Small High-Risk Uveal Melanomas Have a Lower Mortality Rate.

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 (>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'.

Spontaneous Necrosis of a Large Choroidal Melanoma: Unusual Presentation in a 49-Year-Old Male.

PURPOSE: To demonstrate a case of massive vitreous haemorrhage obscuring the underlying diagnosis of a large mixed-cell choroidal melanoma which had undergone spontaneous necrosis. CASE REPORT: A 49-year-old man in good general health suddenly lost vision in his right eye due to an extensive vitreous haemorrhage 1 day after a workout at the gym. He reported good vision prior to that without any symptoms of flashes, floaters, or shadows. He was referred to the vitreoretinal department of a tertiary eye hospital, where he presented with a drop in vision to light perception only in the right phakic eye. Pars plana vitrectomy was performed in the right eye, which revealed intraoperatively massive retinal ischemia and choroidal haemorrhage, but no obvious tumour mass that could have been biopsied. The vitrectomy cassette specimen was sent for histopathology, where "ghost-like" melanoma cells were identified. The eye was subsequently enucleated, revealing an extensively necrotic and haemorrhagic choroidal melanoma of mixed cell type with only small viable tumour foci at the base and almost complete lysis of the detached retina. CONCLUSION: Some uveal melanomas (UMs) undergo spontaneous necrosis due to rapid growth, with the centre of the tumour outstripping its established blood supply in the "watershed area" of the eye, and becoming hypoxic with associated necrosis of intraocular structures. Such UMs are often associated with haemorrhage and/or inflammation and usually cause significant destruction of ocular tissues, resulting in enucleation as the only treatment option.

Effects of plaque brachytherapy and proton beam radiotherapy on prognostic testing: a comparison of uveal melanoma genotyped by microsatellite analysis.

BACKGROUND/AIMS: Proton 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. METHODS: 407 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. RESULTS: Genotyping 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), p<0.001) was significantly associated with increased risk of metastatic death. CONCLUSIONS AND RELEVANCE: This 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.

Prognostic biopsy of choroidal melanoma: an optimised surgical and laboratory approach.

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.

Retinal and vitreous metastases from hepatocholangiocarcinoma.

BACKGROUND: To report a case of metastatic hepatocholangiocarcinoma to the vitreous and retina. CASE PRESENTATION: A 70-year-old male, who was recently diagnosed with hepatocholangiocarcinoma, was complaining of floaters in his right eye over the past 5 months and was referred to the Liverpool Ocular Oncology Centre. On presentation, his visual acuity in the right eye was 6/24. Fundus exam revealed a whitish, unilateral, full-thickness retinal lesion at the inferotemporal arcade of his right eye, with vitreous infiltration and subretinal fluid. The patient underwent 25G pars plana vitrectomy with biopsy, resection of the lesion and intravitreal bevacizumab injection. Histopathology testing of the surgical specimens confirmed the diagnosis of metastatic carcinoma to the eye. Two months postoperatively his visual acuity had improved to 6/7.5 and there was no sign of active disease in his right eye, while 9 months postoperatively his visual acuity decreased to 6/9.5 due to developing nuclear sclerotic cataract in his right eye. CONCLUSION: The current report presents the first case of a hepatocholangiocarcinoma metastasis to the vitreous and retina.

Core Endoresection as Neoadjuvant Treatment of Uveal Melanoma.

AIM: To present a case of neoadjuvant treatment of uveal melanoma with a limited core endoresection, which enabled ruthenium plaque radiotherapy to be administered. MATERIAL AND METHODS: A 77-year-old woman presented in 2005 with a ciliochoroidal uveal melanoma measuring 7.2 by 6.5 mm basally with a thickness of 6.2 mm. The vision in the affected eye was 6/9. Because of diagnostic uncertainty, we performed a biopsy, which produced a copious sample. The biopsy serendipitously reduced the tumour thickness to 4.4 mm, making ruthenium plaque brachytherapy possible. RESULTS: Histopathological examination showed the tumour to be a melanoma predominantly of spindle cell type. Postoperative complications included a dense vitreous haemorrhage, which cleared spontaneously, and raised intraocular pressure, controlled with latanoprost. Seven years after brachytherapy, the vision was 6/5 and the thickness of the residual tumour was 2.5 mm. Nine years after treatment, there was no evidence of any intra- or extraocular seeding or distant metastases. CONCLUSIONS: Core endoresection of a ciliochoroidal melanoma may reduce tumour thickness enough to allow subsequent ruthenium plaque radiotherapy.

