No differences in the long-term prognosis of iris and choroidal melanomas when adjusting for tumor thickness and diameter.

OBJECTIVE: To assess the long-term prognosis for patients with iris melanomas and compare it with the prognosis for small choroidal melanomas. DESIGN: Retrospective observational case series. METHODS: All patients treated for iris melanomas at a single referral institution between January 1st 1986 and January 1st 2016 were included. Patients treated for small choroidal melanomas during the same period were included for comparison. The cumulative incidence of melanoma-related mortality was calculated. Patient and tumor characteristics and size-adjusted hazard ratio (HR) for melanoma-related mortality were compared between iris and small choroidal melanomas. RESULTS: Forty-five iris melanomas and 268 small choroidal melanomas were included. Twenty-four iris melanomas (53%) had been treated with local resection, 12 (27%) with Ruthenium-106 brachytherapy, 7 (16%) with enucleation and 2 (4%) with proton beam irradiation. Twenty-one (68%), 7 (16%) and 2 (4%) of the iris melanomas were of the spindle, mixed and epithelioid cell types, respectively. Twenty-three patients had deceased before the end of follow-up. Median follow-up for the 22 survivors was 13.3 years (SD 9.4). Patients with iris melanomas were more often asymptomatic at presentation and had a trend towards significantly lower age (59 versus 63 years, Student's T-tests p = 0.057). Further, iris melanomas had significantly smaller basal diameter (5.8 versus 8.0 mm, p < 0.0001) and tumor volume (79 mm3 versus 93 mm mm3, p < 0.0001) but greater thickness (3.0 versus 2.5 mm, p < 0.0001). The cumulative incidence of iris melanoma-related mortality was 5% at 5 years after diagnosis, and 8% at 10, 15 and 20 years. The incidence was not significantly different to small choroidal melanomas (Wilcoxon p = 0.46). In multivariate Cox regression with tumor diameter and thickness as covariates, patients with choroidal melanomas did not have increased HR for melanoma-related mortality (HR 2.2, 95% CI 0.5-9.6, p = 0.29). Similarly, there were no significant survival differences in matched subgroups (Wilcoxon p = 0.82). CONCLUSIONS: There are no survival differences between iris and choroidal melanomas when adjusting for tumor size. The reason for the relatively favorable prognosis of iris melanomas compared to melanomas of the choroid and ciliary body is likely that they are diagnosed at a smaller size.

Small choroidal melanoma: outcomes following apical height dose brachytherapy.

AIM: To assess the outcomes of small choroidal melanoma following iodine-125 episcleral brachytherapy (apical height dose of 85 Gy). METHODS: Patients with small choroidal melanoma that underwent iodine-125 episcleral brachytherapy between January 2004 and December 2017 were reviewed. Inclusion criterion for this study was the COMS small tumour size (tumour apical height of 1.0-2.5 mm and largest basal diameter (LBD) <16.0 mm). Patients that received any form of prior therapy or adjuvant transpupillary thermotherapy were excluded. Outcome measures were visual acuity (VA), recurrence, ocular survival and metastasis at 3 years. Kaplan-Meier estimation was calculated for VA, recurrence, ocular survival and survival outcome (overall and metastasis-free survival rate) at 3 years. RESULTS: 161 cases of choroidal melanoma were included in this study, with the mean (SD) age of 59.6 (14.1) years, and 93 (58%) were males. The mean (SD) apical height for the tumours were 2.1 (0.4) mm and mean (SD) LBD was 8.3 (2.2) mm. The mean (SD, median) follow-up was 40.7 months (37.1, 25 months). The VA was 20/50 or better in 69%. Only one recurrence event (1%) and one enucleation event (1%) were observed. Overall survival was 97%, and no metastatic events were observed at 3 years. CONCLUSION: Small choroidal melanomas treated with iodine-125 episcleral brachytherapy have excellent outcomes. The majority (69%) of patients retained VA of 20/50 or better with very high local control and ocular survival rate (99.3%) with the absence of metastasis (100%).

Effect of plaque brachytherapy dose and dose rate on risk for disease-related mortality in 1238 patients with choroidal melanoma.

