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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., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest. They alone are responsible for the content and writing of this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest Arun D. Singh. is the Editor-in-Chief of Ocular Oncology and Pathology. A.D.S. has reported having relevant financial activities outside the submitted work: Aura Biosciences (stock options), IsoAid LLC (consultancy), Immunocore (consultancy), Isoaid (consultancy), and Eckert and Zeigler (consultancy). This work was supported by a Research to Prevent Blindness Challenge Grant, Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine. None of the remaining contributing authors have relevant financial activities to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Clevenger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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.

Objective: To analyse ocular and systemic findings of patients presenting with systemic metastasis., Methods and Analysis: It is an international, multicentre, internet-enabled, registry-based retrospective data analysis. Patients were diagnosed between 2001 and 2011. Data included: primary tumour dimensions, extrascleral extension, ciliary body involvement, American Joint Committee on Cancer (AJCC)-tumour, node, metastasis staging, characteristics of metastases., Results: Of 3610 patients with uveal melanoma, 69 (1.9%; 95% CI 1.5 to 2.4) presented with clinical metastasis (stage IV). These melanomas originated in the iris, ciliary body and choroid in 4%, 16% and 80% of eyes, respectively. Using eighth edition AJCC, 8 (11%), 20 (29%), 24 (35%), and 17 (25%) belonged to AJCC T-categories T1-T4. Risk of synchronous metastases increased from 0.7% (T1) to 1.5% (T2), 2.6% (T3) and 7.9% (T4). Regional lymph node metastases (N1a) were detected in 9 (13%) patients of whom 6 (67%) had extrascleral extension. Stage of systemic metastases (known for 40 (59%) stage IV patients) revealed 14 (35%), 25 (63%) and 1 (2%) had small (M1a), medium-sized (M1b) and large-sized (M1c) metastases, respectively. Location of metastases in stage IV patients were liver (91%), lung (16%), bone (9%), brain (6%), subcutaneous tissue (4%) and others (5%). Multiple sites of metastases were noted in 24%. Compared with the 98.1% of patients who did not present with metastases, those with synchronous metastases had larger intraocular tumours, more frequent extrascleral extension, ciliary body involvement and thus a higher AJCC T-category., Conclusions: Though higher AJCC T-stage was associated with risk for metastases at diagnosis, even small T1 tumours were stage IV at initial presentation. The liver was the most common site of metastases; however, frequent multiorgan involvement supports initial whole-body staging., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To assess outcomes of small and medium choroidal melanoma (less than 5.0 mm in height) following Iodine-125 episcleral brachytherapy., Methods and Materials: Patients with small and medium choroidal melanoma that underwent Iodine-125 brachytherapy with apical height of 1.0 mm to 5.0 mm and largest basal diameter of ≤16.0 mm were included. Data were extracted from the original dosimetry plans to determine doses to vision critical structures with the prescription point to the apical height (actual dose, ABS guidelines) and, after simulation, with the prescription point to the height of 5.0 mm (simulated dose, COMS protocol). Visual acuity (VA) outcomes with actual dose and that predicted with the simulated dose were estimated along with local recurrence, ocular survival, and survival at 5 years., Results: A total of 339 patients with a mean age of 61.5 years with a mean follow up duration of 43.4 months were included. The mean dose reduction for lens, optic disc, and fovea was 34%, 39.4%, and 41.4%, respectively with actual dose when compared with simulated dose. The Kaplan-Meier estimations for 3 year event free rate of VA of 20/50 or better were 56% and 31% for actual dose and simulated dose, respectively. Only 3 events of local recurrence were observed (enucleated) yielding 5 year local control and ocular survival rate of 98%. Overall survival (OS) and metastasis free survival (MFS) were 95% and 87.5% at 5 years, respectively., Conclusions: Small and medium choroidal melanoma treated according to ABS has excellent outcomes. Brachytherapy planning using ABS guidelines as compared to COMS protocol may be associated with lower rates of radiation toxicity and vision loss., (Copyright © 2021 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

To determine the response rate of choroidal melanoma following primary photodynamic therapy, we conducted a meta-analysis of published studies. A total of 7 studies reporting photodynamic therapy as primary treatment of choroidal melanoma in 162 patients with a mean tumor height of 2.8 mm (1.4 to 4.2) were identified. Forty-six percent of tumors were amelanotic, 48% were fully pigmented, and 6% had partial pigmentation. The photodynamic therapy parameters in all studies included 10-minute intravenous infusion of verteporfin (6 mg/m 2 ), but varied in number of sessions (1 to 3), fluence (1× to 19×), and number of spots (single or multiple). The response was defined as tumor regression (partial or total) or lack of growth after initial treatment. The response to photodynamic therapy was predominantly observed as regression (126 [78%]). Overall response rate was 80% (mean) with a wide range among studies (58%-100%) over a period of 50 months (mean) with variable follow-up (range, 1-156 months). None of the studies reported progression- or recurrence-free survival; however, the recurrence rate was not related to the follow-up duration. Favorable prognostic factors were smaller size and lack of pigmentation. The overall response rate of 80% suggests that photodynamic therapy may be an effective primary treatment for small choroidal melanoma, especially in cases without pigmentation. Artifacts in study design (inclusion criteria and outcome measure) may have contributed to the variable observed response rate. Further studies with uniform inclusion criteria, standardized treatment parameters, well-defined outcome measures, and long follow-up are needed., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To investigate conditional survival in patients with uveal melanoma in the United States., Design: Cohort study., Participants: Patients were identified using International Classification of Disease for Oncology, Third Edition, codes for both morphologic features (melanoma, 8720-8790) and site (retina, C69.2; choroid, C69.3; and ciliary body, C69.4) from 1975 through 2011 using the Surveillance, Epidemiology, and End Results (SEER) database SEER 18., Methods: Observed metastasis-free survival (MFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Conditional metastasis-free survival (cMFS) and conditional overall survival were calculated based on the observed MFS and OS. Relative survival also was calculated using the actuarial method. Survival to 5 and 10 years after diagnosis were calculated, conditioned on various numbers of years already survived., Main Outcome Measures: Conditional MFS, conditional OS, and conditional relative survival., Results: A total of 6863 cases of uveal melanoma were identified. Median follow-up among survivors was 11 years. During follow-up, 3883 patients died of any cause, and of these, 2131 deaths were the result of metastatic uveal melanoma. The nonconditional 5-year MFS was 80%. After surviving 1, 2, 3, or 4 years after diagnosis, the 5-year cMFS estimates increased to 82%, 87%, 92%, and 96%, respectively. The nonconditional MFS at 10 years was estimated to be 69%. After having survived 5, 6, 7, 8, or 9 years after diagnosis, the 10-year cMFS estimates increased to 87%, 90%, 93%, 96%, and 98%, respectively. This result pattern was confirmed with estimates of relative survival., Conclusions: Conditional survival estimates of uveal melanoma improve with time since primary diagnosis. Among patients who already have survived for at least 5 years, 10-year conditional survival rates are high. Conditional survival analysis can provide specific guidance for counselling patients., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: The long-term survival of uveal melanoma patients in the US is not known. We compared long-term survival estimates using relative survival, excess absolute risk (EAR), Kaplan-Meier (KM), and competing risk analyses., Setting: Population based cohort study., Study Population: Pooled databases from Surveillance, Epidemiology, and End Results data (SEER, SEER-9+SEER-13+SEER-18)., Main Outcome Measure: Overall Survival (OS), Metastasis Free Survival (MFS) and relative survival, computed directly or estimated via a model fitted to excess mortality., Results: There were 10678 cases of uveal melanoma spanning a period of 42 years (1975-2016). The median age at diagnosis was 63 years (range 3-99). Over half the patients were still alive at the end of 2016 (53%, 5625). The KM estimates of MFS were 0.729 (0.719, 0.74), 0.648 (0.633, 0.663), and 0.616 (0.596, 0.636) at 10, 20, and 30 years, respectively. The cumulative probabilities of melanoma metastatic death at 10, 20 and 30 years were 0.241 (0.236, 0.245), 0.289 (0.283, 0.294), and 0.301 (0.295, 0.307). In the first 5 years since diagnosis of uveal melanoma, the proportion of deaths attributable to uveal melanoma were 1.3 with rapid fall after 10 years. Death due to melanoma were rare beyond 20 years. Relative survival (RS) plateaued to ~60% across 20 to 30 years. EAR parametric modeling yielded a survival probability of 57%., Conclusions: Relative survival methods can be used to estimate long term survival of uveal melanoma patients without knowing the exact cause of death. RS and EAR provide more realistic estimates as they compare the survival to that of a normal matched population. Death due to melanoma were rare beyond 20 years with normal life expectancy reached at 25 years after primary therapy., Competing Interests: We have no competing interests.