Vitreoretinal surgery for complications of choroidal tumor biopsy.

OBJECTIVE: To determine the outcomes of vitreoretinal surgery after choroidal tumor biopsy. DESIGN: Retrospective, single-center, consecutive case series. PARTICIPANTS: A total of 739 consecutive patients undergoing choroidal tumor biopsy. METHODS: All subjects who underwent transretinal or transscleral choroidal tumor biopsy for diagnostic or prognostic purposes between May 1993 and May 2013 were identified in our database. We then reviewed patients who subsequently required secondary vitreoretinal surgery for complications arising from such biopsies. MAIN OUTCOME MEASURES: Reason for vitreoretinal surgery, association with biopsy procedure, best-corrected visual acuity (BCVA; logarithm of the minimum angle of resolution [logMAR]), intraocular or extrascleral tumor dissemination, resolution of vitreous hemorrhage, reattachment of the retina with a single vitreoretinal procedure, number of additional vitrectomies undertaken, and number of enucleations. RESULTS: A total of 20 of 739 eyes (2.7%) underwent vitreoretinal surgery for complications arising from choroidal tumor biopsy. The tumors consisted of choroidal melanoma in all 20 eyes. The reasons for the secondary surgery included persistent vitreous hemorrhage in 1.9% (14/739), rhegmatogenous retinal detachment in 0.7% (5/739), and endophthalmitis in 0.14% (1/739). Median BCVA improved from 2.0 logMAR (mean, 1.92 logMAR; range, 0.8-2.7 logMAR) before vitrectomy to 0.72 logMAR (mean, 0.88 logMAR; range, -0.14 to 2.7 logMAR) after vitrectomy and 0.76 logMAR (mean, 1.14 logMAR; range, 0.1-3.0 logMAR) at the final visit (P < 0.0001, t test). Permanent resolution of vitreous hemorrhage was achieved in 6 of 14 patients, and reattachment of the retina was achieved in 2 of 5 patients after the first vitrectomy. A median of 1 (mean, 1.5; range, 1-3) additional vitrectomy was performed. Enucleation was necessary in 3 of 20 eyes (15%). There were no cases of intraocular invasion or extrascleral extension after vitrectomy. CONCLUSIONS: Vitrectomy for complications of choroidal tumor biopsy is rare. Such corrective surgery is complex and is best undertaken by specialized ocular oncologists or vitreoretinal surgeons with experience in managing this problem.

Does choroidal melanoma regression correlate with chromosome 3 loss after ruthenium brachytherapy?

AIM: To determine the reduction of choroidal melanoma thickness 6 months after ruthenium 106-brachytherapy according to chromosome 3 status, which correlates strongly with metastatic death. METHODS: Transscleral fine needle aspiration biopsy was performed prior to the insertion of a radioactive plaque if the tumour was deemed sufficiently thick and anterior for such a procedure. Transretinal biopsy with a 25-gauge vitreous cutter was performed for thin and posterior tumour within a month of plaque removal. The chromosome 3 status was determined by fluorescence in situ hybridisation from 2002 until 2006, and by either multiplex ligation-dependent probe amplification and/or microsatellite analysis after this period until the end of the study. The choroidal melanoma dimensions were obtained from outpatient visits. RESULTS: 149 eyes from 149 patients were included. The mean age was 60.8 years. 84 eyes (56.4%) had disomy 3 and 65 eyes (43.6%) monosomy 3. The median pretreatment tumour thickness was 3.0 mm in disomy 3 and 4.1 mm in monosomy 3 tumours (p=0.018). The follow-up duration medians were 6.3 months for disomy 3 and 6.4 months for monosomy 3 tumours (p=0.68). The rates of thickness reduction were 6.7% and 7.0% per month, respectively (p=0.59). Thickness reduction exceeding 50% occurred in 32 (38.1%) disomy 3 and 24 (36.9%) monosomy 3 tumours. CONCLUSIONS: The rate of choroidal melanoma regression after ruthenium-106 brachytherapy does not appear to correlate with chromosome 3 loss, suggesting that tumour thickness reduction 6 months after treatment is unlikely to predict survival.