BACKGROUND: Episcleral brachytherapy is the most common treatment for medium-sized choroidal melanomas. Although controversial, inadequate brachytherapy dose and dose rates have at least a hypothetical implication on patient survival. METHODS: All patients who received ruthenium-106 or iodine-125 brachytherapy for choroidal melanoma at St. Erik Eye Hospital 1996 to 2016 were included (n=1238). Cox regression hazard ratios for melanoma-related mortality across deciles, quartiles and individual integers of apex radiation doses (Gy) and dose rates (Gy/hour) were calculated, adjusted for tumour size and location. RESULTS: The average radiation dose at the tumour apex ranged from 73.0 Gy in the first decile to 108.6 Gy in the tenth. Decreasing apex dose by 1 Gy increments or by decile or quartile group was not associated with melanoma-related mortality (p>0.2) The average radiation dose rate at the tumour apex ranged from 0.5 Gy/hour in the first decile to 2.8 Gy/hour in the tenth. Similarly, decreasing apex dose rate by 1 Gy/hour increments or by decile or quartile groups was not associated with melanoma-related mortality (p>0.5). CONCLUSION: There are no increased hazards for choroidal melanoma-related mortality after brachytherapy with decreasing doses between 108.6 and 73.0 Gy, or with decreasing dose rates between 2.8 and 0.5 Gy/hour.

Parsimonious Models for Predicting Mortality from Choroidal Melanoma.

Purpose: To develop parsimonious models for estimating metastasis mortality in patients with choroidal melanoma for situations where use of the Liverpool Uveal Melanoma Prognosticator Online (LUMPO) or Tumor, Node, Metastasis (TNM) staging system is not possible. Methods: A backward-selection algorithm identified largest basal tumor diameter (LBTD) and chromosome 3 status (C3S) as the most informative predictors of metastatic death. We defined two prognostic models, based on LBTD with or without known C3S, that took into account competing risks of death from other causes by using the Aalen estimator. The bootstrap procedure was used to estimate discrimination accuracy, expressed by the C-index. Results: The cohort was comprised of 8348 patients with choroidal melanoma, 4174 of whom had known chromosome 3 status; of the 1553 deaths that occurred among these patients, 956 were attributed to metastasis. For LBTD with or without known C3S, the metastatic-death-specific C-indices at 2, 5, and 10 years were 0.85, 0.85, and 0.84 and 0.79, 0.77, and 0.74, respectively, as compared with 0.81, 0.79, and 0.76 for Kaplan-Meier prognostication using the 8th edition of the TNM staging system. Conclusions: We have developed parsimonious models for predicting the absolute risks of metastatic death from choroidal melanoma that take into account competing causes of death and which compare favorably with the current version of the TNM staging system. There is a need for further studies to validate the use of these models in situations where use of the TNM or LUMPO is not possible.

Uveal melanoma-associated survival in Scotland.

BACKGROUND/OBJECTIVES: The Scottish Ocular Oncology Service (SOOS) manages all patients with uveal melanoma (UM) in Scotland. Our aim was to determine the long-term all-cause and cause-specific survival of patients with UM, irrespective of treatment modality. SUBJECTS/METHODS: A retrospective single-centre cohort study including all patients diagnosed with UM by the SOOS between 1/1/1998 and 31/12/2002. Data from the SOOS database were correlated with death records held by National Records of Scotland, which provided date, and all listed causes, of death for all deceased patients. RESULTS: Two hundred and eighteen patients were newly diagnosed with UM between 1/1/1998 and 31/12/2002. One hundred and fifteen (52.8%) were female. The mean (median) age at diagnosis was 63(65) years (range: 16-89). Of 179 choroidal melanomas, melanoma-specific survival was 92.3%, 87.4% and 83.8% at 5, 10 and 15 years, respectively. Cancer-specific survival was 85.8%, 71.8% and 62.3%. All-cause survival was 81.6% (146/179), 62.0% (111/179) and 46.7% (computed, fraction inexpressible). Of 26 ciliary body melanomas, melanoma-specific survival was 87.2%, 81.3% and 81.3% at 5, 10 and 15 years. Cancer-specific survival was 62.9%, 40.6% and 40.6%. All-cause survival was 61.5% (16/26), 38.5% (10/26) and 26.9% (7/26). Of 13 iris melanomas, at all three timepoints (5/10/15 years), melanoma-specific survival was 100%, cancer-specific survival was 92.3%, and all-cause survival was 76.9% (10/13). CONCLUSIONS: Correlation of SOOS and national records survival data confirms 15-year melanoma-specific survival of 83.8%, 81.3% and 100% for choroidal, ciliary body and iris melanomas, respectively. We can now provide accurate survival data to our patients in Scotland.

The Small Fatal Choroidal Melanoma Study. A Survey by the European Ophthalmic Oncology Group.

