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OBJECTIVES To determine survival outcomes following enucleation for uveal melanoma. To compare these outcomes with the 8th edition AJCC classification and determine the influence of cytogenetics, using Fluorescent in situ Hybridisation (FISH), on survival. To determine whether failure to gain sufficient sample for cytogenetics using Fine Needle Aspiration Biopsy (FNAB) correlates with survival. SUBJECTS/METHODS All patients undergoing primary enucleation for uveal melanoma at Moorfields Eye Hospital between 2012 and 2015 were included. Clinical, pathological, cytological and survival data were analysed for all patients. RESULTS In total, 155 subjects were included. Mean age at enucleation was 65.9 years (SD 14.13). 88 (56.8%) patients died at a mean of three (SD 1.9) years following enucleation. Of these, 52 (33.5%) died from metastatic melanoma, 16 (10.3%) from other causes and 20 (12.9%) causes of death were unknown. Cumulative incidence analysis demonstrated AJCC grade, chromosome 8q gain and monosomy three all predict metastatic mortality. The greatest 5-year mortality rate (62%, SD10.1%) was in those with both chromosome abnormalities and AJCC stage III (Stage IV patients excluded due to low numbers). Largest basal diameter and chromosome status, both independently (p = 0.02 and p

Purpose Prognostication in cancer is growing in importance as increasingly accurate tools are developed. Prognostic accuracy intensifies ethical concerns that a poor prognosis could be psychologically harmful to survivors. Uveal melanoma (UM) prognostication allows survivors to be reliably told that life expectancy is either normal (good prognosis) or severely curtailed because of metastatic disease (poor prognosis). Treatment cannot change life expectancy. To identify whether prognosis is associated with psychological harm, we compared harm in UM survivors with good and poor prognoses and those who declined testing and compared these outcomes to general population norms. Methods Non-randomized 5-year study of a consecutive series of 708 UM survivors (51.6% male, mean age 69.03, SD=12.12) with observations at 6, 12, 24, 36, 48 and 60 months. We operationalized psychological harm as anxiety and depression symptoms, worry about cancer recurrence (WREC) and poor quality of life (QoL). Results Compared to other groups, survivors with poor prognoses showed initially elevated anxiety and depression and consistently elevated worry about local or distant recurrence over 5 years. Good prognoses were not associated with outcomes. Generally, no prognostic groups reported anxiety, depression and WREC or QoL scores that exceeded general population norms. Conclusions Using a large sample, we found that harm accruing from a poor prognosis was statistically significant over 5 years, but did not exceed general non-cancer population norms. Implications for Cancer Survivors Survivors desire prognostic information. At a population level, we do not believe that our findings show sufficiently strong links between prognostication outcome and psychological harm to deny patients the option of knowing their prognosis. Nonetheless, it is important that patients are informed of potential adverse psychological consequences of a poor prognosis.

Purpose: To compare the adverse side effects of fractionated stereotactic photon beam radiotherapy (fSRT) with proton beam radiotherapy (PBR) in patients with uveal melanoma (UM). Methods: A retrospective study investigating 306 UM patients treated with fSRT (N=153) by the Rotterdam Ocular Melanoma Study group (ROMS), The Netherlands, between 1999–2014 or with PBR (N=153) at the Royal Liverpool University Hospital and the Clatterbridge Cancer Centre, Bebington, United Kingdom, between 1993–2014. The tumours treated with fSRT were matched with tumours treated with PBR based on sex, left or right eye, TNM classification, posterior margin ≤ or > 3mm of the fovea and of the optic disc. Results: The five-year actuarial rates of tumour recurrence were 4.5% for fSRT and 6.1% for PBR. For fSRT and PBR, the five-year actuarial rates of maculopathy were 14.9% and 12.4%, and for vitreous haemorrhage were 29.4% and 4.7%, respectively. Only vitreous haemorrhage (HR: 0.19, 95% CI: 0.07–0.56) was more common after fSRT compared to PBR. Overall, larger tumours were risk factors for maculopathy and secondary enucleation. Conclusions: Both treatments have excellent local tumour control. In matched groups, vitreous haemorrhage was the only adverse side effect showing a significant difference between groups.

Clinical relevance: The malignant potential of choroidal melanocytic tumours detected incidentally in the community is thought to be low, but this has not been assessed using a validated screening tool. An accurate characterisation of the malignant potential of these lesions has implications for resource allocation, service provision, education, and training.Background: MOLES (Mushroom shape, Orange Pigment, Large size, Enlargement, and Subretinal fluid) categorises tumours as 'common naevus', 'low-risk naevus', 'high-risk naevus', and 'probable melanoma'. The MOLES system recommends that patients with common naevi (score = 0) undergo review by a community optometrist every two years, ideally with sequential colour photography. For the remaining patients (score ≥ 1), specialist imaging and assessment are recommended, with referral triaged as non-urgent for patients with low-risk (score = 1) or high-risk naevi (score = 2) and urgent for patients with probable melanoma (score > 2).Methods: Lesions flagged as choroidal melanocytic tumours on retinal photographs taken during the Australian National Eye Health Survey were retrospectively analysed by an ocular oncologist. Each lesion was assigned a MOLES score and categorised as common, low-risk, high-risk or probable melanoma.Results: Seventy-seven choroidal naevi were identified. Seventy-five (97%) of the choroidal naevi were categorised as common naevi, with a MOLES score of 0. Two (3%) choroidal naevi had a score of 1 and diagnosed as low-risk naevi due to their size. No naevi had a score of 2 or more.Conclusion: All choroidal naevi detected in this nationally representative population survey were innocuous. This suggests that the vast majority of choroidal melanocytic tumours that are incidentally detected in Australia can be managed in primary eye care settings without the need for specialist referral. MOLES provides a simple evidence-based method for choroidal naevi assessment in primary care.

Background: The aim of this study was to report 2 cases of pulmonary air embolism developing several hours after choroidal melanoma endoresection without the use of air infusion during the surgery, with fatality in 1 patient. Methods: The method of this study was case report. Participants: Two patients with large choroidal melanomas who collapsed several hours after endoresection without air infusion as a result of pulmonary air embolism. Results: A 72-year-old man collapsed 4 h and 30 min after endoresection without air infusion. Computerized tomography angiography confirmed air embolism. The patient died after 86 min of cardiopulmonary resuscitation. A 41-year-old woman collapsed 5 h and 30 min after endoresection, performed without air infusion and with close monitoring, which included right internal jugular vein catheterization intraoperatively. Transthoracic and transesophageal echography, performed preoperatively, intraoperatively, and postoperatively, revealed air embolism only after collapse occurred. Imaging showed the embolism to be biventricular because of patent foramen ovale. The patient was treated promptly with extracorporeal membrane oxygenation and mechanical ventilation, which resulted in a full recovery. Conclusions: Air embolism can develop after endoresection for choroidal melanoma, despite avoiding air infusion. Further studies are needed to understand how this occurs. Special measures are indicated to detect this complication and to treat it promptly and effectively.

