Faculty Bibliography

PURPOSE/UNASSIGNED:Pd) eye plaque brachytherapy for multifocal iris melanoma. METHODS/UNASSIGNED:Interventional case series of 11 patients with multifocal iris melanomas. Anterior segment ultrasound revealed tumor size, location, and intraocular margins. Epicorneal amniotic membrane grafts protected the cornea and decreased pain during total anterior segment 103-Pd ophthalmic plaque brachytherapy. RESULTS/UNASSIGNED:Eleven diffuse iris melanomas were American Joint Committee on Cancer 8th edition-classified as T1 (n = 5, 45.5%) and T2 (n = 6, 54.5%). Plaque radiation was completed to a minimum mean tumor dose of 85 Gy (mean dose rate, 58.1 cGy/h). Ultrasonographic tumor thickness regression was 41% (follow up mean 58.7, median 50, range: 8-139 months). Despite 100% local control and 100% eye retention, one patient (9.1%) developed metastatic disease. Four eyes required cataract surgery. There was no corneal stem-cell deficiency, corneal opacity, radiation maculopathy, or optic neuropathy. While visual acuity prior to treatment was 20/40 or better in 10 (91%), 9 were 20/40 or better (81.9%) at last follow-up. Four (36%) had glaucoma prior to treatment and three eyes developed glaucoma after treatment for a total of 63%. CONCLUSION/UNASSIGNED:Pd) plaque brachytherapy resulted in local control, good visual acuity, eye and life preservation in the treatment of multifocal iris melanoma.

BACKGROUNDS/AIMS/OBJECTIVE:To date, this is the largest cohort study on extranodal marginal zone B-cell lymphoma (EMZL) of the ocular adnexa (OA). The aim of the study was to characterise the clinical features of OA-EMZL. METHODS:A retrospective multicentre study involving seven international eye cancer centres. Data were collected from 1 January 1980 through 31 December 2017. A total of 689 patients with OA-EMZL were included. RESULTS:The median follow-up time was 42 months. The median age was 62 years (range, 8-100 years), and 55 % (378/689 patients) of patients were women. The majority of patients (82%, 558/680 patients) were diagnosed with primary OA-EMZL with Ann Arbor stage IE (90%, 485/541 patients) and American Joint Committee on Cancer stage T2 (61%, 340/557 patients) at the time of diagnosis. The orbit (66%, 452/689 patients) and the conjunctiva (37%, 255/689 patients) were the most frequently involved anatomical structures. The 5-year, 10-year and 20-year disease-specific survival (DSS) were 96%, 91% and 90%, respectively. Stage IE patients treated with external beam radiation therapy (EBRT) as monotherapy (10-year DSS, 95%) were found to have a better DSS than stage IE patients treated with chemotherapy (10-year DSS, 86%). Stage IIIE/IVE patients treated with chemotherapy and rituximab had a better DSS (10-year DSS, 96%) than stage IIIE/IVE patients treated with chemotherapy without rituximab (10-year DSS, 63%). CONCLUSIONS AND RELEVANCE/CONCLUSIONS:EMZL is a slow-growing tumour with an excellent long-term survival. Low-dose EBRT as monotherapy should be considered in localised OA-EMZL. Rituximab-based chemotherapy should be chosen in those patients with disseminated disease.

