sample, indicative of absence of a germline RB1 pathogenic variant. In case 3, a heterozygous c.2326-14T>A substitution on allele 1 and loss of heterozygosity on allele 2 were identified in the tumor and AH (allele frequency of 97%), with the same heterozygous mutation in the blood sample, indicating presence of a germline RB1 pathogenic variant. CONCLUSIONS: The pathogenic RB1 variant results from AH in all 3 eyes were concordant with direct tumor DNA sampling, suggesting that AH can serve as a surrogate for tumor tissue. Because the AH can be accessed during treatment, specific testing can be performed even in the absence of enucleation.

Small Choroidal Melanoma: Outcomes After Surveillance Versus Immediate Treatment.

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.