Purpose: To estimate point prevalence of uveal melanoma in the patients with germline BAP1 pathogenic variant., Design: Cohort study with risk assessment using Bayesian analysis., Methods: The point prevalence estimate was obtained by Bayes's rule of reverse conditional probabilities. The probability of uveal melanoma given that BAP1 mutation exists was derived from the prevalence of uveal melanoma, prevalence of germline BAP1 pathogenic variants, and the probability of germline BAP1 pathogenic variant given that uveal melanoma is present. Confidence intervals (CIs) for each variable were calculated as the mean of Bernoulli random variables and for the risk estimate, by the delta method. The age at diagnosis and the gender of the uveal melanoma patients with BAP1 germline pathogenic variants obtained from previous publications or from authors' unpublished cohort was compared with those in the Surveillance, Epidemiology, and End Results (SEER) database., Results: The point prevalence of uveal melanoma in patients with the germline BAP1 pathogenic variants in the US population was estimated to be 2.8% (95% CI, 0.88%-4.81%). In the SEER database, the median age at diagnosis of uveal melanomas was 63 (range 3-99 years) with a male-to-female ratio of 1.01:1. In comparison, uveal melanoma cases with BAP1 germline pathogenic variants from the US population (n = 27) had a median age at diagnosis of 50.5 years (range 16-71)., Conclusions: Quantification of the risk of developing uveal melanoma can enhance counseling regarding surveillance in patients with germline BAP1 pathogenic variant., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Importance: The extent to which uveal melanoma is cured by ocular therapy is not known., Objective: To estimate cured fractions (CF) of uveal melanoma using combination of institutional and Surveillance, Epidemiology, and End Results (SEER) data., Design, Setting, and Participants: Integrative analysis of 42 years of SEER data (1975-2016) with 25 years (1993-2018) of complementary institutional data. The analysis included SEER US patients and molecularly prognosticated patients in the United States and Europe. Three SEER databases (SEER-9, SEER-13, and SEER-18) were merged. A total of 10 678 SEER cases of uveal melanoma diagnosed from 1975 to 2016 using International Classification of Disease for Oncology morphology codes 8720-8790 (for melanoma) and site codes C69.2-4 (for choroid, ciliary body, and iris) were downloaded April 16, 2019. The institutional data included 5 institutional cohorts of 788 molecularly prognosticated patients (diagnosed prior to July 2019) with 3115 person-years at risk of death and 262 observed deaths., Main Outcomes and Measures: Excess absolute risks of death (EAR) and cured fraction (CF) indicates lifetime area under the EAR curve. These are applied to populations and subpopulations., Results: The SEER EAR, with sexes and races pooled, can be modeled as a sum of 2 waves. The first wave peaks at approximately 3 years and is negligible by 15 years, at which time the second wave peaks. Institutional data suggest that the first wave is owing to BAP1 mutant cases (204 of 355 [57.5%]; 95% CI, 52%-63%) and that the second wave is owing to BAP1 wild-type SF3B1 mutant cases (60 of 355 [17%]; 95% CI, 13%-21%). There is also a third group with a low flat EAR time course (91 of 355 [25.5%]; 95% CI, 21%-30%). The overall statistical CF of 60% is reached by approximately 25 years., Conclusions and Relevance: These findings suggest that the benefits of ocular therapy for curing uveal melanoma may be questionable because statistical cures reflect deaths of poor prognosis cases and survival of good prognosis cases. Changes in uveal melanoma patient management may be needed to improve survival.