Objective The objective of this study is to characterise the natural history of conjunctival naevi in a paediatric and adolescent population. Methods All children and adolescents referred to Moorfields Ocular Oncology Service for evaluation between January 2015 and 2020 were included. Exclusion criteria included age >20 years old and lack of anterior segment photographs. A total of 77 patients were included with a mean age of 12 years (standard deviation: 3.9; range, 4-20). The main outcome measures were: number of conjunctival naevi that grew, changed in pigmentation, required excisional biopsy, or were histologically malignant. If there was growth, the percentage increase in size was measured. Results At their first visit, 13% of patients (10/77) were discharged to local follow-up and 10% (8/77) proceeded to excisional biopsy, four further patients underwent excisional biopsy after a period of follow-up. On histopathological assessment, 92% (11/12) of lesions were benign conjunctival naevi. One patient, who had suspicious clinical features at presentation, had conjunctival melanoma. Fifty-nine patients were followed over a median of 1.1 years (interquartile range: 1.54; range, 3 months to 4 years). Eight per cent (5/59) of conjunctival naevi enlarged in diameter by a mean percentage increase in size of 2%, whereas 5% (3/59) showed increased pigmentation and 8.5% (5/59) showed decreased pigmentation. Conclusions Growth of conjunctival naevi in children is infrequent (8%) and the large majority of those excised are benign. Because of a lack of evidence, these patients are often followed for years in ophthalmic practice. This series demonstrates that prolonged follow-up may not be necessary.

Objective: To define the characteristics of solitary idiopathic choroiditis (SIC) in a consecutive series of patients and propose a nomenclature change to idiopathic scleroma. Materials and Methods: Electronic patient records were retrospectively interrogated to identify all patients diagnosed with SIC between 2002 and 2019 in a tertiary referral ophthalmic hospital in the United Kingdom. Results: Thirty-four eyes of 34 patients were found to have SIC. The mean age at diagnosis was 48 years (range 24–78) and 23 patients (68%) were female. All lesions were located posterior to the equator, most frequently in the inferotemporal quadrant (13 eyes, 38%). The lesions had a mean largest basal diameter of 1.2 ± 0.4 disc diameters (range 0.5–2) and their distance to the optic disc had a mean of 1.2 ± 0.9 disc diameters (range 0–3.3). All lesions were intrascleral on enhanced depth imaging optical coherence tomography, demonstrating a hypo-reflective zone within the sclera, with an underlying hyper-reflective zone in some cases. No lesion enlarged or developed features consistent with active inflammation after a median follow-up time of 0.9 years (range 0–16.8). Discussion/Conclusion: Optical coherence tomography shows SIC to be an intrascleral lesion. Furthermore, we found no evidence of any inflammatory component. A nomenclature change to idiopathic scleroma is appropriate to prevent unnecessary investigation.

Purpose: To report the outcome of a previously vitrectomized eye having less lymphoma disease burden compared with the contralateral nonvitrectomized eye over the course of 3.5 years while on systemic chemotherapy. Methods: Case report. Results: A 51-year-old man with vitreoretinal lymphoma with central nervous system involvement underwent vitrectomy in his left eye. Over the following 3.5 years on systemic chemotherapy, the left eye had less lymphoma disease burden compared with the contralateral nonvitrectomized right eye. Conclusion: Therapeutic vitrectomy may be a useful adjunct to systemic chemotherapy in vitreoretinal lymphoma, particularly in cases of vitreous predominant disease manifestation.

OBJECTIVE The fear of cancer recurrence (FCR) in later survivorship can lead to poorer mental health, quality of life and physical and functional recovery. Later-occurring FCR may be a consequence of late-emerging physical symptoms and functional problems from cancer or its treatment. Based on the self-regulation model, we predicted that persistent or escalating symptoms and functional problems would prospectively predict FCR observed 2-5 years after diagnosis and treatment. METHODS This is a five-year study of 708 uveal melanoma (UM) patients, measuring self-reported visual and ocular symptoms, functional problems and FCR at 6, 12, 24, 36, 48 and 60 months post-diagnosis. A mixed measures design over four levels with observations staggered to represent prospective prediction. Criterion variables were FCR at 24, 36, 48 and 60 months. Predictors were symptom and function scores measured at the previous two observations to FCR. Controls were FCR measured at the previous observation to the criterion FCR measure and demographic, clinical and treatment variables. RESULTS Linear mixed modelling showed that FCR was uniquely predicted by enduring symptoms, those that emerged two observations previously, but not symptoms arising at the previous observation. FCR was predicted by functional problems, which emerged in the observation prior to FCR, but not the observation previous to that. CONCLUSIONS Persistent or emerging post-treatment symptoms and functional limitations are probable risk factors for late-occurring FCR in UM survivors. IMPLICATIONS FOR CANCER SURVIVORS Monitoring symptoms and functional limitations assists in identifying at-risk survivors and targeting preventive interventions. Self-regulation theory suggests that helping survivors to more realistically appraise symptoms and functional problems may prevent FCR.

Our aim was to determine whether size impacts on the difference in metastatic mortality of genetically high-risk (monosomy 3) uveal melanomas (UM). We undertook a retrospective analysis of data from a patient cohort with genetically characterized UM. All patients treated for UM in the Liverpool Ocular Oncology Centre between 2007 and 2014, who had a prognostic genetic tumor analysis. Patients were subdivided into those with small (≤2.5 mm thickness) and large (&gt, 2.5 mm thickness) tumors. Survival analyses were performed using Gray rank statistics to calculate absolute probabilities of dying as a result of metastatic UM. The 5-year absolute risk of metastatic mortality of those with small monosomy 3 UM was significantly lower (23%) compared to the larger tumor group (50%) (p = 0.003). Small disomy 3 UM also had a lower absolute risk of metastatic mortality (0.8%) than large disomy 3 UM (6.4%) (p = 0.007). Hazard rates showed similar differences even with lead time bias correction estimates. We therefore conclude that earlier treatment of all small UM, particularly monosomy 3 UM, reduces the risk of metastatic disease and death. Our results would support molecular studies of even small UM, rather than ‘watch-and-wait strategies’.