Importance/UNASSIGNED:Eye cancer staging systems used for standardizing patient care and research need to be validated. Objective/UNASSIGNED:To evaluate the accuracy of the eighth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual in estimating metastatis and mortality rates of conjunctival melanoma. Design, Setting, and Participants/UNASSIGNED:This international, multicenter, registry-based case series pooled data from 10 ophthalmic oncology centers from 9 countries on 4 continents. A total of 288 patients diagnosed with conjunctival melanoma from January 1, 2001, to December 31, 2013, were studied. Data analysis was performed from July 7, 2018, to September 11, 2018. Interventions/UNASSIGNED:Treatments included excision biopsy, cryotherapy, topical chemotherapy, radiation therapy, enucleation, and exenteration. Main Outcomes and Measures/UNASSIGNED:Metastasis rates and 5-year and 10-year Kaplan-Meier mortality rates according to the clinical T categories and subcategories of the eighth edition of the AJCC Cancer Staging Manual. Results/UNASSIGNED:A total of 288 eyes from 288 patients (mean [SD] age, 59.7 [16.8] years; 147 [51.0%] male) with conjunctival melanoma were studied. Clinical primary tumors (cT) were staged at presentation as cT1 in 218 patients (75.7%), cT2 in 34 (11.8%), cT3 in 15 (5.2%), and cTx in 21 (7.3%). There were no T4 tumors. Pathological T categories (pT) were pTis in 43 patients (14.9%), pT1 in 169 (58.7%), pT2 in 33 (11.5%), pT3 in 12 (4.2%), and pTx in 31 (10.8%). Metastasis at presentation was seen in 5 patients (1.7%). Metastasis during follow-up developed in 24 patients (8.5%) after a median time of 4.3 years (interquartile range, 2.9-6.0 years). Of the 288 patients, 29 died (melanoma-related mortality, 10.1%) at a median time of 5.3 years (interquartile range, 1.8-7.0 years). The cumulative rates of mortality among patients with cT1 tumors were 0% at 1 year, 2.5% (95% CI, 0.7%-7.7%) at 5 years, and 15.2% (95% CI, 8.1%-27.4%) at 10 years of follow-up; among patients with cT2 tumors, 0% at 1 year, 28.6% (95% CI, 12.9%-58.4%) at 5 years, and 43.6% (95% CI, 19.6%-77.9%) at 10 years of follow-up; and among patients with cT3 tumors, 21.1% (95% CI, 8.1%-52.7%) at 1 year of follow-up and 31.6% (95% CI, 13.5%-64.9%) at 5 years of follow-up. Patients with cT2 and cT3 tumors had a significantly higher cumulative mortality rate compared with those presenting with cT1 tumors (log-rank P < .001). Patients with ulcerated melanomas had significantly higher risk of mortality (hazard ratio, 7.58; 95% CI, 1.02-56.32; P = .04). Conclusions and Relevance/UNASSIGNED:This multicenter, international, collaborative study yielded evidence that the conjunctival melanoma staging system in the eighth edition of the AJCC Cancer Staging Manual can be used to accurately estimate metastasis and mortality rates. These findings appear to support the use of AJCC staging as a tool for patient care and research.

Relatively little is known about the genetic aberrations of conjunctival melanomas (CoM) and their correlation with clinical and histomorphological features as well as prognosis. The aim of this large collaborative multicenter study was to determine potential key biomarkers for metastatic risk and any druggable targets for high metastatic risk CoM. Using Affymetrix single nucleotide polymorphism genotyping arrays on 59 CoM, we detected frequent amplifications on chromosome (chr) 6p and deletions on 7q, and characterized mutation-specific copy number alterations. Deletions on chr 10q11.21-26.2, a region harboring the tumor suppressor genes, PDCD4, SUFU, NEURL1, PTEN, RASSF4, DMBT1, and C10orf90 and C10orf99, significantly correlated with metastasis (Fisher's exact, p ≤ 0.04), lymphatic invasion (Fisher's exact, p ≤ 0.02), increasing tumor thickness (Mann-Whitney, p ≤ 0.02), and BRAF mutation (Fisher's exact, p ≤ 0.05). This enhanced insight into CoM biology is a step toward identifying patients at risk of metastasis and potential therapeutic targets for systemic disease.

PURPOSE:/UNASSIGNED:To report that metastatic choroidal melanoma (systemic and intraocular) can respond to systemic immunotherapy. METHODS:/UNASSIGNED:In 2010, a 64-year-old woman with a choroidal melanoma was treated with palladium-103 plaque brachytherapy. Developing 2.5 years later, radiation maculopathy was suppressed with periodic intravitreal anti-vascular endothelial growth factor injections for five additional years. Development of a new, discrete choroidal melanoma in the same eye prompted radiographic imaging of the orbits, abdomen/pelvis, and chest. Multi-organ metastasis in the eye, the liver, and nodes was treated with systemic combination immunotherapy with ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) intravenous every 3 weeks for four cycles followed by nivolumab (3 mg/kg) intravenous every 4 weeks as maintenance. Subsequent ophthalmic and systemic surveillance were performed. RESULTS:/UNASSIGNED:All sites of metastases were found to regress on systemic immunotherapy. For example, ophthalmic ultrasound imaging revealed that the intraocular metastasis was reduced from 6.6 to 1.5 mm in thickness. Synchronously, serial radiographic imaging revealed progressive shrinkage and disappearance of hepatic and nodal metastasis (except for one gastrohepatic node). However, combination stereotactic body radiation therapy (30 Gy) with nivolumab maintenance was found to induce a significant reduction in this remaining node. Continued periodic intraocular anti-vascular endothelial growth factor therapy has suppressed her radiation maculopathy resulting in 20/25 vision, now 8 ½ years after initial plaque therapy. CONCLUSION:/UNASSIGNED:This case shows that metastatic choroidal melanoma can present in the same eye as the primary tumor. It also shows that systemic immunotherapy can control both ocular and systemic metastases as well as prolong both life and sight.