Purpose: Investigate the influence of tumor size by American Joint Committee on Cancer (AJCC) stage, Collaborative Ocular Melanoma Study (COMS) size, tumor largest basal diameter (LBD), and tumor thickness on prognostication by gene expression profiling (GEP) class., Design: Two-center retrospective study., Participants: Two hundred fifteen consecutive patients diagnosed with posterior uveal melanoma over a 5-year period who were evaluated with prognostic fine-needle aspiration biopsy at the time of primary treatment., Methods: Patient demographics, tumor clinical size, AJCC stage, COMS size, GEP class, presence of metastasis, and mortality data were collected. Metastasis-free-survival (MFS) was defined as time to metastasis or death from any cause. Comparisons were made using Pearson chi-square tests or Fisher exact tests for categorical factors, and t tests or Kruskal-Wallis tests for continuous measures. Cox proportional hazards models were fit to identify whether size measurements increased the prognostic discrimination index (C-statistic)., Main Outcome Measures: Metastasis-free-survival., Results: The average follow-up interval was 22.0 months (range, 12.0-37.0 months). Eighty-nine tumors were class 1A, 48 class 1B, and 78 class 2. Twenty-one patients developed metastatic disease detected by surveillance and confirmed by liver biopsy. Three-year MFS was 96% for class 1 and 63% for class 2. Five-year MFS was 96% for class 1 and 49% for class 2. All size measures significantly improved prognostic discrimination index by GEP class, as shown by increase in the C-statistic with addition of size variables (C-statistic 0.750 GEP alone, 0.830 GEP with AJCC [P = 0.016], 0.822 GEP with COMS [P < 0.001], 0.842 GEP with LBD [P <0.001], and 0.847 GEP with tumor thickness [P < 0.001]). Class 2 patients with metastasis had larger tumors compared with nonmetastatic class 2 tumors (AJCC class, P = 0.004; COMS class, P = 0.024; with metastasis mean thickness 6.5 mm [interquartile range (IQR), 3.8-9.5 mm]; without metastasis, 3.9 mm [SD, 3.1-6.0 mm]; P = 0.008), with metastasis mean LBD 14.9±2.8 mm, without metastasis, 12.3±2.7 mm (P < 0.001). All class 1 tumors with metastasis were large and required enucleation., Conclusions: Incorporation of tumor size enhances the prognostic discrimination index of the GEP test in patients with posterior uveal melanoma. All size tumor parameters are equivalent in their ability to enhance GEP prognostication., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background/aim: Molecular prognostication provides clinically applicable prognostic information for patients with uveal melanoma. Most ocular oncologists recommend intensive metastatic surveillance for patients with high-risk tumours. However, socioeconomic variables may limit a patient's ability to adhere to recommended surveillance. We aim to analyse socioeconomic data from patients with uveal melanoma who underwent molecular prognostication to determine which variables influence adherence., Methods: This was a retrospective review of 107 consecutive patients who were diagnosed and treated for uveal melanoma from January 2014 to June 2015. Patients were categorised into low/unknown risk and high risk for metastasis. The low-risk group was followed with hepatic ultrasonography every 6 months. The high-risk group was followed with more frequent hepatic imaging or incorporation of hepatic CT/MRI into the surveillance protocol. Adherence to surveillance recommendations was recorded for the first 2 years following primary treatment. Socioeconomic data including age at diagnosis, baseline systemic staging, gene expression profile status, marital status, insurance, distance of primary residence, median household income and Charlson Comorbidity Index score were recorded. Frequency/modality of imaging and metastatic status were also recorded., Results: High-risk patients were more likely to develop metastasis than low-risk/unknown-risk patients (p<0.001). High-risk patients were more likely to have scans at baseline (p=0.008) and to have expected scans relative to low-risk/unknown-risk patients (p<0.001). There was no significant relationship between the likelihood of adhering to recommended surveillance and the other variables analysed., Conclusions: Prognostic risk level is a significant predictor of surveillance and remains significant after adjustment for socioeconomic variables. Adherence to surveillance recommendations for high-risk patients may translate into improved survival., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Uveal melanoma is a primary malignancy of the eye with oncogenic mutations in GNAQ, GNA11, or CYSLTR2 , and additional mutations in BAP1 (usually associated with LOH of Chr 3), SF3B1 , or EIF1AX . There are other characteristic chromosomal alterations, but their significance is not clear., Experimental Design: To investigate genes driving chromosomal alterations, we integrated copy number, transcriptome, and mutation data from three cohorts and followed up key findings., Results: We observed significant enrichment of transcripts on chromosomes 1p, 3, 6, 8, and 16q and identified seven shared focal copy number alterations (FCNAs) on Chr 1p36, 2q37, 3, 6q25, 6q27, and 8q24. Integrated analyses revealed clusters of genes in focal copy number regions whose expression was associated with metastasis and worse overall survival. This included genes from Chr 1p36, 3p21, and 8q24.3. At Chr 6q27, we identified two tumors with homozygous deletion of PHF10/BAF45a and one with a frameshift mutation with concomitant loss of the wild-type allele. Downregulation of PHF10 in uveal melanoma cell lines and tumors altered a number of biological pathways including development and adhesion. These findings provide support for a role for PHF10 as a novel tumor suppressor at Chr 6q27., Conclusions: Integration of copy number, transcriptome, and mutation data revealed novel candidate genes playing a role in uveal melanoma pathogenesis and a potential tumor suppressor role for PHF10 ., (©2019 American Association for Cancer Research.)

Topic: Survival of patients with uveal melanoma classified to have a bad prognosis., Clinical Relevance: To explore reasons for reported variability in survival of patients with uveal melanoma classified to have a bad prognosis., Methods: We searched PUBMED, MEDLINE, and EMBASE for studies reporting survival data for uveal melanoma undergoing prognostic testing with chromosome 3 status by fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), microsatellite analysis (MSA), multiplex ligation-dependent probe amplification (MLPA), single nucleotide polymorphism (SNP), gene expression profiling (GEP) class, and exon sequencing. Only studies reporting 1-year, 3-year, or 5-year survival were included in the study., Results: The initial search resulted in 49 studies. Only 12 studies met inclusion criteria. Three studies reported survival data for FISH, 1 study reported survival data for CGH, 1 study reported survival data for MSA, 3 studies reported survival data for MLPA, 3 studies reported survival data for SNP, 3 studies reported survival data for GEP, and 2 studies reported survival data for a combination of tests. No studies reported survival data for exon sequencing. Six studies reported percent free of metastatic death, 2 studies reported metastasis-free survival (MFS), 2 studies reported overall survival (OS), and 2 studies reported probability of metastasis. Metastasis-free survival (5 years) for monosomy 3 by FISH was 40% to 60%, by MLPA was 30% to 40%, by SNP was 72%, and for GEP class 2 was not reported. Overall survival (5 years) for monosomy 3 and disomy 8 tumors by MLPA and GEP class 2 were not comparable (81% and 55%, respectively)., Conclusions: Variability exists in reported survival for uveal melanoma with a bad prognosis. Several factors, including composition of study population (tumor size, exclusion of iris melanoma, duration of median follow-up), method of obtaining tumor sample, type of prognostic test, and use of variable outcome measures, can explain some of the observed differences in survival. Variations in determining the cause of death (metastatic or nonmetastatic) may be the major reason for the observed differences. Standardization of study methods and outcome measures will allow comparison of survival data derived from different prognostic tests., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To report the case of a melanocytoma of the optic disc leading to severe vision loss, raising concern for possible malignant transformation and optic nerve infiltration., Methods: Case report., Results: A 36-year-old Arabic woman presented to an outside facility with severe vision loss and a clinical picture concerning for optic neuritis with central retinal vein occlusion. On referral to the authors' institution 1 month after initial presentation, the vision of the patient was no light perception in the affected eye, and examination revealed the presence of a pigmented lesion adjacent to the nerve. Although standard 3-T magnetic resonance imaging orbits suggested 15 mm of optic nerve involvement, ultrahigh resolution 7-T magnetic resonance imaging was able to detect only 2 mm of optic nerve involvement., Conclusion: Melanocytoma of the optic disc is most often benign and causes few visual symptoms. However, in rare cases it can lead to severe vision loss and raise concern for malignant transformation. A 7-T magnetic resonance imaging provides higher resolution optic nerve images.

Purpose: To build multivariate models to assess correctly and efficiently the contribution of tumor characteristics on the rate of regression of choroidal melanomas after brachytherapy in a way that adjusts for confounding and takes into account variation in tumor regression patterns., Design: Modeling of longitudinal observational data., Participants: Ultrasound images from 330 of 388 consecutive choroidal melanomas (87%) irradiated from 2000 through 2008 at the Helsinki University Hospital, Helsinki, Finland, a national referral center., Methods: Images were obtained with a 10-MHz B-scan during 3 years of follow-up. Change in tumor thickness and cross-sectional area were modeled using a polynomial growth-curve function in a nested mixed linear regression model considering regression pattern and tumor levels. Initial tumor dimensions, tumor-node-metastasis (TNM) stage, shape, ciliary body involvement, pigmentation, isotope, plaque size, detached muscles, and radiation parameters were considered as covariates., Main Outcome Measures: Covariates that independently predict tumor regression., Results: Initial tumor thickness, largest basal diameter, ciliary body involvement, TNM stage, tumor shape group, break in Bruch's membrane, having muscles detached, and radiation dose to tumor base predicted faster regression, whether considering all tumors or those that regressed in a pattern compatible with exponential decay. Dark brown pigmentation was associated with slower regression. In multivariate modeling, initial tumor thickness remained the predominant and robust predictor of tumor regression (P < 0.0001). In addition, use of ruthenium isotope as opposed to iodine isotope (P = 0.018) independently contributed to faster regression of tumor thickness. For both isotopes considered alone, initial tumor thickness was the sole clinical predictor of regression (P < 0.0001)., Conclusions: Regression of choroidal melanoma after brachytherapy was associated with several clinical tumor and treatment parameters, most of which were shown to reflect initial tumor size. An independent predictor of regression of tumor thickness was the isotope used. These 2 covariates need to be adjusted for when exploring the associations with the rate of regression of histopathologic or genetic features of the tumor. Our model allows such future analyses efficiently without matching., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To report cytopathological observations on the cells retrieved from the 25-G cannula used during prognostic transvitreal fine-needle aspiration biopsy of choroidal melanoma., Methods: Transvitreal fine-needle aspiration biopsy of choroidal melanoma was performed through a 25-G valved cannula. Twenty samples from 20 consecutive patients were obtained. Most tumors were treated with plaque radiation therapy (16/20, 80%) following standard clinical guidelines. Four enucleated globes (4/20, 20%) were subjected to a similar transvitreal biopsy before enucleation., Results: Cytopathological analysis of the cells retrieved from the cannula revealed the absence of any cells in 4 of 20 samples (20%). In the remaining 16 samples, definite melanoma cells and atypical cells (probable melanoma cells) were observed in 2 samples each (total 4, 25%). Histiocytes (4/16, 25%) and lymphocytes (1/16, 6%) were also observed. Thirteen samples (13/16, 81%) contained conjunctival epithelial epithelium. Prognostication could be performed on all fine-needle aspiration biopsy samples (20, 100%)., Conclusion: Use of a 25-G valved cannula offers potential advantages by isolating the needle tract and by allowing retrieval of the contaminating cells without affecting the prognostic yield of the fine-needle aspiration biopsy sample.