PURPOSE: To determine the size at which choroidal melanomas can metastasize and to report the characteristics of small fatal choroidal melanomas (SFCM). DESIGN: Retrospective case series. METHODS: Ten ocular oncology services submitted 45 patients with a choroidal melanoma 3 mm or less in thickness and 9 mm or less in largest basal diameter (LBD), when treated, who developed metastases. RESULTS: Median tumor thickness was 2.4 mm (range, 1.0-3.0 mm) and LBD 7.3 mm (range, 3.0-9.0 mm). Of 14 (31%) tumors that were first observed, 12 grew a median of 0.5 mm (range, 0.1-1.2 mm) in thickness and 1.0 mm (range, 0-3.0 mm) in LBD within a median of 7 months; 3 were initially smaller than 3 mm in LBD. Number of risk factors for growth and metastasis was 0 for 4% of the tumors; 60% were over 2 mm in thickness, 63% had subretinal fluid, 84% caused symptoms, 57% had orange pigment, and 92% were within 3 mm of the disc. Local recurrence occurred in 8 of 31 eyes (26%) treated conservatively. Median metastasis-free survival was 4.5 years (range, 0.8-15.7 years). Kaplan-Meier estimate of metastasis developing was 15% (95% confidence interval [CI], 7-26), 51% (95% CI, 36-64) and 85% (95% CI, 71-92) by 2, 5, and 10 years, respectively. By the time of analysis, 37 patients had died of metastasis after a median of 7 months. CONCLUSIONS: Choroidal melanomas less than 3.0 mm in LBD are highly unlikely to metastasize. Risk factors of an SFCM are similar to those for all choroidal melanomas of similar size.

Clinical Features, Metastasis, and Survival in Patients Younger Than 21 Years With Posterior Uveal Melanoma.

Importance: Given the rarity of posterior uveal melanoma in patients younger than 21 years, reporting clinical experience in this area has relevance. Objective: To describe the baseline clinical features, treatment, and clinical course of a group of patients younger than 21 years who have primary posterior uveal melanoma. Design, Setting, and Participants: This retrospective descriptive case series of patients younger than 21 years who have a primary choroidal or ciliochoroidal melanoma was conducted at a single-center subspecialty referral practice. Patients in the relevant age group who were treated in a single practice between July 1980 and December 2013 were included; clinical data collected through December 2017 were captured to permit adequate follow-up time in all cases. Main Outcomes and Measures: Conventional descriptive statistics of relevant clinical variables (eg, demographic, tumor, treatment, and outcome variables) of each patient were recorded. Actuarial metastasis-free and overall survival curves were computed and plotted, as was a postdetection survival curve of patients who developed metastasis during available follow-up. Results: Of 2265 patients with posterior uveal melanoma encountered by the authors during the study interval, 18 (0.8%) were younger than 21 years when diagnosed and treated. Ten were female and 8 male, and the mean (SD) age was 16.6 (4.2) years. Through available follow-up, 8 of these patients had developed metastatic uveal melanoma (44%). All 8 died of metastasis. Actuarial survival analysis showed that the cumulative probability of metastatic death in this group exceeded 50%. The median overall survival time after treatment of the primary intraocular tumor was 11.9 (95% CI, 7.3-16.5) years. The median survival time after detection of metastasis in the 8 patients who developed metastasis was 2.3 months (95% CI, 0.0-5.2) months. Conclusions and Relevance: Posterior uveal melanoma in patients younger than 21 years appears to have a similar if not worse prognosis than patients with PUM in the population overall. Owing to the later onset of metastasis observed, patients younger than 21 years should continue to have surveillance tests for more than 10 years after treatment.

Prognostication of metastatic death in uveal melanoma patients: A Markov multi-state model.

BACKGROUND/AIMS: Uveal melanoma is fatal in almost 50% of patients. We previously developed a prognostic model to predict all-cause mortality. The aim of this study was to improve our model by predicting metastatic death as a cause-specific event distinct from other causes of death. METHODS: Patients treated in Liverpool were included if they resided in England, Scotland or Wales and if their uveal melanoma involved the choroid. They were flagged at the National Health Service Cancer Registry, which automatically informed us of the date and cause of death of any deceased patients. A semiparametric Markov multi-state model was fitted. Two different baseline hazard rates were assumed, with state transition-specific covariates. For both failure types, age at treatment and sex were used. For the metastatic death case, these factors were added: anterior margin position, largest basal tumour diameter, tumour thickness, extra-ocular extension, presence of epithelioid melanoma cells, presence of closed connective tissue loops, increased mitotic count, chromosome 3 loss, and chromosome 8q gain. Missing data required a multiple-imputation procedure. RESULTS: The cohort comprised 4161 patients, 893 of whom died of metastastic disease with another 772 dying of other causes. The optimism-corrected, bootstrapped C-index for metastatic death prediction was 0.86, denoting very good discriminative performance. Bootstrapped calibration curves at two and five years also showed very good performance. CONCLUSIONS: Our improved model provides reliable, personalised metastatic death prognostication using clinical, histological and genetic information, and it can be used as a decision support tool to individualize patient care in a clinical environment.