Purpose To study Damato Multifixation Campimetry Online (DMCO), an inexpensive online visual field test, used for screening at optician shops in Denmark. Methods This was an evaluation of a diagnostic test and customers were included if minimum 50 years old, with a visual acuity of minimum 0.5 and with less myopia than 6 D. Standard equipment was a computer, a wireless mouse and a computer monitor. We used the ‘DMCO STANDARD 4,5’ algorithm for screening. DMCO results were electronically transmitted to the authors. Customers with a positive DMCO test received an eye examination including the reference standard Humphrey Visual Field Analyzer 30–2 SITA Fast test. A subset of control participants with a negative DMCO test received the same examination in order to estimate the number of false and true negatives. DMCO specificity and sensitivity were estimated according to five reference standards with 95% confidence intervals. Results The population comprised 627 individuals, 381 women and 246 men, from 13 optician shops. Mean age was 62 years (SD 7.4). DMCO was positive in 32 individuals and 27 individuals were classified as ‘true positives’ with diagnoses such as glaucoma, cataract and neurological visual field defects. Of the 595 individuals with a negative DMCO test, 110 were examined and nine individuals were classified as ‘false negatives’ according to diagnoses. Depending on reference the specificity was 97–99% and sensitivity was 14–69%. Conclusion Screening with DMCO demonstrated high specificity, whereas sensitivity was unsatisfactory. Future studies with enough power to estimate the true sensitivity is needed.

Objective: The aim of this study was to determine the sensitivity and specificity of the MOLES scoring system in differentiating choroidal melanomas from nevi according to Mushroom shape, Orange pigment, Large tumor size, Enlarging tumor, and Subretinal fluid (SRF). Methods: Color photographs, fundus-autofluorescence images, and optical coherence tomography of 222 melanocytic choroidal tumors were reviewed. Each MOLES feature was retrospectively scored between 0 and 2 and tumors categorized as “common nevus,” “low-risk nevus,” “high-risk nevus,” and “probable melanoma” according to the total score. MOLES scores were compared with the experts’ diagnosis of melanoma. Results: The MOLES scoring system indicated melanoma in all 81 tumors diagnosed as such by ocular oncologists (100% sensitivity) and nevus in 135 of 141 tumors given this diagnosis by these experts (95.7% specificity). Of the 6 tumors with discordant diagnoses, 4 had basal diameters exceeding 6 mm, all with SRF and/or orange pigment, and 2 small tumors showed either significant SRF with traces of orange pigment, or vice versa. Conclusions: The MOLES system for diagnosing melanocytic choroidal tumors compares well with expert diagnosis but needs to be evaluated when deployed by ophthalmologists and community optometrists in a wide variety of working environments.

We thank Capasso et al [...]

The COVID-19 pandemic has had an unprecedented impact on the National Health Service in United Kingdom. The UK Ocular Oncology Services evaluated the impact on the adult eye cancer care in the UK. All four adult Ocular Oncology centres participated in a multicentre retrospective review comparing uveal melanoma referral patterns and treatments in a 4-month period during the national lockdown and first wave of the COVID-19 pandemic in 2020 with corresponding periods in previous 2 years. During the national lockdown, referral numbers and confirmed uveal melanoma cases reduced considerably, equalling to ~120 fewer diagnosed uveal melanoma cases compared to previous 2 years. Contrary to the recent trend, increased caseloads of enucleation and stereotactic radiosurgery (p > 0.05), in comparison to fewer proton beam therapy (p

Objective Cancer survivors commonly experience long-term anxiety and depression. Anxiety and depression might result from problems emerging during survivorship rather than illness and treatment. This study tested three potential causal paths: (a) concerns about physical symptoms and functional problems and fear of cancer recurrence (FCR) arising during survivorship directly cause anxiety and depression, (b) an indirect path whereby FCR mediates effects of concerns about physical symptoms and functional problems on anxiety and depression, and (c) a reciprocal path whereby anxiety and depression cause concerns about physical symptoms and functional problems and FCR, which exacerbate later anxiety and depression. Methods Sample of 453 uveal melanoma survivors who completed observations 6-, 12-, 24-, 36-, 48- and 60-months post-diagnosis and did not miss two consecutive observations. Cross-lagged analyses were conducted to predict Hospital Anxiety and Depression Scale subscale scores. Symptoms and functional problems were measured using the EORTC OPT 30 scale, and FCR operationalised by the EORTC OPT 30 worry about recurrence scale. Covariates were age, gender, treatment modality, and visual acuity of the fellow eye and chromosome-3 status (which accurately predicts 10-year survival), worry and anxiety or depression. Results All paths received some support, although the indirect path emerged only for anxiety in females. Concerns about physical symptoms, functional problems, and FCR originated in survivorship and appeared to both influence and be influenced by anxiety and depression. Conclusions Findings emphasise the importance of actively monitoring survivors to prevent, detect, and intervene in the development of anxiety and depression during survivorship.

Purpose To report local disease control and all-cause mortality in patients with extraocular extension (EOE) of uveal melanoma undergoing enucleation followed by observation or external beam radiotherapy (EBRT). Methods Charts of patients enucleated between January 1, 1997 and December 31, 2019, with histopathological evidence of EOE of uveal melanoma were reviewed. Results The cohort comprised 51 patients with a mean age of 67 ± 15 years, 22 (43%) of whom underwent adjuvant postenucleation EBRT. Risk factors for metastasis included presence of epithelioid cells (29/45; 88%), closed loops (20/43; 47%), monosomy 3 (16/25; 64%), and gain of 8q (20/22; 91%). Patients undergoing EBRT had more extensive EOE (median: 5.1 mm vs. 2.6 mm, p = 0.008) and surgical excision was less likely to be histologically complete (2/20; 10% vs. 14/25; 56%, p = 0.002). Local side effects following EBRT were seen in 64% (14/22). At latest follow up, 59% of patients (30/51) were alive, with a median follow up of 1.8 years (interquartile range: 2.9; range: 0.1-6.5]. By Kaplan-Meier survival analysis, the 5- and 10-year overall survival rates were 56% and 12%, respectively. There was no difference in all-cause mortality between those receiving adjuvant EBRT and those who were observed (log rank, p = 0.273). No cases of orbital recurrence were documented. Conclusions Orbital EBRT causes significant morbidity. Cases with relatively small EOE undergoing enucleation can be safely observed, without adjuvant EBRT. Multicenter studies are required to better assess the role of EBRT when EOE is more extensive.

Purpose To determine the usefulness of a comprehensive, targeted-capture next-generation sequencing (NGS) assay for the clinical management of children undergoing enucleation for retinoblastoma. Design Cohort study. Participants Thirty-two children with retinoblastoma. Methods We performed targeted NGS using the UCSF500 Cancer Panel (University of California, San Francisco, San Francisco, CA) on formalin-fixed, paraffin-embedded tumor tissue along with constitutional DNA isolated from peripheral blood, buccal swab, or uninvolved optic nerve. Peripheral blood samples were also sent to a commercial laboratory for germline RB1 mutation testing. Main Outcome Measures Presence or absence of germline RB1 mutation or deletion, tumor genetic profile, and association of genetic alterations with clinicopathologic features. Results Germline mutation or deletion of the RB1 gene was identified in all children with bilateral retinoblastoma (n = 12), and these NGS results were 100% concordant with commercial germline RB1 mutation analysis. In tumor tissue tested with NGS, biallelic inactivation of RB1 was identified in 28 tumors and focal MYCN amplification was identified in 4 tumors (2 with wild-type RB1 and 2 with biallelic RB1 inactivation). Additional likely pathogenic alterations beyond RB1 were identified in 13 tumors (41%), several of which have not been reported previously in retinoblastoma. These included focal amplifications of MDM4 and RAF1, as well as damaging mutations involving BCOR, ARID1A, MGA, FAT1, and ATRX. The presence of additional likely pathogenetic mutations beyond RB1 inactivation was associated with aggressive histopathologic features, including higher histologic grade and anaplasia, and also with both unilateral and sporadic disease. Conclusions Comprehensive NGS analysis reliably detects relevant mutations, amplifications, and chromosomal copy number changes in retinoblastoma. The presence of genetic alterations beyond RB1 inactivation correlates with aggressive histopathologic features.