Trans-scleral local resection of toxic choroidal melanoma after proton beam radiotherapy.

AIM: To report on trans-scleral local resection of choroidal melanoma for exudative retinal detachment and neovascular glaucoma (toxic tumour syndrome) after proton beam radiotherapy (PBR). METHODS: A non-randomised, prospective study of secondary trans-scleral local resection of choroidal melanoma for exudative retinal detachment with or without neovascular glaucoma after PBR. The patients were treated at the Liverpool Ocular Oncology Centre between February 2000 and April 2008. The trans-scleral local resection was performed with a lamellar-scleral flap, using systemic hypotension to reduce haemorrhage. RESULTS: 12 patients (six women, six men) with a mean age of 51 years (range 20-75) were included in this study. The tumour margins extended anterior to ora serrata in six patients. On ultrasonography, the largest basal tumour dimension averaged 12.4 mm (range 6.8-18.1) and the tumour height averaged 7.1 mm (range 4.2-10.7). The retinal detachment was total in seven patients. Neovascular glaucoma was present in four patients. The time between PBR and local resection had a mean of 17.4 months (range 1-84). The ophthalmic follow-up time after the local resection had a mean of 46.2 months (range 14-99). At the latest known status, the eye was conserved in 10 patients, with a flat retina in all these patients and visual acuity equal or better than 6/30 in four patients. The reasons for enucleation were: patient request for enucleation when rhegmatogenous retinal detachment complicated the resection (one patient) and phthisis (one patient). CONCLUSIONS: Exudative retinal detachment, rubeosis and neovascular glaucoma after PBR of a choroidal melanoma can resolve after trans-scleral local resection of the tumour. Our findings suggest that these complications are caused by the persistence of the irradiated tumour within the eye ('toxic tumour syndrome').

Long-term outcome of primary endoresection of choroidal melanoma.

BACKGROUND: Endoresection of choroidal melanoma may offer the best hope of conserving vision in some patients but is controversial because of concerns regarding iatrogenic tumour dissemination. METHODS: Retrospective, non-randomised study of consecutive patients who underwent endoresection for choroidal melanoma at the Liverpool Ocular Oncology Centre between 1996 and 2010. RESULTS: The study included 71 patients with a mean age of 58.7 years. The tumour extended within 2 disc diameters of the optic disc in 46 (65%) eyes, involving the disc in 24 (34%) eyes. The mean largest basal tumour diameter and tumour thickness were 9.5 mm and 4.4 mm, respectively. The median follow-up was 4.1 years. The visual acuity at the latest follow-up was better than 6/30 in 31% eyes. The main causes of visual loss were foveal excision, rhegmatogenous retinal detachment (RD) and proliferative vitreo-retinopathy (PVR). Local recurrence developed in two patients (3%), who were treated by enucleation and proton beam radiotherapy, respectively. RD occurred in 16 cases (22%). Three (4%) eyes were enucleated, two because of PVR and one because of local tumour recurrence. Five patients died of metastatic disease. CONCLUSIONS: Endoresection achieved high rates of local tumour control. This operation would seem to be a useful alternative to radiotherapy as a means of conserving vision in eyes with juxtapapillary melanoma.

Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre.