Purpose: To compare the rates of tumour recurrence following episcleral brachytherapy for uveal melanoma before and after implementation of intraoperative echographic confirmation of plaque placement., Materials and Methods: All patients with primary single ciliary body or choroidal melanoma treated with iodine-125 or ruthenium-106 plaque brachytherapy between 1 January 2004 and 30 December 2013 were included. Exclusion criteria were patients with previous radiation treatment and patients who received adjuvant transpupillary thermotherapy. Since February 2007, intraoperative echographic confirmation was initiated to ensure that the plaque was centred on the tumour base and/or all tumour margins were covered by the plaque., Results: 252 patients were included in the study. Local tumour control after primary brachytherapy was achieved in 242/252 (96.0%). Of the 10 patients with treatment failure, 8 patients had local recurrence and 2 patients had failure to response. With the incorporation of the intraoperative echographic confirmation for plaque positioning the treatment failure rate decreased from 9.3% (5/54 patients) to 1.5% (3/198 patients). Continuous and categorical univariable predictors of recurrence were analysed for statistical significance. The only statistically significant variable was the intraoperative echographic confirmation (HR: 0.16; p=0.032) for recurrence within the first 24 months., Conclusions: Intraoperative echographic confirmation of plaque placement during episcleral brachytherapy for choroidal melanoma reduces the risk of early local recurrence., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Purpose: To evaluate the patterns, the risk factors, and the management of recurrence following brachytherapy in patients with posterior uveal melanoma, given that an understanding of the recurrence patterns can improve early recognition and management of local treatment failure in such patients., Design: Retrospective cohort study., Methods: Setting: Multispecialty tertiary care center., Participants: A total of 375 eyes treated with episcleral brachytherapy for posterior uveal melanoma from January 2004 to December 2014. Exclusion criteria included inadequate follow-up (<1 year) and previous radiation therapy. Main Outcomes and Measures: Local control rate and time to recurrence were the primary endpoints. Kaplan-Meier estimation and Cox proportional hazards models were conducted to identify risk factors for recurrence., Results: Twenty-one patients (5.6%) experienced recurrence (follow-up range 12-156 months; median 47 months). The median time to recurrence was 18 months (range 4-156 months). Five-year estimated local recurrence rate was 6.6%. The majority (90.5%) of the recurrences occurred within the first 5 years. The predominant site of recurrence was at the tumor margin (12 patients, 57.1%). Univariate analysis identified 3 statistically significant recurrence risk factors: advanced age, largest basal diameter, and the use of adjuvant transpupillary thermotherapy (TTT). Recurrent tumors were managed by repeat brachytherapy, TTT, or enucleation., Conclusions: Local recurrences following brachytherapy are uncommon 5 years after episcleral brachytherapy. Follow-up intervals can be adjusted to reflect time to recurrence. Most of the eyes with recurrent tumor can be salvaged by conservative methods., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To report the outcome after limbal stem cell preservation during proton beam irradiation for diffuse iris melanoma., Methods: This is a single-case report of diffuse iris melanoma that was managed with proton beam radiation (53 Gy), wherein preemptively harvested superior and inferior limbal stem cells before radiation were replaced after irradiation. Regeneration of the palisades of Vogt and the limbal stem cells was documented by an optical coherence tomography-based imaging protocol., Results: At 24 months after radiation therapy, best-corrected visual acuity was 20/25. The cornea was clear without evidence of limbal stem cell dysfunction. Clinical examination (including gonioscopy and ultrasound biomicroscopy [UBM]) was indicative of local control, and systemic surveillance was negative for metastatic disease. At posttransplant (21 months), there were more palisade structures visible in both anterior and posterior regions of the superior and inferior limbus, and the linear presentation of the inferior palisades appears to have regenerated., Conclusions: Diffuse iris melanoma can be managed successfully with proton beam radiation while preserving corneal limbal stem cells by harvesting them before radiation and then replacing them after irradiation. Regeneration of the palisades of Vogt could be documented by an optical coherence tomography-based imaging protocol.

Natural killer (NK) cells are implicated in the control of metastasis in uveal melanoma, a process that has been ascribed to its cancer stem cell subpopulation. NK cell activation is regulated by specific microRNA (miR). The NK cell sensitivity and regulatory miR production of uveal melanoma cancer stem cells was examined. Cancer stem cells enriched from aggressively metastatic MUM2B uveal melanoma cells by selecting CD271 + cells or propagating as non-adherent spheres in stem-cell supportive were more resistant to NK cell cytolysis than cancer stem cells enriched from less aggressively metastatic OCM1 uveal melanoma cells. Both MUM2B and OCM1 cells expressed and secreted NK cell regulatory miRs, including miR 146a, 181a, 20a, and 223. MUM2B cells expressed and secreted miR-155; OCM1 cells did not. Transfecting MUM2B cells with anti-miR-155 increased NK cell sensitivity. CD271 + cells were identified in the blood of patients with metastatic uveal melanoma and were characterized by low expression of melanocyte differentiation determinants and by the ability to form non-adherent spheres in stem-cell supportive media. These cells also expressed NK cell regulatory miRs, including miR-155. These results indicate that uveal melanoma cancer stem cells can vary in their sensitivity to NK cell lysis and their expression of NK cell regulatory miRs. Circulating CD271 + cells from patients with metastatic uveal melanoma manifest cancer stem cell features and express miRs associated with NK cell suppression, including miR-155, that may contribute to metastatic progression.