At the time of writing this article, the COVID-19 pandemic is severely disrupting the care of patients with choroidal melanoma in Britain and elsewhere. Vast numbers of individuals are developing severe illness with thousands of fatalities.1 Many ophthalmic workers have died (such as Li Wenliang) or are absent from duty because of illness or isolation. Others are redeployed at COVID-19 units. Patients are avoiding medical care, because they are afraid of catching coronavirus. Routine community optometry has largely been suspended. Non-urgent hospital clinic appointments are being deferred, as are surgical procedures, laser sessions and intravitreal injections of antiangiogenic agents. This lull will inevitably be followed by a surge of referrals and a backlog of patients needing assessment and treatment. Patients with choroidal melanoma will present with more advanced disease with lost opportunities for conserving vision and the eye in some cases.2 There will inevitably be deaths from metastatic disease, undoubtedly stirring concerns about whether any fatalities might have been prevented if the COVID-19 epidemic had not delayed treatment.3 The immediate crisis is expected to be followed by long-term national and personal financial difficulties, which will diminish healthcare resources and which will make it unaffordable for many patients to attend hospital clinics, especially if these are located far from their home. COVID-19 may permanently disrupt healthcare if it causes perennial epidemics, like influenza. These constraints demand drastic improvements in clinical practice to avoid unnecessary costs for patients and to conserve healthcare resources while maintaining quality of care after the COVID-19 …

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.

Purpose To investigate whether early detection and treatment of uveal melanoma by screening was associated with a lower mortality rate. Methods Retrospective assessment of prospectively collected data comparing 132 patients with uveal melanoma referred by the National Diabetic Screening Service with 608 control patients referred through other means. Results Mean tumor diameter was smaller in the diabetic screening group (11.1 mm vs. 12.5 mm) as was tumor thickness (3.4 mm vs. 5.4 mm). The prevalence of high-risk monosomy 3 was also lower (17/40, 43% vs. 62/110, 56%). Despite a higher rate of systemic comorbidities in the patients diagnosed through screening and despite older age at diagnosis, the 5-year all-cause mortality was similar in both groups (17% vs. 20%); however, the metastatic mortality was lower in the diabetic screening group (11/132, 8% vs. 95/608, 16%). Conclusion Despite higher rates of comorbidities, the patients detected at diabetic screening had a lower 5-year mortality rate. The diabetic screening programme enabled detection and treatment of posterior uveal melanomas at an earlier stage. However, the confounding factors of lead and length time bias are not to be ignored.

Uveal melanoma (UM) is fatal in ~50% of patients as a result of disseminated disease. This study aims to externally validate the Liverpool Uveal Melanoma Prognosticator Online V3 (LUMPO3) to determine its reliability in predicting survival after treatment for choroidal melanoma when utilizing external data from other ocular oncology centers. Anonymized data of 1836 UM patients from seven international ocular oncology centers were analyzed with LUMPO3 to predict the 10-year survival for each patient in each external dataset. The analysts were masked to the patient outcomes. Model predictions were sent to an independent statistician to evaluate LUMPO3&rsquo, s performance using discrimination and calibration methods. LUMPO3&rsquo, s ability to discriminate between UM patients who died of metastatic UM and those who were still alive was fair-to-good, with C-statistics ranging from 0.64 to 0.85 at year 1. The pooled estimate for all external centers was 0.72 (95% confidence interval: 0.68 to 0.75). Agreement between observed and predicted survival probabilities was generally good given differences in case mix and survival rates between different centers. Despite the differences between the international cohorts of patients with primary UM, LUMPO3 is a valuable tool for predicting all-cause mortality in this disease when using data from external centers.

We report a 61-year-old female who presented to our service with recent growth of a thickened, pigmented, sub-conjunctival lesion within an area of ocular melanocytosis in her left eye. Lamellar sclerectomy was performed. Histopathological assessment revealed a localized melanocytic proliferation with features of blue nevus arising within the area of ocular melanocytosis. There was a small zone of cells showing cytological atypia and expansion of the scleral stroma. We believe this case to be the first report of intrascleral blue nevus arising within an area of ocular melanocytosis. Given the cytological atypia, the blue nevus may perhaps represent an intermediate stage within a progression from ocular melanocytosis towards melanoma. Patients with oculodermal melanocytosis merit regular long-term surveillance for early detection of melanoma, not only in the uvea, but also in the orbit and potentially the ocular surface.

Purpose: To test the hypothesis that patients treated with radiotherapy for choroidal melanoma enjoy better quality of life (QoL) than patients who have undergone enucleation. Methods: In this nonrandomized study, patients with choroidal melanoma treated at the Royal Liverpool University Hospital, Liverpool, UK, were invited to complete QoL questionnaires approximately 6 months postoperatively and then on each anniversary of their primary treatment. These instruments consisted of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-OPT30 questionnaire, Hospital Anxiety & Depression Scale, and the Functional Assessment of Cancer Treatment questionnaire. Patient-reported outcomes were correlated with demographics, ocular treatment, social factors, presenting tumor and ocular status, self-reported general health, marital status, and employment status. Results: The 1596 patients were treated with radiotherapy (72.3%) or enucleation (27.7%). Enucleation was associated with male sex (χ2, P = .004), older age (t test, P < .001), larger tumor diameter (t test, P < .001), monosomy 3 (χ2, P < .001), depression (linear regression, 95% confidence interval [CI], .17 to 1.01), and reduced physical and functional well-being (linear regression, 95% CI, −1.14 to −0.12 and −1.96 to −0.47), respectively. Poor QoL was attributed to the ocular disease by 21% and 20% of enucleated and irradiated patients, respectively (χ2, P = .938). Conclusions: Patient-reported outcomes and QoL were worse in patients who had undergone primary enucleation for choroidal melanoma. These outcomes may partly have been caused by factors predisposing to enucleation rather than enucleation itself, because enucleated patients tended to be older, with more advanced disease at presentation, and a worse prognosis for survival. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

BackgroundConjunctival melanoma is the second most common conjunctival malignant tumour after squamous cell carcinoma, usually arising from primary acquired melanosis and less commonly from a conjunctival naevus or de novo. We report four cases of conjunctival melanoma masquerading as ocular surface squamous neoplasia.MethodsFour patients (2 females and 2 males; mean age 60.7 years; range 41–72 years) were referred for suspicious conjunctival lesions. In all cases, the lesions had a perilimbal location, were non-pigmented (cases 1 and 3) or mildly pigmented (cases 2 and 4), had a fleshy (cases 1, 2 and 4) or papillomatous (case 3) appearance and involved the corneal surface. In each case, our main clinical differential diagnosis included conjunctival intraepithelial neoplasia and squamous cell carcinoma. All four patients underwent an excisional biopsy with double freeze-thaw cryotherapy and alcohol keratoepitheliectomy.ResultsIn all four cases, the histopathological diagnosis was of invasive conjunctival melanoma with extension to the deep surgical margins. Adjuvant therapy consisting of strontium-90 β radiotherapy (all 4 patients) and topical Mitomicyn C (patient 2) was administered.ConclusionConjunctival melanoma can clinically resemble ocular surface squamous neoplasia. Clinical impressions therefore need to be confirmed histopathologically.