BACKGROUND: Uveal metastasis is the most common intraocular malignancy. METHODS: This was a retrospective study of all patients with uveal metastases referred to the Liverpool Ocular Oncology Centre between January 2007 and December 2012. Biopsy was performed as a primary investigation if the clinical examination suggested metastasis with no evidence of any extraocular metastases. RESULTS: Ninety-six patients (109 eyes) were included. Breast and lung carcinomas were the most common primary malignancies, affecting 41 and 27 patients, respectively. The median time interval between detection of primary cancer and uveal metastasis was 24 months (range 1-288 months). Thirty-nine patients underwent ocular biopsy, confirming the diagnosis in all patients. The biopsy indicated the site of origin in 24 out of the 27 without a known primary tumour. In 7 of these 27 cases, previous systemic investigations had failed to identify the primary tumour. Seventy-three patients received external beam irradiation; two patients received photodynamic therapy; and two patients had Ru-106 plaque radiotherapy. The visual acuity was stable or improved in 75.5% of the cases. CONCLUSIONS: Immediate biopsy provides a quick diagnosis that may expedite treatment and improve any opportunities for conserving vision while facilitating the general oncologic management on these patients.

Validation of an online referral guide for melanocytic fundus lesions.

AIM: To assess the validity of an online referral guide for melanocytic fund us lesions available to optometrists. METHODS: A prospective inter-observer agreement assessment of a novel grading system for melanocytic fundus lesions using digital images from the Liverpool Ocular Oncology Centre. RESULTS: The study was completed by 94.5% (52/55) of optometrists recruited. A total of 2594 valid grading scores were obtained for 400 different melanocytic lesions which were assigned to three management categories (monitor, routine referral or urgent referral). The linear weighted kappa value between the optometrists and the ocular oncologist was 0.66 (95% CI 0.64-0.68). Optometrist inter-observer agreement was 0.62 (95%CI 0.57-0.67). CONCLUSIONS: This online referral guide for melanocytic lesions shows substantial agreement between optometrists and a gold standard opinion. It is easily accessible and could be helpful to community optometrists managing patients with a melanocytic fundus lesion.

Intravitreal bevacizumab for retinal vein occlusion and early growth of epiretinal membrane: a possible secondary effect?

AIMS: To report the early development of epiretinal membranes (ERM) in eyes with retinal vein occlusions (RVO) treated with intravitreal bevacizumab and to describe possible mechanisms that may be involved in the growth and contraction of these lesions. METHODS: Retrospective and interventional study that included 25 eyes of 25 patients with RVO (16 eyes with central retinal vein occlusion and nine eyes with branch retinal vein occlusion). After an initial 2.5mg/0.1ml intravitreal bevacizumab injection all patients were followed-up every 6 weeks. Re-treatments were based on visual acuity and optical coherence tomography findings. Results Twenty-five eyes were treated with bevacizumab and followed for 8.3 (range 4.5-13.5) months. Four eyes developed an ERM within 6-7weeks after the administration of bevacizumab. ERM was not associated with further deterioration of visual acuity or metamorphopsia in these patients. A rebound of macular oedema was observed in one patient with ERM and in two other patients. No other side effects were observed. CONCLUSIONS: Intravitreal bevacizumab may be associated with an early growth of ERM in eyes with RVO, although a causative relationship cannot be established. Future randomised clinical trials are necessary to determine the efficacy and safety profile of this novel therapy.

Extraocular seeding of choroidal melanoma after a transretinal biopsy with a 25-gauge vitrector.

PURPOSE: To report an isolated case of extraocular seeding of choroidal melanoma after a transretinal biopsy. METHODS: A 74-year-old man with a choroidal melanoma in the left eye underwent a 3-port transconjunctival 25-gauge transretinal biopsy (for cytogenetic prognostication) followed by proton beam radiotherapy. Biopsy showed the melanoma to be predominantly of spindle cell type with chromosome 3 loss. He presented 14 months later with two pigmented conjunctival lesions, corresponding to the site of the pars plana sclerotomy. RESULTS: Excision biopsy of the conjunctival lesions confirmed subconjunctival seeding of melanoma cells at the sites of sclerotomy. CONCLUSION: The seeding of melanoma corresponded to the sites of sclerotomy, indicating extraocular seeding of the primary tumor after transretinal biopsy. We discuss the possible reasons for this occurrence and strategies to prevent extraocular seeding of melanoma after transretinal biopsy.

Transretinal choroidal tumor biopsy with a 25-gauge vitrector.