Background: Epigenetic events mediated by methylation and histone modifications have been associated with the development of metastasis in patients with uveal melanoma. The role of epigenetic events mediated by microRNA (miR) is less clear. Tumor and plasma miR expression was examined in patients with primary uveal melanoma with tumor monosomy-3, a predictor of metastasis., Results: miR profiling of tumors by microarray found six miRs over-expressed and 19 under-expressed in 33 tumors with monosomy-3 compared to 22 without. None of the miRs differentially expressed in tumors with and without monosomy-3 was differentially expressed in tumors with and without tumor infiltrating lymphocytes. Tumors manifesting monosomy-3 were also characterized by higher levels of TARBP2 and DDX17 and by lower levels of XPO5 and HIWI, miR biogenesis factors. miR profiling of plasma by a quantitative nuclease protection assay found elevated levels of 11 miRs and reduction in four in patients with tumor monosomy-3. Only three miRs differentially expressed in the tumor arrays were detectable in plasma. miRs implicated in uveal melanoma development were not differentially expressed. Elevated plasma levels in patients with tumor monosomy-3 of miR-92b, identified in the tumor array, and of miR-199-5p and miR-223, identified in the plasma array, were confirmed by quantitative real-time polymerase chain reaction. Levels were also higher in patients compared to normal controls., Conclusions: These results support a role for epigenetic mechanisms in the development of metastasis in patients with uveal melanoma and the analysis of miRs as biomarkers of metastatic risk. They also suggest that potentially useful blood miRs may be derived from the host response as well as the tumor.

Importance: Vision loss following episcleral brachytherapy for uveal melanoma is difficult to predict for individual patients., Objective: To generate a risk calculator for vision loss following episcleral brachytherapy for uveal melanoma., Design, Setting, and Participants: A retrospective review of data was conducted at a multispecialty tertiary care center in Cleveland, Ohio. All patients with primary ciliary body or choroidal melanoma treated with iodine 125 or ruthenium 106 episcleral brachytherapy between January 1, 2004, and December 30, 2013, were included. Univariate and multivariable Cox proportional hazards were used to determine the influence of baseline patient factors on vision loss. Kaplan-Meier curves (log-rank analyses) were used to estimate freedom from vision loss. Bootstrap resampling was performed to bias correct this estimate., Main Outcomes and Measures: Vision loss (to visual acuity [VA] worse than 20/50 and worse than 20/200)., Results: A total of 311 patients were included in the study, with a mean (SD) age of 62 (14.7) years at start of treatment and a median follow-up of 36 months (interquartile range, 18-60 months). At presentation, VA was better than or equal to 20/50 in 199 patients (64%) and better than or equal to 20/200 in 289 patients (93%). By Kaplan-Meier analysis, VA less than 20/200 at 3 years was not associated with sex, diabetes, systemic hypertension, or hypercholesterolemia but was associated with history of ocular comorbidities, type of isotope (ruthenium 106 or iodine 125), and initial VA ( >20/50 or <20/50). By multivariable analysis, age (hazard ratio [HR], 0.97; 95% CI, 0.94-1.00; P = .06), largest basal diameter (HR, 1.25; 95% CI, 1.16-1.34; P = <.001), total radiation dose to the fovea (HR, 1.03; 95% CI, 1.01-1.04; P = .001) and optic disc (HR, 1.01; 95% CI, 1.00-1.01; P = .005), and initial VA worse than 20/50 (HR, 1.85; 95% CI, 1.20-2.85; P = .005) were predictive of vision loss to a VA of less than 20/200. The concordance index for the full data set was 0.77. Using these data, an online risk calculator was developed to predict vision loss following episcleral brachytherapy., Conclusions and Relevance: The vision prognostication tool presented herein needs to be validated by independent data sets. This tool may improve counseling for patients being evaluated for episcleral brachytherapy. At-risk individuals identified by this tool could be considered for inclusion into trials exploring prevention or treatment of radiation retinopathy and alternative therapies of uveal melanoma.

Background: Choroidal and ciliary body melanomas divide into two approximately equal groups. Local therapy cures one group while the other metastasizes and proves lethal. Monosomy 3 strongly associates with aggressive behavior. We analyzed a series of choroidal and ciliary body melanomas to describe the cellular features and to compare them to monosomy 3 status using the latter as a surrogate for survival., Methods: One hundred eleven specimens met the study's inclusion criteria. Following ThinPrep processing, samples were analyzed for cellular features including: cell type, nuclear grade, tumor infiltrating lymphocytes, and the presence of necrosis and melanin. FISH analysis for monosomy 3 was performed on ThinPrep slides using a threshold of 20% monosomic cells per 200 melanoma cells., Results: Seventy-two tumors (65%) had a mixed cell type while spindle cell type and epithelioid cell type occurred in 37 (33%) and 2 (1.8%), respectively. Seventy-five tumors (68%) had Grade 2 nuclear atypia. Monosomy 3 occurred in 57 tumors (51%). Significantly more tumors with Grade 3 nuclei had monosomy 3 (79% vs.43%, P = 0.002) and metastases (29% vs. 8%, P = 0.01). None of the 11 pure spindle cell tumors with Grade 1 nuclei metastasized or had monosomy 3., Conclusions: Uveal melanoma has a relatively consistent cellular appearance, characterized by a mixed cell pattern and no more than moderate nuclear atypia. This consistent appearance aids in the cellular diagnosis but limits prognostication using cellular features. Cellular features significantly associate with monosomy 3 status only in the minority of tumors at the extremes of the morphologic spectrum., (© 2016 Wiley Periodicals, Inc.)

Purpose: To report outcomes and complications of fine-needle aspiration biopsy (FNAB) of uveal melanoma performed for diagnostic and prognostic purposes., Methods: Prospective interventional case series of 150 consecutive patients with a clinical diagnosis of uveal melanoma. The FNAB approach (transcorneal (TCO), transscleral (TSC) and transvitreal (TVT) was primarily determined by the location of the tumour. The FNAB was performed using a 25-gauge needle using a previously published technique. Prognostication was done using fluorescent in situ hybridisation detection of monosomy of chromosome 3., Results: FNAB was obtained via TCO (8), TSC (71) and TVT (64) approach and impression smear in seven cases. Diagnostic yield was 92%. False-negative results were observed in 8%. Diagnostic yield was significantly correlated to biopsy approach (TCO 100%, TSC 96%, TSV 86%; p=0.029) and tumour size (basal diameter >5.0 mm; height >2.5 mm). Persistent haemorrhage (subretinal haemorrhage or vitreous) requiring surgical intervention (1%) and rhegmatogenous retinal detachment (1%) were rare. Endophthalmitis, hypotony, tumour recurrence, episcleral seeding were not observed over the average follow-up of 37 months. Prognostication could be performed in 85% of cases. Overall, only 47% of eligible patients enrolled into the adjuvant therapy trial., Conclusions: FNAB for uveal melanoma with 25-gauge needle is a safe procedure that can yield diagnostic and prognostic information in vast majority of cases (92% and 85%, respectively). Even so, only about half of the eligible cases eventually enrolled into the adjuvant therapy trial. Possibility of negative FNAB yield should be considered when counselling patients with small tumours. Alternative means of diagnostic biopsy and methods of prognostication need to be assessed for small tumours., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Purpose: To describe and analyze cases of circumscribed choroidal melanoma initially treated as circumscribed choroidal hemangioma., Methods: A retrospective case series including five eyes of five patients with choroidal melanoma that were originally diagnosed and treated as choroidal hemangioma., Results: Four men and 1 woman (26-61 years) were included. All patients were white and presented with nonspecific symptoms (visual field defect, decreased visual acuity, and metamorphopsia) and visual acuity ranging from 20/30 to 20/80. Four of the five tumors were yellow and/or orange and one was partially melanotic. All tumors were dome shaped (one bilobed) and had associated subretinal fluid overlying the lesion. Two tumors had high internal reflectivity on standardized A-scan ultrasonography, whereas others had low internal reflectivity. Three tumors were hypofluorescent on early phases of indocyanine green and intrinsic vasculature was also observed in two of these three. Four of five patients who were initially treated by photodynamic therapy did not respond to treatment. However, they did respond to radiation therapy (after revised diagnosis), with documented regression and no evidence of detectable metastasis (mean follow-up 24.2 months)., Conclusion: Differentiating between amelanotic melanoma and choroidal hemangioma can be challenging. Relying solely on ophthalmoscopic features can be misleading. Ancillary studies such as indocyanine green and standardized A-scan ultrasonography bring clarity in differentiating circumscribed choroidal hemangioma from choroidal melanoma. Although cytology or histopathology is the only definitive method of establishing the diagnosis, careful emphasis on key diagnostic features can obviate the need for diagnostic fine-needle aspiration biopsy in most cases.