Background/Aims: Current retinoblastoma staging systems do not adequately describe the disease, especially in eyes with multiple tumors. The aims of this study were to develop methods for documenting individual tumors and to score disease burden over time. Methods: A coding system was devised to describe each tumor according to affected eye, meridian, anteroposterior location, activity, growth pattern, type of seed, and treatment. A scoring system for quantifying disease burden was developed, taking account of tumor number, size, spread, and secondary effects on the eye. Results: Our coding system allowed contemporaneous tumor documentation, producing datasets that enabled generation of fundus diagrams, Kaplan-Meier curves, and tables summarizing disease progression in individual tumors and eyes. Our data showed disparities between ocular and tumor documentation, e.g., indicating earlier tumor development in the left eye but younger age at presentation if disease was worse in the right eye. Actuarial rates of local treatment failure were lower when individual tumors were analyzed than when data were reported in terms of whole eyes. Conclusion: Our methods for documenting individual retinoblastomas have facilitated the review of patients’ progress in our routine practice and may provide data that could be used to refine retinoblastoma classifications in the future.

Objective We examined the role of posttreatment symptoms and functional problems and of worry about recurrent disease (WREC) in predicting probable anxiety and depression cases 24 months after diagnosis in survivors of posterior uveal melanoma. We examined whether WREC mediates links between symptoms, functional problems, and probable anxiety and depression cases. Methods Prospective cohort study of 261 treated uveal melanoma survivors 6, 12, and 24 months after diagnosis. Hierarchical logistic regression analyses predicting anxiety and depression 24 months after diagnosis identified by Hospital Anxiety and Depression Scale cutoff scores. Symptoms, functional problems, and WREC 6-month posttreatment were entered into the analyses as predictors, then the same variables at 12 months. We controlled anxiety or depression at 6 and 12 months and chromosome 3 status, which accurately predicts 10-year survival. Mediation of links between 6-month symptoms and functional problems and 24-month anxiety and depression by 12-month WREC was tested. Results Anxiety caseness at 24 months was predicted by 6-month ocular irritation, headache, and functional problems and 12-month WREC. Depression caseness at 24 months was predicted by 6-month headache and functional problems. Worry about recurrent disease at 12 months mediated prediction of anxiety caseness by 6-month symptoms and functional problems. Chromosome 3 status predicted neither anxiety nor depression. Conclusions Survivors reporting symptoms, functional problems, and WREC should be monitored for anxiety and depression. Appropriate reassurance that symptoms do not signify future disease might help prevent anxiety.

Background and purpose The purpose of this article is to estimate the distribution of superselective intra-arterial chemotherapy (IAC) delivery to ocular target tissue using quantitative digital subtraction angiography (qDSA). Materials and methods From March 2010 to January 2016, 50 ophthalmic artery contrast DSAs obtained immediately prior to IAC infusions in 22 patients were analyzed. This study was conducted under a retrospective review IRB (no. 10-01862). Parametric color-coded DSAs (iFlow, Siemens Medical) were post-processed (MATLAB, The Mathworks Inc.) using two methods: two box regions of interest (pre-retina and globe) and four custom regions of interest (ROIs—ophthalmic artery, choroid, supraclinoid internal carotid artery (ICA), cavernous ICA). Mean interobserver reliability of custom ROI selection is presented as a 95% confidence interval of interclass correlation, and fractional chemotherapy delivery to selected ROIs as means ± standard deviation in this study. Results The estimated fraction of chemotherapy delivered to the globe with the first method was 79.5%. Percentage regional delivery using the second method was as follows: ophthalmic artery, 85.8%; choroid, 60.5%; supraclinoid ICA, 14.2%. The cavernous ICA ROI (encompassing distal catheter and potential reflux) gave a signal equivalent to 9.3% of total delivery. Conclusion Parametric color-coded qDSA can estimate the fraction of IAC delivered to the retina and other orbital structures in ocular retinoblastoma patients. This information can inform delivery location and dosing strategies on a patient-specific basis.

Background: Ocular melanomas threaten patients with early death, visual handicap, and loss of the eye. The aims of this study were to identify aspects of care that patients with ocular melanoma considered most important and to determine whether patients felt their needs had been adequately addressed. Methods: A cross-sectional study including US ocular melanoma patients and their caregivers. An online survey of US ocular melanoma patients was designed and conducted by the Ocular Melanoma Foundation. Results: The cohort included 180 patients with uveal melanoma and 4 with conjunctival melanoma. Median follow-up was 3 years. A third of patients reported that their uveal melanoma had initially been diagnosed as a nevus. Most uveal melanomas were treated with brachytherapy. Almost 50% of patients had no genetic tumor analysis. Screening methods reported most commonly were computed tomography and liver function tests. Metastatic disease developed in 11% of patients. Few patients (13.3%) reported an offer of psychological support. Most dissatisfaction was with lack of advice on financial aspects of care and lack of psychological counseling, with women tending to express more dissatisfaction with care. Many patients complained about the way ophthalmologists delivered bad news to them. Conclusions: This patients' perspective highlights directions for research, education, and other measures to improve the care of patients with ocular melanoma in the US and elsewhere.

Background/Aims: To report the case of a 77-year-old male with a blind, painful eye, referred for suspected corneal mass, with finding of choroidal B-cell lymphoma on pathology of enucleated globe. Methods: This is a retrospective case report of a single patient. Results: A 77-year-old male with a longstanding history of poor vision in the left eye was referred for a scarred, vascularized corneal mass. The patient had reported occasional mild ocular discomfort in the left eye and loss of light perception over the last year. Visual acuity was 20/20 in the right eye and no light perception in the left eye. Intraocular pressure was 32 mm Hg in the left eye. Fundoscopic visualization was not possible due to corneal opacity. B-scan ultrasound showed an infiltrative, low-reflective choroidal lesion and inferior retinal detachment. Pathology from the enucleated globe revealed diffuse sheets of CD20+ small B cells replacing the choroid, characteristic of a low-grade small B-cell extranodal marginal zone lymphoma. Conclusion: This is an unusual presentation of choroidal lymphoma in an eye with severe corneal opacification and scarring, and underscores the diagnostic value of ultrasonography in examination of eyes without view to the posterior segment.