Mortality after deferral of treatment or no treatment for choroidal melanoma.

PURPOSE: To report mortality of patients who were eligible for enrollment in the Collaborative Ocular Melanoma Study (COMS) clinical trials of medium-sized choroidal melanoma or large-sized choroidal melanoma but chose to defer treatment or receive no melanoma treatment. DESIGN: Prospective nonrandomized multicenter cohort study as an adjunct to COMS randomized clinical trials. METHODS: Patient follow-up procedures included examinations, correspondence, telephone contacts, and National Death Index searches. Primary outcome was patient death measured by all-cause mortality. Secondary outcomes were melanoma treatment and melanoma metastasis. RESULTS: Of 77 patients eligible for COMS clinical trials who chose to defer or receive no melanoma treatment, 61 were appropriate candidates and 45 (74%) enrolled in the natural history study (NHS). In all, 42 patients (42 eyes) had medium melanoma, and the median follow-up was 5.3 years (range, 4-10.7 years). In all, 22 patients (52%) had subsequent melanoma treatment, and 20 (48%) had no melanoma treatment. For the 42 patients, Kaplan-Meier estimate of 5-year mortality was approximately 30% [95% confidence interval (CI), 18%-47%]. For COMS medium melanoma trial, 5-year mortality was 18% (95% CI, 16%-20%), not statistically significantly different from the NHS patients. After adjusting for differences in age and longest basal diameter, the 5-year risk of death for NHS patients versus COMS trial patients was 1.54 (95% CI, 0.93-2.56). Three patients had large melanoma. Melanoma metastasis was confirmed or suspected in 8 (42%) of 19 deaths. CONCLUSION: Greater mortality and higher risk of death for NHS patients are probative but not conclusive evidence of a beneficial, life-extending effect of medium melanoma treatment.

Ocular treatment of choroidal melanoma in relation to the prevention of metastatic death - A personal view.

About 50% of patients with choroidal melanoma develop metastatic disease, despite successful eradication of the primary tumor. Patient care is complicated by the fact that we do not know whether ocular treatment ever influences survival and if so in whom. Some authorities believe that metastatic spread is never preventable, because it has always occurred by the time the ocular tumor is detected. Others hold the view that metastatic spread can occur late, at least in some patients, in whom timely and successful treatment is life-saving. Some melanomas never seem to metastasize, even if they reach an advanced stage. It is likely that many patients are undergoing futile enucleation or experiencing severe ocular morbidity and visual loss from excessive radiation safety margins in the hope of living longer. Some of these patients would do better with tumor resection, often rejected because of concerns about iatrogenic tumor dissemination. At the same time, many patients with a small melanoma are being left untreated for years until growth is documented, possibly missing opportunities for prolonging life. Metastatic disease is highly likely when genetic tumor analysis detects monosomy 3, chromosome 8q gain, a class 2 gene expression profile, and/or BAP1 loss. Do these lethal genetic aberrations ever develop while the patient is under observation? If so, can these be predicted by genetic analysis? Do lethal mutations and metastasis ever occur because ocular treatment has failed to eradicate the tumor completely? Answers to these questions would profoundly change the management of patients with uveal melanoma.

Patterns of care and outcomes of proton and eye plaque brachytherapy for uveal melanoma: Review of the National Cancer Database.