Importance: There is a lack of information regarding the role of systemic surveillance in patients with primary uveal melanoma., Objective: To evaluate the utility of serial hepatic ultrasonography (USG) for detection of asymptomatic liver metastases in patients undergoing surveillance after primary treatment of uveal melanoma., Design, Setting, and Participants: Retrospective cohort study reviewing data from patients with primary uveal melanoma treated between October 2003 and October 2012 at a multispecialty tertiary care center. Patients were managed using a standardized protocol. Initial staging was done with contrast-enhanced computed tomography of the chest, abdomen, and pelvis. This was followed by periodic surveillance with hepatic USG and liver function tests scheduled every 6 months for the first 5 years and annually thereafter. Abnormal surveillance hepatic USG findings were categorized as (1) cyst or hemangioma, (2) indeterminate lesion, (3) suspicious for metastasis, or (4) consistent with metastasis. If indicated, hepatic USG abnormalities were confirmed by additional imaging modalities (confirmatory scans) such as computed tomography or magnetic resonance imaging. Liver biopsy was performed only if the confirmatory scan was positive., Main Outcomes and Measures: Sensitivity, specificity, and positive predictive value of hepatic USG for detecting asymptomatic liver metastases., Results: In 263 patients (121 men, 142 women; mean [SD] age at diagnosis, 61.1 [13.9] years), a total of 1390 hepatic USGs were performed, with a mean of 5.3 per patient (range, 1-17 per patient). Overall, 86 hepatic USGs of 71 patients (27%) were reported as abnormal. Of the 13 lesions identified as a cyst/hemangioma and 17 as indeterminate, 1 was found to be metastatic in each group (8% and 6%, respectively). Of 36 patients with findings suspicious for metastasis, 23 (64%) had metastasis confirmed. All 5 patients (100%) with findings consistent with metastasis had biopsy-proven metastasis. The sensitivity, specificity, and positive predictive value of hepatic USG for findings that were indeterminate or suspicious for metastasis were 96% (95% CI, 80%-99%), 88% (95% CI, 83%-91%), and 45% (95% CI, 33%-59%), respectively. Specificity of the confirmatory scan was greater than that of hepatic USG (93% [95% CI, 89%-96%] vs 88% [95% CI, 83%-91%], respectively; P < .001). Only 4 of 30 patients (13%) with metastasis had abnormal findings on simultaneous liver function tests., Conclusions and Relevance: A stepwise surveillance protocol based on serial hepatic USGs followed by confirmatory scans offers high likelihood of detecting asymptomatic metastases in patients with primary uveal melanoma.

Importance: To our knowledge, longitudinal assessment of depression, anxiety, and decision regret (a sense of disappointment or dissatisfaction in the decision) in patients undergoing prognostication for uveal melanoma does not exist., Objective: To report on depression, anxiety, and decision regret before and after testing to estimate uveal melanoma prognosis., Design, Setting, and Participants: Prospective interventional case series conducted at an institutional referral practice of 96 patients with clinical diagnosis of uveal melanoma who underwent prognostication at the time of primary therapy., Main Outcomes and Measures: Depression, anxiety, and decision regret prior to prognostication (baseline) and at 3 and 12 months afterwards. The Hospital Anxiety and Depression Scale (HADS) and Decision Regret Scale were self-administered by the patients prior to prognostication (baseline) and at 3 and 12 months afterwards. Data were summarized using means and standard deviations for continuous measures, frequencies, and percentages for categorical factors. A mixed model was used to assess the trajectory of HADS anxiety and the associations between HADS anxiety and baseline HADS depression, baseline decision regret, prognostication test result, and adjuvant therapy, respectively, while adjusting for age and sex., Results: Ninety-six patients (median age 60.7 years) completed baseline questionnaires. The mean (SD) HADS anxiety score at baseline (7.4 [4.0]) was higher than at 3 months (5.4 [3.7]; P < .001) or 12 months (4.7 [3.4]; P < .001), and decreased with older age (coefficient estimate [SD], -0.06 [0.02]; P < .001). The decision regret score was associated with baseline HADS depression score (coefficient estimate [SE], -1.17 [0.43]; P < .007), and HADS depression score increased with baseline HADS anxiety score (coefficient estimate [SE], 0.39 [0.06]; P < .001)., Conclusions and Relevance: Our study raises questions about decision regret in patients who agree to have a prognostic test that may not help guide treatment. Although decision regret appears to lessen or dissipate with time, study on larger numbers of patients is necessary to elucidate factors that may be addressed to mitigate decision regret.

A 3-month-old infant with a white mother and Asian father presented with discoloration and prominence of the left eye since birth. Examination revealed a normal right eye. The left eye had hyperchromic heterochromia and an enlarged cornea (diameter, 13.0 mm) with intraocular pressure of 26 mm Hg. There were multiple areas of subconjunctival nodular pigmentation that extended posteriorly into the superior fornix. Fundus examination showed a large ciliochoroidal pigmented mass extending from 10:30 to 3:00 o'clock position involving the superior half of the choroid and adjacent ciliary body. The eye was enucleated, confirming the diagnosis of diffuse uveal melanoma with extraocular extension. Systemic surveillance (hepatic panel and ultrasonography of the liver) performed every 6 months for 5 years was has been negative for metastases. The tumor was investigated intensively for the panel of genes (BAP1, BRAF, NRAS12, NRAS61, GNAQ, Kit 9,11,13,17,18) implicated in pathogenesis of blue nevus, cutaneous melanoma, and mucosal melanomas with negative results. Moreover, germline BAP1 mutation could not be identified. This case possibly represents as yet unidentified uveal melanocytic proliferation rather than a true variant of uveal melanoma., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Antigens that may be involved in the immune response to uveal melanoma have not been identified. Cellular and humoral responses to melanoma differentiation antigens, as well as to BRCA1-associated protein 1 (BAP1) and α-enolase, alterations of which are associated with metastatic disease, were examined in patients with uveal melanoma. Blood was collected from 66 patients with primary and 13 patients with metastatic uveal melanoma. These included 11 patients treated with immunotherapy. Peripheral blood mononuclear cells were stimulated with gp100, MART-1, tyrosinase, NY-ESO-1, BAP1, and α-enolase peptides and/or proteins, and cytokine production was assessed by bead array or enzyme-linked immunosorbent assay. Autoantibodies to the protein were assessed by enzyme-linked immunosorbent assay. A cellular or humoral response to one or more of the antigens was observed in 23% of the primary and 62% of the metastatic patients tested. Th1 and Th2 cellular and humoral responses to gp100, MART-1, and tyrosinase were observed in primary and metastatic patients. Cellular responses to NY-ESO-1 were not observed nor were Th17-associated responses. Cellular and humoral responses to BAP1 and α-enolase were also observed, predominantly in primary patients with tumor monosomy-3 and in metastatic patients. Individual patients treated with immunotherapy developed new reactivity to MART-1, tyrosinase, and/or α-enolase. Patients with primary and metastatic uveal melanomas manifest spontaneous immune responses to melanoma differentiation antigens, BAP1, and α-enolase. Both Th1-associated and Th2-associated responses are observed and can be modified by therapy. These results may help the development and monitoring of immunotherapy and studies of immune surveillance in uveal melanoma.