Simple Summary Long-term surveillance following radiotherapy for choroidal melanoma is important for detecting recurrence. There is a perceived notion that regular ultrasonography is required to detect recurrence. The skills required to perform ocular ultrasound are not widely available, which can prevent patients being seen close to home. We aimed to determine whether local treatment failure can reliably be detected with colour fundus photography alone. We found that in 74 out of 75 patients (98.7%), with a clear view of their fundus, recurrence could be detected using colour photography alone. One patient with a clear fundal view developed extraocular extension which was detected on ultrasound without visible change in the intraocular part of the tumour. We conclude that most treated choroidal melanomas can be monitored without ultrasonography if they can be adequately imaged with colour photography. Abstract Prompt detection and treatment of local treatment failure after radiotherapy for choroidal melanoma optimises any opportunities for conserving vision and the eye, possibly reducing an increased risk of metastatic disease. Long-term surveillance is therefore required but is hampered by the perceived need to perform ultrasonography, which may not be available at a patient’s local hospital. The aim of this study was to determine whether local treatment failure can reliably be detected with colour fundus photography alone, and, if so, in which patients. Patients were included in the study if diagnosed with local treatment failure between April 2016 and February 2021 after eye-conserving therapy for choroidal melanoma. Wide-field colour and fundal autofluorescence (FAF) images, optical coherence tomography (OCT), and ultrasonography (US) were analysed by two of the authors (GN and UH). The cohort included 87 patients with local treatment failure. In 75 patients with clear media, tumour progression was detected by colour photography alone in 74 (98.7%) patients. Sensitivity was not increased by the addition of either OCT or AF. One patient with clear media developed extraocular extension detected with US without visible change in the intraocular part of the tumour. In the other 12 patients, US was required because of opaque media and a consequently poor fundal view. Local treatment failure after radiotherapy for choroidal melanoma is detected in 98.7% of cases with colour photography when the media are clear. Ultrasonography is useful when photography is prevented by opaque media or tumours having locations in the far periphery.

To determine the accuracy of estimated tumour location and required plaque position using fundus diagrams, and to evaluate their applicability in daily clinical practice. Between September 2013 and March 2016, all patients treated with ruthenium plaque brachytherapy for choroidal melanoma at the Department of Ophthalmology in Poznan underwent pretreatment planning with the use of printed or electronic fundus diagrams www.oculonco.com The estimated distances were then verified intraoperatively. There were 40 eyes of 40 patients: 15 men, 25 women, with a median age of 61 years (range: 21–88). The median longitudinal basal diameter (LBD) of the treated melanomas was 10.4 mm (range: 6.5–14.9) and the median thickness was 4.1 mm (range: 1.9–6). The final postition of the anterior tumour margin was within 1 mm of the estimated location in 39 cases (97 %), and within 2 mm in 1 case (3 %). Median follow-up was 15 months (range: 3–36). By the close of the study, there was one local tumour recurrence (3%) and one patient died of unrelated cause 1 year after treatment. No patient developed metastases by study close. The plaque planning system using the paper fundus diagrams proved to be accurate, easily applicable and should aid plaque placement where computer modelling is not possible.

We report a case of multifocal choroidal melanoma in the same eye, separated in presentation by 20 years. A 57-year-old Caucasian male initially presented with a choroidal melanoma of the right eye that was treated with transpupillary thermotherapy. Due to recurrence, the patient underwent proton beam therapy with subsequent tumor regression. A second small choroidal lesion was noted in the right eye during his surveillance examinations that was closely monitored and demonstrated stable dimensions and features suggestive of a choroidal nevus. Twenty years after his first presentation, the second lesion exhibited accelerated growth with imaging studies indicative of transformation to a distinct choroidal melanoma. The patient underwent a second globe salvage treatment of proton beam therapy. We describe the clinical course, radiographic, and imaging findings of this rare choroidal melanoma.

Background Accurate survival prognostication for patients with uveal melanoma (UM) enables effective patient counselling and permits personalised systemic surveillance for the early detection of metastases and, in high-risk patients, enrolment in any trials of systemic adjuvant therapy. The aim of this work is to determine the success of prognostic UM tumour biopsy using an improved surgical approach and optimised sample handling workflow. Methods Patients with UM treated by primary radiotherapy between 2011 and 2013 and who underwent a prognostic biopsy with cytology, multiplex ligation-dependent probe amplification and/or microsatellite analysis were included. The main outcomes and measures were success of cytology and genetic studies, and surgical complications. Results The cohort comprised 232 patients with UM having a median age of 59 years (range, 25–82) at treatment. The median largest basal diameter was 11.4 mm (range, 4.1–20.8) and tumour height was 3.4 mm (range, 0.7–10.3). Ciliary body involvement was noted in 42 cases. Treatment consisted of Ru-106 brachytherapy in 151 cases (65%) and proton beam radiotherapy in 81 cases (35%). With improvements in surgical techniques and laboratory methods over time, cytology success increased from 92% (131/142) to 99% (89/90) and the numbers of samples with sufficient DNA for genetic testing increased from 79% (104/131) to 93% (83/89). Overall, chromosome 3 loss was noted in 64/187 (34%) cases. Surgical complications, including transient localised bleeding, vitreous haemorrhage and retinal perforation, decreased over time. Eight patients required additional surgery. Conclusions Improved surgical techniques and laboratory methods yielded successful cytology and genetic information in the majority of cases. Precis Analysis of data from 232 patients with uveal melanoma undergoing prognostic tumour biopsy demonstrated that improved surgical techniques and laboratory methods yielded successful cytology and genetic information in 99% and 89% of cases, respectively.

A challenge in precision medicine is the identification of actionable driver mutations. Alterations can be identified within the tumor tissue, by small biopsy or fine‐needle aspirates, or by noninvasive methods, such as circulating tumor cells or circulating tumor DNA. This article presents a case of atypical neuroendocrine tumor metastatic to the bone and brain for which circulating tumor DNA analysis found an ALK translocation., A challenge in precision medicine requires identification of actionable driver mutations. Critical to such effort is the deployment of sensitive and well‐validated assays for mutation detection. Although identification of such alterations within the tumor tissue remains the gold standard, many advanced non‐small cell lung cancer cases have only limited tissue samples, derived from small biopsies or fine‐needle aspirates, available for testing. More recently, noninvasive methods using either circulating tumor cells or tumor DNA (ctDNA) have become an alternative method for identifying molecular biomarkers and screening patients eligible for targeted therapies. In this article, we present a case of a 52‐year‐old never‐smoking male who presented with widely metastatic atypical neuroendocrine tumor to the bones and the brain. Molecular genotyping using DNA harvested from a bone metastasis was unsuccessful due to limited material. Subsequent ctDNA analysis revealed an ALK translocation. The clinical significance of the mutation in this particular cancer type and therapeutic strategies are discussed. Key Points. To our knowledge, this index case represents the first reported ALK translocation identified in an atypical carcinoid tumor.Liquid biopsy such as circulating tumor DNA is a feasible alternative platform for identifying sensitizing genomic alterations.Second‐generation ALK inhibitors represent a new paradigm for treating ALK‐positive patients with brain metastases.