PURPOSE: To examine national practice patterns and outcomes of eye plaque brachytherapy compared to proton external beam radiotherapy in the treatment of choroid melanoma. METHODS AND MATERIALS: Demographic and clinical data for 1224 patients with choroid melanoma treated with either brachytherapy or proton beam therapy from 2004 to 2013 were obtained from the National Cancer Database. Logistic regression and propensity score matching was used to create a 1:1 matched cohort. Kaplan-Meier and Cox regression analyses were performed to evaluate survival in brachytherapy and proton groups. RESULTS: Median followup was 37 and 29 months for brachytherapy and protons, respectively. Most patients were treated with brachytherapy (n = 996) vs. protons (n = 228). Proton patients came from more urban, affluent, and educated zip codes, and they were more likely to be treated at an academic center (all p < 0.004). In the propensity-score matched cohort, 2-year overall survival was 97% vs. 93%, and 5-year overall survival was 77% vs. 51% for brachytherapy and protons, respectively (p = 0.008). Multivariate Cox regression found older age (hazard ratio [HR] = 1.06, 95% confidence interval (CI) = 1.03-1.09), larger tumor diameter (12-18 mm, HR = 2.48, 95% CI = 1.40-4.42, >18 mm, HR = 6.41, 95% CI = 1.45-28.35), and protons (HR = 1.89, 95% CI = 1.06-3.37) were negative prognosticators of survival. CONCLUSIONS: Patients selected for proton treatment have inferior survival outcomes compared to brachytherapy in this retrospective analysis. There may be unaccounted variables that influence survival, warranting further prospective studies.

Long-term Outcomes After Proton Beam Irradiation in Patients With Large Choroidal Melanomas.

Importance: Although radiotherapy has been used more frequently in past decades for the management of large melanomas, long-term efficacy of proton beam irradiation (PBI) of large choroidal melanomas has not been reported. Objective: To evaluate long-term outcomes in patients who underwent PBI for the treatment of large choroidal melanomas. Design, Setting, and Participants: Data were obtained at a single Boston, Massachusetts, academic tertiary referral practice for this retrospective cohort study. In total, 336 patients with large tumors treated over a 13-year period from January 1, 1985, to December 31, 1997, and followed up until the end points were reached or until December 31, 2008, were included. Data analyses were initially completed in February 2017 and finalized in July 2017. Large tumors were those with a height 10 mm or greater or a longest linear diameter greater than 16 mm or a height greater than 8 mm when the optic nerve was involved. Intervention: Proton beam irradiation (total 70 Gy) delivered in 5 equal fractions. Main Outcomes and Measures: The primary outcomes of rates of visual acuity retention, eye retention, tumor recurrence, and melanoma-related mortality were calculated using Kaplan-Meier estimates, and Cox proportional hazards regression analyses were completed to evaluate risk factors for tumor recurrence and melanoma-related mortality. Results: In this cohort of 336 patients with large tumors, 150 were women and 329 were white; mean (SD) age was 60.0 (14.0) years. Of 178 patients without optic nerve involvement (tumor >1 disc diameter from optic nerve), the mean (SD) largest basal diameter was 18.1 (1.9) mm and mean height was 8.2 (2.7) mm. Optic nerve involvement and tumors greater than 8 mm were observed in 109 patients (32.4% of the cohort). Baseline visual acuity of 20/200 or better was observed in 244 patients (72.6%), and worse than 20/800 in 52 (15.5%). Ten-year rates of visual acuity retention were 8.7% (95% CI, 4.1%-15.6%) for at least 20/200 and 22.4% (95% CI, 15.4%-30.4%) for at least counting fingers. Ten years after PBI therapy, the eye was retained (70.4%; 95% CI, 61.5%-77.6%) and tumor controlled (87.5%; 95% CI, 76.8%-93.5%) in most patients. The 10-year all-cause mortality rate was 60.7% (95% CI, 55.5%-65.9%). Approximately half of the patients died of metastatic uveal melanoma (10-year rate, 48.5%; 95% CI, 43.0%-54.4%). Conclusions and Relevance: This study demonstrates that eye conservation is possible in most cases, with ambulatory vision retained in a small proportion of patients 10 years after PBI. Tumor recurrence rates were low and mortality rates were comparable to those observed after enucleation.

Clinical outcomes of hypofractionated radiation therapy for choroidal metastases: Symptom palliation, tumor control, and survival.