Purpose: The purpose of this study is to study the genomic evolution of primary uveal melanoma., Methods: Primary uveal melanoma genomic DNA was assayed on the Illumina Human660W-Quad v1.0 DNA Analysis BeadChip. Raw signal intensity data were quantile normalized to estimate copy number aberration with the Genome Alteration Print algorithm. Distance between samples was calculated as the Manhattan distance between the copy number profiles of the tumors. From the distance matrix, a phylogenetic network (evolutionary relationship inference) was estimated using SplitsTree4., Results: Of the 57 tumors, one (1.8%) was discarded because of a failed assay, and seven (12.3%) were revealed to be mixtures of several cell populations that could not be resolved. Three clades of tumor were identified (A [59.2%], B [32.7%], and C [6.1%]), each following a distinct evolutionary path and each associated with metastatic status (P = 0.01). One tumor (2.0%) did not fit into any clade. From a normal diploid melanocyte, a few tumors (clade C) lose a large portion of chromosome 6q, but do not develop any mutations on 8q. In an alternate path, the vast majority of tumors (clade A and clade B [91.9%]) gain a copy of the telomeric half of 8q. A majority of these tumors (clade A) subsequently lose a copy of chromosome 3, as well as gain the centromeric half of 8q. The other tumors (clade B) gain copies of 6p, as well as regions on 11p and 22q., Conclusions: Our data suggest that there is little overlap in the subtypes of uveal melanoma after divergence (identified as clades A and B) and that these distinct subtypes are not likely to crossover or transform from one major clade to another.

Background: Uveal melanoma is the most common malignancy of the adult eye. The overall mortality rate is high because this aggressive cancer often metastasizes before ophthalmic diagnosis. Quantitative proteomic analysis of primary metastasizing and non-metastasizing tumors was pursued for insights into mechanisms and biomarkers of uveal melanoma metastasis., Methods: Eight metastatic and 7 non-metastatic human primary uveal melanoma tumors were analyzed by LC MS/MS iTRAQ technology with Bruch's membrane/choroid complex from normal postmortem eyes as control tissue. Tryptic peptides from tumor and control proteins were labeled with iTRAQ tags, fractionated by cation exchange chromatography, and analyzed by LC MS/MS. Protein identification utilized the Mascot search engine and the human Uni-Prot/Swiss-Protein database with false discovery ≤ 1%; protein quantitation utilized the Mascot weighted average method. Proteins designated differentially expressed exhibited quantitative differences (p ≤ 0.05, t-test) in a training set of five metastatic and five non-metastatic tumors. Logistic regression models developed from the training set were used to classify the metastatic status of five independent tumors., Results: Of 1644 proteins identified and quantified in 5 metastatic and 5 non-metastatic tumors, 12 proteins were found uniquely in ≥ 3 metastatic tumors, 28 were found significantly elevated and 30 significantly decreased only in metastatic tumors, and 31 were designated differentially expressed between metastatic and non-metastatic tumors. Logistic regression modeling of differentially expressed collagen alpha-3(VI) and heat shock protein beta-1 allowed correct prediction of metastasis status for each of five independent tumor specimens., Conclusions: The present data provide new clues to molecular differences in metastatic and non-metastatic uveal melanoma tumors. While sample size is limited and validation required, the results support collagen alpha-3(VI) and heat shock protein beta-1 as candidate biomarkers of uveal melanoma metastasis and establish a quantitative proteomic database for uveal melanoma primary tumors.

Purpose: To report the cytologic characteristics of uveal melanoma., Design: This is a prospective, single-center study of consecutive patients., Subjects: All patients with a clinical diagnosis of uveal melanoma from May 2009 to July 2013 who underwent prognostication fine-needle aspiration biopsy (FNAB) were included., Methods: The cytologic characteristics of uveal melanoma were analyzed for 150 consecutive patients with a clinical diagnosis of uveal melanoma who were treated at the Cleveland Clinic Cole Eye Institute between May 2009 and August 2012., Main Outcome Measures: Cellular features of all cases were analyzed for cell type, presence of melanin, nuclear grade, tumor-infiltrating lymphocytes, and necrosis. Cytology was then correlated with histopathology in enucleated eyes., Results: A total of 150 patients were included. Seven samples of tumor resections were excluded from the study because they were studied by impression smears. A total of 143 FNAB samples of 143 patients formed the basis for analysis. Fifty-three percent of the patients were male, and the average age for all patients was 60 years. Transcorneal (n = 8), transscleral (n = 71), and transvitreal (n = 64) approaches were used. Of 143 samples, 131 were adequate. Among these, spindle cells were observed in 98% (63% mixed and 35% spindle only), whereas only epithelioid cells were observed in 2 samples. Melanin granules were observed in 80% of samples. Tumor nuclear grade (atypia) increased with tumor height and by tumor location (least atypia with iris tumors)., Conclusions: Cytologic features such as spindle cells and melanin granules, present in 98% and 80% of samples, respectively, are important cytologic diagnostic features. Tumor nuclear grade (atypia) increased with tumor height. Iris melanoma has bland features compared with ciliary and choroidal melanoma., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: To evaluate the prevalence of BAP1 germline mutations in a series of young patients with uveal melanoma (UM), diagnosed before age 30., Materials and Methods: The study was carried out on 14 young uveal melanoma patients (average age 21.4 years, range 3 months to 29 years). Germline DNA was extracted from peripheral blood. BAP1 sequencing was carried out using direct sequencing of all exons and adjacent intronic sequences. We also tested for germline mutations in additional melanoma-associated candidate genes CDKN2A and CDK4 (exon 4)., Results: We identified one patient with a pathogenic mutation (c. 1717delC, p.L573fs*3) in BAP1. This patient was diagnosed with UM at age 18 years and had a family history of a father with UM and a paternal grandfather with cancer of unknown origin. One additional patient had an intronic variant of uncertain significance (c.123-48T > G) in BAP1 while the remaining 12 patients had no alteration. None of the patients had CDKN2A or CDK4 (Exon 4) mutations. Family history was positive for a number of additional malignancies in this series, in particular for cutaneous melanoma, prostate, breast and colon cancers. There were no families with a history of mesothelioma or renal cell carcinoma., Conclusions: This study suggests that a small subset of patients with early onset UM has germline mutation in BAP1. While young patients with UM should be screened for germline BAP1 mutations, our results suggest that there is a need to identify other candidate genes which are responsible for UM in young patients.

Purpose: The aim of this study was to describe a case of iris melanoma diagnosed by fine-needle aspiration biopsy (FNAB) with review of the literature., Design: This study presents a case report and review of the literature., Methods: A 76-year-old white man presented with iris melanoma arising from preexisting iris nevus that was confirmed cytologically by a transcorneal FNAB., Results: A pigmented lesion on the left iris extending from 3 to 8:30 o'clock, from the iris root to the pupillary margin without ectropion uveae, was biopsied through 1-mm clear corneal incision. A short 25-gauge needle was inserted into the tumor while applying aspiration, and 10-0 suture was used to close the wound. Cytopathology confirmed the presence of spindle-shaped cells with conspicuous cytoplasmic melanin and nuclear atypia consistent with the diagnosis of melanoma. There were no intraoperative or postoperative complications. The patient was subsequently treated with radiation plaque brachytherapy., Conclusions: Although indicated only in minority of cases, it is important to consider FNAB for the diagnosis and management of iris lesions.