This article reviews recent developments in ocular oncology, focusing on uveal melanoma, retinoblastoma, choroidal metastasis, retinal lymphoma, conjunctival melanoma and conjunctival carcinoma. The management of patients with uveal melanoma has been revolutionized by studies revealing genetic predictors of metastatic disease. Ocular treatment continues to develop, so that vision is conserved more successfully. Treatment for radiation-induced ocular morbidity has become more effective thanks to anti-angiogenic agents and ablation or excision of the ‘toxic’ irradiated tumor. The management of patients with retinoblastoma has improved thanks to intra-arterial and intra-vitreal chemotherapy as well as advances in genetics. Choroidal metastases are increasingly diagnosed by biopsy. Novel anti-cancer therapies have resulted in a wide variety of novel adverse effects. The management of patients with vitreoretinal lymphoma has advanced with developments in imaging and laboratory analyses as well as immunotherapy and therapeutic vitrectomy. Conjunctial tumors are treated more successfully with greater use of adjunctive radiotherapy as well as topical therapy with interferon and chemotherapeutic agents. Patients with ocular malignancy are increasingly being treated in specialist ocular oncology centers because of greater awareness of the need for more holistic care, provided by experienced multidisciplinary teams.

Background/aimsProton beam radiotherapy and plaque brachytherapy are commonly applied in primary uveal melanoma (UM); however, their effect on chromosome 3 classification of UM by microsatellite analysis (MSA) for prognostication purposes is unknown, where the tumour is sampled post-irradiation. This study examined the prognostic accuracy of genotyping UM biopsied before or after administration of radiotherapy, by MSA.Methods407 UM patients treated at the Liverpool Ocular Oncology Centre between January 2011 to December 2017, were genotyped for chromosome 3 by MSA; 172 and 176 primary UM were sampled prior to and post irradiation, respectively.ResultsGenotyping by MSA was successful in 396/407 (97%) of UM samples (196 males, 211 females; median age of 61 years (range 12 to 93) at primary treatment). There was no demonstrable association between a failure of MSA to produce a chromosome 3 classification and whether radiation was performed pre-biopsy or post-biopsy with an OR of 0.96 (95% CI 0.30 to 3.00, p=0.94). There was no evidence of association (measured as HRs) between risk of metastatic death and sampling of a primary UM before administration of radiotherapy (HR 1.1 (0.49 to 2.50), p=0.81). Monosomy 3 (HR 12.0 (4.1 to 35.0), pConclusions and relevanceThis study revealed that successful genotyping of UM using MSA is possible, irrespective of irradiation status. Moreover, we found no evidence that biopsy prior to radiotherapy increases metastatic mortality.

Despite an established history of intraocular antivascular endothelial growth factor (anti-VEGF) agents therapy in a variety of ocular pathologies as well as other cancer forms, use in the primary treatment of uveal melanoma has not been well assessed. This was a two-stage therapeutic and exploratory phase II, non-randomised, single centre trial involving intraocular treatment with 0.5 mg in 0.05 ml of ranibizumab via six intravitreous injections over 6 months in patients with primary ocular melanoma that otherwise required radical surgery because of tumour size. Seven patients were recruited with a median age of 66 years. At baseline, the longest basal diameter was 15.1 mm (mean, range 10-20.4 mm) with a height measured by ultrasonography of 9.2 mm (mean, range 6.6-12.7 mm). No patients achieved complete or partial response at any visit. All required enucleation. Histopathological analysis revealed mixed cell melanoma in 5/7 (71%) and spindle cell morphology in 2/7 (29%) with ciliary body involvement in 4/7 (57%) and the presence of closed loops also in 4/7 (57%). Genetic analysis demonstrated loss of chromosome 3 in 5/7 (71%) but abnormalities in chromosome 1,6 or 8 in all cases. Our study was terminated early as alternative treatments were clearly superior for local tumour control. There continues to be a role of intravitreal anti-VEGF for the treatment of the sequelae of local radiotherapy in the form of radiation retinopathy and so these agents may be used as adjuncts in the treatment of uveal melanoma rather than as a primary treatment.

Background/objectives To evaluate retinal lymphoma treatment at the University of California San Francisco. Subjects/methods Prospective observational audit. Patients were treated systemically, usually with: methotrexate, temozolomide, and rituximab induction; etoposide consolidation; and maintenance with lenalidomide or another immunomodulatory agent. Persistent disease was treated initially by ocular radiotherapy or intravitreal melphalan and latterly by vitrectomy. Results The cohort comprised eight females and two males. The median age was 58 years (range, 38–73). Ocular manifestations were initially unilateral in four patients. Vitreous and subretinal infiltrates were initially present in 16 and 12 eyes, respectively, with three eyes having vision of 20/200 or worse. Four patients had a history of central nervous system (CNS) lymphoma. The median ophthalmic follow-up was 37 months (range, 8–56). Diagnostic and therapeutic vitrectomy were performed in 10 and 2 eyes, respectively. All patients had systemic chemotherapy and eight received maintenance immunotherapy. Four patients underwent ocular radiotherapy, bilaterally in two. One patient received bilateral intravitreal melphalan injections. Two eyes of four patients developed lymphoma during the study and two patients developed CNS disease. At study close, subretinal deposits were subtle in nine eyes and more prominent in two, whereas vitreous infiltrates were minimal in nine eyes, mild in one and moderate in one. The latest visual acuity was significantly worse than at presentation in two eyes and better in two. All patients were alive with no active CNS disease. Conclusions Subretinal lymphomatous infiltrates respond to systemic chemotherapy with immunomodulatory maintenance, but dense vitreous infiltrates require therapeutic vitrectomy.