PURPOSE: External beam radiation therapy (RT) is an effective palliative treatment for patients with choroidal metastases and is aimed at preserving vision and obtaining local tumor control. Delivery of 30 to 40 Gy in 2-Gy daily fractions is a standard approach at many centers. This study reports the outcomes of a hypofractionated schedule of 20 Gy in 5 fractions in this palliative setting. METHODS AND MATERIALS: We conducted a retrospective review of patients who were treated with RT (20 Gy in 5 fractions) for choroidal metastases between January 1999 and November 2012. The primary outcome measures were change in visual acuity and tumor response. Secondary outcomes included toxicities of RT, tumor control, and overall survival (OS) from diagnosis of choroidal metastases. Univariate and multivariable Cox regression modeling was used to investigate the predictors for OS. RESULTS: Fifty-five patients with 71 affected eyes were included. Decreased vision was the presenting symptom in 43 eyes (61%). Visual acuity improved from a median of 20/70 at baseline to 20/40 at last follow-up and remained stable or improved in 56 eyes (80%). Tumor regression was observed in 64 eyes (91%) with complete response in 47 eyes (67%). Local progression occurred in 4 eyes (6%). The median survival after diagnosis of choroidal metastases was 13 months. No acute complications were observed in 49 patients (89%). Mild acute toxicities included transitory dryness in 5 patients and episcleritis in 1 patient. Cataracts, retinopathy, optic neuropathy, pigmentary maculopathy, and neovascular glaucoma developed in 4 eyes (6%), 1 eye, 7 eyes (10%), 5 eyes (7%), and 1 eye, respectively. No variables were statistically significantly associated with OS. CONCLUSIONS: A short fractionation schedule of 20 Gy in 5 fractions is a well-tolerated treatment that effectively preserves vision and gains local tumor control for many patients with choroidal metastases. This hypofractionated approach would help reduce the burden of a longer treatment course in this palliative patient population.

Juxtapapillary and circumpapillary choroidal melanoma: globe-sparing treatment outcomes with iodine-125 notched plaque brachytherapy.

PURPOSE: Managing juxtapapillary and circumpapillary choroidal melanoma with brachytherapy is challenging because of technical complications with accurate plaque placement and high radiation toxicity given tumor proximity to the optic nerve. We evaluated our center's experience using ultrasound-guided, Iodine (I)-125 notched plaque brachytherapy for treating choroidal melanoma contiguous with (juxtapapillary) and at least partially surrounding the optic disc (circumpapillary). METHODS: All cases of choroidal melanoma treated with I-125 notched plaque brachytherapy at our center from September 2003-December 2013 were retrospectively reviewed. Only patients with ≥18 months of follow-up who had lesions contiguous with the optic disc (0 mm of separation) were included. The tumor apex prescription dose was 85 Gy. Outcomes evaluated included local control, distant metastasis-free survival (DMFS), cancer-specific survival (CSS), overall survival (OS), visual acuity, and radiation toxicity. RESULTS: Thirty-four patients were included with a median follow-up of 44.1 months (range 18.2-129.0). AJCC T-category was T1 in 58.8%, T2 in 26.5%, and T3 in 14.7%. Median circumferential optic disc involvement was 50% (range 10%-100%). Eye retention was achieved in 94.1%. Actuarial 2- and 4-year rates of local recurrence were 3.1% and 7.6%, DMFS were 97.0% and 88.5%, CSS were 97.0% and 92.8%, and OS were 97.0% and 88.9%, respectively. In addition, 23.5% had visual acuity ≥20/200 at last follow-up. CONCLUSIONS: I-125 notched plaque brachytherapy provides high eye preservation rates with acceptable longer-term post-treatment visual outcomes. Based on our experience, choroidal melanoma directly contiguous with and partially encasing the optic disc may be effectively treated with this technique.

[Size-based classification of choroidal melanoma and its role in treatment decision-making].

AIM: To specify indications for brachytherapy (BT) in large choroidal melanoma (CM) so that tumor size and vital prognosis were considered. MATERIAL AND METHODS: We retrospectively analyzed data from 161 CM patients who were treated with BT and followed-up at either the Ophthalmological Clinical Hospital or some other Moscow medical facility and also registered by the City Cancer Registry. RESULTS: Patient age at the time of starting the treatment lied within the range of 17 to 84 years and averaged 56.89±1.93 years. During the follow-up period (12-275 months, 95.65±8.4 months on average) hematogenous metastases were found in 23 (14.29%) patients. Liver involvement was diagnosed in 8 patients within the average of 23.13 months after treatment. Their average survival time was 11 months. A total of 142 patients were followed up for more than 36 months (104.87 months on average). Of them, 15 patients were diagnosed with metastatic CM within 37-167 months after BT (80.27 months on average). Despite metastatic disease they generally survived 2.8 time longer than the aforementioned patients (30.8 months). The cases were then divided into 3 groups according to J. Shields classification of CM. Small melanoma patients did not develop metastases within 99.96±12.47 months of follow-up. In medium melanomas, as many as 13.35% of cases were metastatic (with the average survival time of 20.66 months); in large melanomas - 19.51% (with the average survival time of 13.5 months). CONCLUSION: Treatment modality and follow-up periods being the same (7-8 years after BT), larger choroidal melanomas has been shown to be associated with higher risk of hematogenous metastases. For local treatment to be successive, the maximal diameter of the tumor should not exceed 10 mm. Every fifth patient of those with CM larger than 15 mm is likely to develop hematogenous metastases. The results obtained indicate the necessity of decreasing the size thresholds for choroidal melanomas, small and medium in the first place.