OBJECTIVE: To describe and evaluate transretinal biopsy of choroidal tumors using 25-gauge vitrectomy instrumentation. DESIGN: Retrospective, consecutive, noncomparative case series. PARTICIPANTS: Fourteen patients undergoing choroidal tumor biopsy at an ocular oncology center. METHODS: The biopsies were performed under local or general anesthesia, alone or in combination with ruthenium plaque or tantalum marker insertion. Immunohistochemistry was performed on all samples, and some melanomas were also analyzed cytogenetically. RESULTS: Surgery was uneventful in all cases. A positive tissue diagnosis was made in 13 of 14 patients, albeit at the second attempt in 1 patient. The only failure occurred because the tumor was calcified. CONCLUSION: Transretinal choroidal biopsy with 25-gauge instrumentation yields a larger sample than fine-needle aspiration biopsy, usually producing sufficient tissue for cytogenetic studies. We did not identify safety concerns in this series of patients. Insufficient samples can occur in some patients, and further studies are needed to understand the reason for such failure.

Can the sequential use of conventional silicone oil and heavy oil be a strategy for the management of proliferative vitreoretinopathy?

INTRODUCTION: Densiron is a novel long-term tamponade. Its specific gravity is 1.06 g/mL and as such it is heavier than water and provides support for the inferior retina. As proliferative vitreoretinopathy (PVR) has a propensity for the inferior retina, we used Densiron on a consecutive series of 97 cases with inferior pathology. We hypothesised that the sequential use of conventional and heavy silicone oil is a strategy for the management of PVR. MATERIALS AND METHODS: A consecutive interventional case series involving the use of Densiron for PVR cases was studied. Patients were selected if conventional silicone oil and Densiron were used sequentially. Anatomical success was defined as total re-attachment in the absence of any tamponade agent for at least 3 months post oil removal. RESULTS: Of the 97 patients, 10 patients fulfilled the criteria. Surgery involving Densiron was successful in re-attaching the retina in 7 of 10 cases, with one sequence of alternating light then heavy oil operation, and with one further surgery using silicone oil in the remaining 3 cases. The mean LogMAR preoperative vision was 1.57 and the postoperative vision was 0.82. In 8 of 10 patients, the final vision was 20/200 or better; in 5 of 10 patients, 20/80 or better. The mean follow-up was 19.5 months (range, 9 to 45). CONCLUSIONS: The sequential use of conventional silicone oil and Densiron may be a strategy in reducing the number of re-operations. Our case series shows that despite multiple surgical procedures, favourable visual outcome can be achieved.

Management of traumatic posterior capsular rupture: corneal approach with high speed vitrector.

A 15-year-old boy was referred for reduced left-eye vision 2 weeks after a blunt trauma. The presenting visual acuities were 6/12 in the right eye and counting fingers in the left eye. Examination revealed a white cataract in the left eye with loss of convexity of the anterior lens surface. Ultrasonography confirmed a ruptured posterior capsule. Removal of the lens was approached via a clear corneal cataract incision. After insertion of an anterior chamber maintainer and capsulorhexis was performed, the lens matter was removed with vitreous cutter via the cataract incision, using its cutting and aspirating modes. A foldable intraocular lens (IOL) was inserted in the capsular bag. Visual acuity improved to 6/18 1 month after surgery and further improved to 6/6 at 6 months. The IOL was stable with no decentration or posterior capsule opacification.

What pressure is exerted on the retina by heavy tamponade agents?

BACKGROUND: Histological changes in the retina during the use of heavy tamponade agents have been linked with the pressure on the retina caused by the increased specific gravity of the agent. This paper calculates the possible increases in pressure due to these agents and questions the validity of this argument. METHODS: A model eye chamber was used to make measurements of the shape of F6H8 bubbles, with incrementally increasing volumes, and thus calculate the maximum possible increase in pressure under the tamponade agent. RESULTS: The maximum increase in pressure under an F6H8 tamponade which completely fills an eye with a diameter of 2.2 cm would be 0.52 mmHg. CONCLUSIONS: This increase in pressure is within normal diurnal pressure changes in the eye; therefore, it would seem unlikely that such an increase could cause the histological changes observed. With increasing volumes of a heavy tamponade agent, aqueous is excluded from a greater area of retina. This could account for the pathological changes reported.