Purpose: To compare hydroxyapatite with acrylic implants after enucleation for uveal melanoma with respect to eyelid position, ocular motility, implant complications, and patient satisfaction. Methods: Patients undergoing primary enucleation for uveal melanoma between May 2005 and November 2012 at the Liverpool Ocular Oncology Centre, United Kingdom, were randomized between hydroxyapatite and acrylic implants. Questionnaires were sent to patients and ocularists to comment on the main outcomes. Results: A total of 416 patients were recruited in the study, of whom 281 were included, with 49.5% (139/281) and 50.5% (142/281) receiving a hydroxyapatite (HA) or acrylic (AC) implant. Mailed questionnaires completed at ≥18 months by patients showed no significant differences between the groups in eyelid position, prosthetic motility, socket complications, and patient satisfaction. Complications included implant extrusion (1% vs 4%), enophthalmos (26% vs 26%), and superior sulcus deformity (24% vs 24%) with HA and AC implants, respectively, (Fisher exact test p > 0.0125 in all, Bonferroni correction). Questionnaires completed by ocularists indicated no significant differences in eyelid opening, prosthetic motility, and other complications at 6 months (Fisher exact test, p > 0.05 in all); there was a higher prevalence of ptosis with AC than HA implants (46% vs 25%, p = 0.03) and a greater need for ocularists’ treatment with HA than AC (50% vs 28%, p = 0.03). Conclusions: Patient-reported outcomes after enucleation for uveal melanoma indicate no major differences between hydroxyapatite and acrylic implants in surgical outcomes and patient satisfaction. There was a higher prevalence of ptosis with AC and a greater need of ocularists’ visits with HA at around 6 months observed by ocularists.

Purpose/Background: The aim of this study was to report a patient with vitreoretinal lymphoma with clinical features providing hypothesis-generating insights into the pathophysiology of this disease. Methods: Clinical history and imaging studies (i.e., fundus photography, optical coherence tomography, fundus autofluorescence, and fluorescein angiography) were documented. Results: A 71-year-old woman presented with a 2-month history of blurred vision in the right eye and bilateral vitreous infiltrates unresponsive to topical and systemic steroids. Vitreous biopsy of the left eye was diagnostic for lymphoma. Bulky subretinal deposits in the right eye responded to systemic therapy. The left fundus showed diffuse hypoautofluorescence and punctate, hyperfluorescent sub-retinal pigment epithelial tumor deposits, which resolved leaving hypoautofluorescent atrophic retinal pigment epithelium (RPE) scars, except inferotemporally, where retinal vasculopathy had occurred. Conclusions: The clinical features suggest that occlusion of the inferotemporal retinal arteriole prevented sub-RPE lymphomatous deposits and subsequent RPE atrophy in this area of vascular nonperfusion. This suggests that “primary” vitreoretinal lymphoma is secondary to hematogenous spread from systemic loci. This finding, together with the ocular tumor control achieved entirely by systemic therapy, indicates scope for studies investigating systemic treatment protocols, especially those including immune-modulatory agents.

Almost 50% of uveal melanoma (UM) patients develop metastatic disease, despite successful ocular treatment. Metastases usually involve the liver and only rarely respond to treatment so that most patients die within a year of onset of symptoms. There are hopes that systemic adjuvant therapy may delay or prevent metastatic disease. This requires targeting of high-risk patients, according to anatomic, histologic, and genetic predictors. Metastatic disease occurs almost exclusively in patients whose tumor shows genetic aberrations such as chromosome 3 loss, chromosome 8q gains, and BAP1 mutation. The detection of lethal genetic aberrations has become more sensitive with the development of methods such as comparative genomic hybridization, microsatellite analysis, multiplex ligation-dependent probe amplification, single-nucleotide polymorphisms, gene expression profiling, next-generation sequencing, and immunohistochemical analysis of nuclear BAP1 expression. The time from ocular treatment to the onset of metastatic disease tends to be shorter in patients with a larger, more extensive ocular tumor and a higher grade of malignancy as evidenced by epithelioid cytomorphology and higher mitotic count. Ideally, prognostication is performed by multivariable analysis using a tool such as the Liverpool Uveal Melanoma Prognosticator Online (LUMPO). Accurate prognostication enhances quality of life, especially in patients with a good prognosis. It also allows targeting of systemic surveillance and systemic adjuvant therapy in high-risk patients and enhances opportunities for research.

Alternatives to fine-needle aspiration biopsy include vitreous cutter aspiration biopsy, incisional biopsy, and excisional biopsy. Vitreous cutter aspiration biopsy is performed with a 25- or 27-gauge vitreous cutter using a three-port, sutureless vitrectomy kit, without vitrectomy, retinopexy, or tamponade. Incisional biopsy of choroidal or ciliary body melanomas can be performed with Essen forceps through a deep sclerotomy under a superficial lamellar scleral flap, using tissue glue to close the flap and seal the wound, thereby preventing seeding of tumor cells into surrounding tissues. Excisional biopsy involves removal of the entire tumor, using techniques described elsewhere. Biopsy can be performed to establish a diagnosis (e.g., to differentiate melanoma from nevus or metastasis), or to identify the likely source of a metastasis, when the primary tumor is unknown, or to estimate the survival probability of a patient with uveal melanoma, by performing genetic tumor typing. Close collaboration with the laboratory is essential.

In 1930, Sir Foster Moore first used brachytherapy for uveal melanoma by inserting radon-222 seeds directly into the tumor (Moore, Br J Ophthalmol 14:145–152, 1930). This technique was later modified by Stallard and eventually further refined using radioactive plaques containing cobalt-60 anchored to the episcleral surface (Stallard, Br J Ophthalmol 32(9):618–639, 1948; Stallard, Br J Ophthalmol 50(3):147–155, 1966). In the United States, this radionuclide was gradually replaced by plaques loaded with iodine-125 seeds, as this provided less radiation to surrounding tissues (Sealy et al., Br J Radiol 49(582):551–554, 1976; Packer and Rotman, Ophthalmology 87(6):582–590, 1980). In Europe, the pioneering work of Lommatzsch in the 1970s led to the introduction of ruthenium-106 as a radioactive source for episcleral brachytherapy of uveal melanoma (Lommatzsch, Surv Ophthalmol 19(2):85–100, 1974). Although observational data suggested that there was no survival difference compared to patients enucleated for uveal melanoma, it had not been confirmed in a randomized control trial until the Collaborative Ocular Melanoma Study (COMS) was launched in the mid-1980s. This included patients with medium-sized uveal melanoma, who had equal 5-year and 10-year survival rates in the enucleation and iodine brachytherapy groups (Collaborative Ocular Melanoma Study Group, Arch Ophthalmol 119:969–982, 2001; Collaborative Ocular Melanoma Study Group, Arch Ophthalmol 124:1684–1693, 2006). Ever since, brachytherapy has been a mainstay treatment within this size group. Smaller tumors are generally observed for growth or in selected cases treated with transpupillary thermotherapy, while patients with larger tumors still undergo enucleation.

Peripheral nerve sheath tumors of the uveal tract arise mainly in the sheath of peripheral nerves that are found in the uvea. The ciliary nerve is most often affected and hence these tumors tend to be located anteriorly, in the ciliary body or peripheral choroid. There are several systemic predisposing risk factors, which include schwannomatosis, neurofibromatosis 1 (NF1) and 2, and other rare genetic syndromes. The benign tumors can be subclassified as neurofibroma and schwannoma. The malignant nerve sheath tumors are more difficult to subclassify if they lose the histological characteristics of their benign counterparts. In this chapter we discuss uveal neurofibroma and schwannoma.