Choroidal melanoma and pregnancy.

PURPOSE: Choroidal melanoma is a rare tumour in adults. The mean age at diagnosis is 60, but the tumour can affect women of childbearing age. A negative effect of pregnancy on patients' survival has not been formally excluded to date. The aim of the present study is to evaluate the effect of pregnancy on the prognosis of choroidal melanoma. METHODS: We conducted a single-centre retrospective study at the Institut Curie on the population of women of childbearing age who were diagnosed with choroidal melanoma between June 1980 and October 2013. We took a particular interest in the prognosis of those who were pregnant at the time of diagnosis and in the prognosis of those who chose to get pregnant after the treatment. RESULTS: We found 27 pregnant patients at the time of diagnosis and 13 patients who became pregnant after the treatment. There was no difference in the survival between these two groups of patients and the group of other women of childbearing age diagnosed with choroidal melanoma (p = 0.52). There was also no difference in metastasis-free survival (p = 0.91). Most women were able to carry their pregnancies to term (67% had a term pregnancy, and only 7% had an abortion). For women who were pregnant when they were diagnosed with choroidal melanoma, a conservative treatment was chosen in 85% of cases, and proton beam therapy was the most widely used treatment. CONCLUSIONS: Survival in women of childbearing age does not appear to be influenced by pregnancy. We show that proton beam therapy can be used to treat women who are pregnant at the time of choroidal melanoma diagnosis.

The Pediatric Choroidal and Ciliary Body Melanoma Study: A Survey by the European Ophthalmic Oncology Group.

PURPOSE: To collect comprehensive data on choroidal and ciliary body melanoma (CCBM) in children and to validate hypotheses regarding pediatric CCBM: children younger than 18 years, males, and those without ciliary body involvement (CBI) have more favorable survival prognosis than young adults 18 to 24 years of age, females, and those with CBI. DESIGN: Retrospective, multicenter observational study. PARTICIPANTS: Two hundred ninety-nine patients from 24 ocular oncology centers, of whom 114 were children (median age, 15.1 years; range, 2.7-17.9 years) and 185 were young adults. METHODS: Data were entered through a secure website and were reviewed centrally. Survival was analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. MAIN OUTCOME MEASURES: Proportion of females, tumor-node-metastasis (TNM) stage, cell type, and melanoma-related mortality. RESULTS: Cumulative frequency of having CCBM diagnosed increased steadily by 0.8% per year of age between 5 and 10 years of age and, after a 6-year transition period, by 8.8% per year from age 17 years onward. Of children and young adults, 57% and 63% were female, respectively, which exceeded the expected 51% among young adults. Cell type, known for 35% of tumors, and TNM stage (I in 22% and 21%, II in 49% and 52%, III in 30% and 28%, respectively) were comparable for children and young adults. Melanoma-related survival was 97% and 90% at 5 years and 92% and 80% at 10 years for children compared with young adults, respectively (P = 0.013). Males tended to have a more favorable survival than females among children (100% vs. 85% at 10 years; P = 0.058). Increasing TNM stage was associated with poorer survival (stages I, II, and III: 100% vs. 86% vs. 76%, respectively; P = 0.0011). By multivariate analysis, being a young adult (adjusted hazard rate [HR], 2.57), a higher TNM stage (HR, 2.88 and 8.38 for stages II and III, respectively), and female gender (HR, 2.38) independently predicted less favorable survival. Ciliary body involvement and cell type were not associated with survival. CONCLUSIONS: This study confirms that children with CCBM have a more favorable survival than young adults 18 to 25 years of age, adjusting for TNM stage and gender. The association between gender and survival varies between age groups.

Brachytherapy vs. external beam radiotherapy for choroidal melanoma: Survival and patterns-of-care analyses.