A sarcoid-like reaction is the presence of noncaseating granulomas due to a T-cell mediated inflammatory reaction in draining lymph nodes of tumors or in the vicinity of tumors. Breast cancer, lymphoma, and cutaneous melanoma have been observed to induce a sarcoid-like reaction. Herein, a patient is reported with conjunctival melanoma in whom multiple noncaseating granulomas were observed in the sentinel lymph node without evidence of micrometastasis. Fungal and mycobacterium stainings were negative and further systemic workup excluded sarcoidosis. This case identifies conjunctival melanoma as a cause of a sarcoid-like reaction.

A 56-year-old woman with neurofibromatosis type 1 (NF1) presented with a left upper eyelid amelanotic nodule with adjacent eyelid margin hyperpigmentation. Physical examination additionally revealed primary acquired melanosis (PAM) on the palpebral conjunctiva of the same eyelid. Full thickness eyelid excision and conjunctival map biopsy identified desmoplastic melanoma of the eyelid in addition to invasive conjunctival melanoma and conjunctival melanoma in situ. Sentinel lymph node biopsy was negative for metastasis. She was treated with surgical excision for the eyelid melanoma and topical mitomycin C for the conjunctival melanoma. We discuss the rare entity of desmoplastic melanoma of the eyelid and its possible association with NF1., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A 22-year-old African American female with neurofibromatosis type 1 and multifocal conjunctival melanoma with scleral invasion. The lesion was detected during pregnancy, and after early induction of childbirth, staging by sentinel lymph node biopsy and imaging studies were performed. Systemic evaluation was negative, and the patient was treated with excisional biopsy and cryotherapy. The recurrent multifocal melanoma with scleral extension was treated with brachytherapy by a 2-stage procedure. Follow-up at 2 years reveals the absence of recurrence and 20/25 visual acuity.

Purpose: To compare the accuracy of indocyanine green (ICG)-guided sentinel lymph node biopsy to sentinel lymph node biopsy performed with technetium-99m in eyelid and in conjunctival malignancies., Methods: Review of a consecutive series of adult patients undergoing sentinel lymph node biopsy for eyelid and conjunctival malignancies between 2009 and 2013. Only patients undergoing both ICG-guided and technetium-99m-guided sentinel lymph node biopsies were included., Results: Five patients were identified: 3 women and 2 men. Four had conjunctival melanoma and 1 had eyelid melanoma. ICG aided in localization and confirmation of the sentinel nodes identified by technetium-99m, and all sentinel lymph nodes identified by technetium-99m were identified by ICG. All patients who underwent both sentinel lymph node modalities had negative lymph node biopsies for micrometastasis, but metastatic disease eventually developed in 1 patient. No safety concerns were identified with the use of ICG in the ocular adnexal region., Conclusions: For certain periocular malignancies, ICG-guided sentinel lymph node biopsy safely identifies sentinel lymph nodes intraoperatively possibly to a similar extent compared with technetium-99m-guided methods.

Background: The immune response has been implicated in the control of uveal melanoma progression. Epigenetic mechanisms mediated by specific microRNAs (miRs) regulate immune responses., Methods: Blood was drawn from six patients with uveal melanoma followed from diagnosis, at which time there was no clinical or radiographic evidence of metastasis, until metastasis manifested. Circulating T cell, natural killer (NK), natural killer T (NKT), and myeloid suppressor cell populations were assessed by flow cytometry. CD3(+), CD15(+), and CD56(+) cells were isolated using immunomagnetic beads. Plasma and cellular levels of immune regulatory miRs were determined by quantitative polymerase chain reaction assays., Results: The development of metastasis was associated with decreases in circulating CD3(-)CD56(dim) NK cells and CD8(+) and double-negative CD3(+)CD56(+) NKT cells. ICOS(+)CD4(+)FoxP3(+) T regulatory cells and CD11b(+)CD14(-)CD15(+) myeloid suppressor cells increased. Plasma levels of miR-20a, 125b, 146a, 155, 181a, and 223 were higher in the study patients at diagnosis compared to controls. Plasma levels of miR-20a, 125b, 146a, 155, and 223 increased, and miR-181a decreased when metastasis manifested. Alterations in immune regulatory miRs were also observed in CD3(+), CD15(+), and CD56(+) cell populations., Conclusions: The development of metastasis in uveal melanoma is associated with changes in immune effector and regulatory cells consistent with lessening tumor immune surveillance. These changes are associated with changes in plasma and cellular levels of immune regulatory miRs. The results may help guide uveal melanoma immunotherapy and biomarker development., (Copyright © 2013. Published by Elsevier Ltd.)

Uveal melanoma (UM) has a strong propensity to metastasize and the prognosis for metastatic disease is very poor. It has been suggested that occult micrometastases are already present, but undetectable, in many patients at the time when the primary ocular tumor is diagnosed and treated. To identify high-risk patients for close monitoring and early intervention with prophylactic adjuvant systemic therapy, an accurate predictive system is necessary for stratifying those patients at risk of developing metastatic disease. To date, many clinical and histopathological features, molecular pathway characteristics, and genetic fingerprints of UM have been suggested for disease prognostication. Among the newest of them, tumor genetics has received the most attention in demonstrating promise as a prognostic tool. Because of the plethora of recent developments, we summarize and compare in this review the important standard and more advanced cytogenetic prognostic markers. We further describe the variety of genetic tests available for prognostication of UM, and provide a critical assessment of the respective advantages and disadvantages of these tools.

Prognostic blood biomarkers for patients with uveal melanoma have not been identified. Tumor monosomy-3 is strongly associated with the development of metastatic disease. Tumor expression of human leukocyte antigen class I molecules and insulin-like growth factor (IGF)-1 receptor has also been associated with the development of metastatic disease. The relationship of blood levels of the human leukocyte antigen-class-I-associated β-2 microglobulin (β2M), IGF-1, and its binding protein, IGFBP-3, with tumor monosomy-3 was evaluated. Blood was drawn from patients with a clinical diagnosis of primary uveal melanoma without metastatic disease before fine-needle aspiration biopsy at the time of brachytherapy or enucleation. Tumor chromosome 3 status was determined by fluorescence in-situ hybridization. β2M, IGF-1, and IGFBP-3 levels were determined using enzyme-linked immunosorbent assays. A total of 76 patients were studied; 47 (62%) underwent brachytherapy and 29 (38%) underwent enucleation. Thirty-three (43%) of the tumors manifested monosomy-3. Most tumors were large, located in the choroid, mixed cell type, and nuclear grade 2. Most tumors did not manifest extraocular extension. Blood levels of IGF-1 and IGFBP-3 were not associated with tumor monosomy-3. In contrast, increases in blood β2M (P≤0.02) were associated with tumor monosomy-3. The independent association of increased blood level of β2M and tumor monosomy-3 status was confirmed in multivariable analysis. In conclusion, measurement of blood levels of β2M in patients with primary uveal melanoma may have prognostic value and may help guide surveillance and adjuvant therapy recommendations.