PURPOSE: No modern randomized trials exist comparing external beam radiotherapy (EBRT) and plaque brachytherapy (BT) for choroidal melanoma, and the optimal treatment modality is currently unknown. This study compares the patterns of care and efficacy of EBRT vs. BT based on data in the Surveillance, Epidemiology, and End Results database. METHODS AND MATERIALS: The Surveillance, Epidemiology, and End Results database was queried for patients aged 20-79 diagnosed with choroidal melanoma from 2004 to 2011, treated with EBRT or BT; included patients were clinically T1-T4, N0, and M0. Overall survival and cause-specific survival curves were calculated by the Kaplan-Meier method. Univariate and multivariate analyses were performed in the survival and patterns-of-care analyses. RESULTS: A total of 1004 cases (380 EBRT and 624 BT) were included in the survival analysis. There was no difference in the 5-year overall survival (83.3% EBRT vs. 82.5% BT, p = 0.69) and 5-year cause-specific survival (88.3% EBRT vs. 88.3% BT, p = 0.92). In the survival analysis, older age and advanced tumor stage were predictors of increased risk of death. In the patterns-of-care analysis, later year of diagnosis and smaller tumor stage were predictors of BT use. CONCLUSIONS: Advanced tumor stage and older age seem to be independent predictors for risk of death from choroidal melanoma. The use of BT favors smaller tumors and later year of diagnosis. There is no difference in survival between those treated with EBRT or BT, and the utilization of BT is increasing.

Expression and prognostic value of putative cancer stem cell markers CD117 and CD15 in choroidal and ciliary body melanoma.

AIMS: The aim of the present study was to immunohistochemically investigate the expression and prognostic significance of putative cancer stem cell markers CD117 (c-kit), CD34, CD20 and CD15 in a cohort of patients with primary choroidal and ciliary body melanoma. METHODS: The immunohistochemical expression of these markers was evaluated using 3,3'-diaminobenzidine tetrahydrochloride (DAB) and 3-amino-9-ethylcarbazole (AEC) chromogens on paraffin-embedded tissue samples from 40 patients who underwent enucleation in the period from 1985 through 2000. Thirty-one patients had adequate tissue specimens for the analysis. RESULTS: CD117 overexpression was observed in 12 of the 31 samples (39%) when AEC chromogen was used and in 14 of 26 (54%) samples when DAB was used. CD15 positivity was seen in three out of 30 (10%) samples with AEC and in six out of 26 (23%) samples with DAB. CD20 and CD34 exhibited no positivity in the tested samples. During the average follow-up time of 8.7 years (range 0.5-22 years), 17 patients (55%) died due to metastatic disease. The Kaplan-Meier plots showed a significantly shorter overall and disease-free survival in CD117-positive patients when the AEC chromogen was used. CD15 expression was not associated with patients' survival. In multivariate analysis, patients expressing the CD117 AEC had 4.13 times higher risk of lethal outcome in comparison with CD117 AEC negative patients. CONCLUSIONS: Our retrospective cohort study has for the first time demonstrated a small proportion of CD15-positive uveal melanomas. CD117 AEC overexpression was associated with a worse outcome in patients with choroidal and ciliary body melanoma. Further studies should confirm the validity of these observations and their potential for targeted treatment modalities.

Clinicopathologic features and prognostic factors in patients with non-cutaneous malignant melanoma: a single-center retrospective study of 71 cases.

OBJECTIVES: This retrospective study was carried out to define the clinical features and prognostic differences in non-cutaneous malignant melanoma (non-CMM) originating from different anatomic sites. METHODS: Clinical and follow-up data for 71 patients with non-CMM were collected and reviewed. RESULTS: Of the 71 non-CMM patients, 59 were diagnosed with mucosal malignant melanoma (MMM) and 12 with ocular malignant melanoma (OMM). In the 59 MMM patients, the nasal cavity was the most common anatomic site (n = 31, 43.7% of all non-CMM), followed by the oral cavity (n = 9, 12.7%), the genitourinary tract (n = 9, 12.7%), the anorectum (n = 8, 11.3%), and the gastrointestinal tract (n = 2, 2.8%). In the 12 patients with OMM, anatomic sites included the choroid (n = 8, 11.3% of all non-CMM) and the conjunctiva (n = 4, 5.6%). The survival outcome of patients with OMM was much better than that of patients with MMM (P < 0.001). In MMM patients, anorectal melanoma was associated with a worse survival outcome. Age of ≥ 70 years (P < 0.001) and tumor size of > 2 cm (P = 0.02) were significantly poor prognostic factors in MMM. Age (relative risk [RR] 1.068, 95% confidence interval [CI] 1.006-1.133; P = 0.03) and tumor size (RR 1.410, 95% CI 1.038-1.915; P = 0.028) were independent predictors for the postoperative survival of MMM patients. Patients with these two risk factors had a higher risk for recurrence or death (RR 3.107, 95% CI 1.627-5.595). CONCLUSIONS: Our findings demonstrate that prognoses differ in patients with different anatomic sites of primary non-CMM. Advanced age and larger tumor size are the main factors affecting prognosis. Patients with poor risk factors should be treated differently to improve their survival outcome.