PURPOSE: To describe a patient with a presumed retinal pigment epithelium (RPE) tumor originating from unilateral RPE dysgenesis. METHODS: Case report. RESULTS: A 30-year-old woman with an unremarkable medical and ocular history was referred for an evaluation of progressive central metamorphopsia in her left eye. Visual acuity was 20/20 in her right eye and 20/25 in her left eye. Funduscopic examination of the left eye revealed an elevated mass within an area of unilateral RPE dysgenesis showing hyperpigmentation and hypopigmentation with scalloped margins. Fundus autofluorescence of the lesion showed a marginal pattern of hyperautofluorescence and hypoautofluorescence that was the inverse of the fluorescein angiography pattern. A well-circumscribed subretinal mass appeared to originate from the unilateral RPE dysgenesis lesion with surrounding subretinal fluid extending beneath the fovea. Ultrasonography showed medium-to-high reflectivity of the mass with no evidence of choroidal involvement. Optical coherence tomography showed a subretinal hyporeflective mass consistent with a tumor of RPE origin. The tumor appeared to invade the overlying retina where fluorescein angiography showed hyperfluorescent leakage and OCT angiography showed retinal vascular deformation. Indocyanine green angiography showed no evidence of choroidal neovascularization. Findings in the right fundus were normal. Over a 5-month follow-up, intravitreal anti-vascular endothelial growth factor therapy induced a resolution of subretinal exudation and modest reduction in tumor thickness. CONCLUSION: To the authors' knowledge, this is the first report of a presumed RPE tumor described as originating from unilateral RPE dysgenesis. Multimodal imaging was crucial for establishing the diagnosis and showing that the patient's visual symptoms were a product of the exudation produced by the tumor's invasion of the retina.

BACKGROUND:Herein, we describe the use of systemic immunotherapy for both locally advanced and metastatic conjunctival melanoma. Current treatments for advanced conjunctival melanoma typically result in poor local control leading to disfiguring orbital exenteration surgery. Locoregional spread of conjunctival malignant melanoma typically requires pre-auricular and cervical lymph node dissection with post-operative adjuvant radiation therapy. In addition, classic systemic chemotherapy has been unsuccessful in the treatment of metastatic disease. METHODS:This is a retrospectively analyzed clinical case series of 5 patients with biopsy proven conjunctival melanoma who were treated with checkpoint inhibition therapy. Of these, 3 patients were treated for residual ocular disease present after failing multiple local therapies and refusing orbital exenteration surgery and two (with local ocular control) for metastatic conjunctival melanoma. Both those with locally advanced disease and patients with metastatic disease received an anti-PD1 agent in combination with another immunotherapeutic agent. All 5 were given multiple cycles of systemic anti-PD1 therapy, 1 was initially treated with single agent ipilimumab (3 mg/kg) prior to approval of anti-PD1 agents and two received interferon eye drops. As part of each ophthalmic examination, photographs of all conjunctival and eyelid surfaces were obtained. Systemic evaluations involved initial staging scans as well as periodic re-imaging. RESULTS:All cases have shown responses. Of the 2 complete responses, 1 was a patient with systemic disease. No patients developed ocular toxicity or loss of vision. However, systemic adverse effects included adrenal insufficiency, Grade-III colitis, Grade-II dermatitis, Grade-II hepatotoxicity and Grade-II pneumonitis. CONCLUSIONS:This report suggests that systemic immunotherapy with or without topical interferon is effective in treatment of malignant melanoma of the conjunctiva. Therefore, it can be considered for patients with advanced local conjunctival melanoma, those who refuse orbital exenteration surgery and those with systemic metastasis.

A black teenager presented with long-standing vision loss in his right eye. Clinical exam revealed increased conjunctival vascularity and total exudative retinal detachment of the right eye. Ultrasound imaging demonstrated a choroidal mass with moderate-to-high reflectivity consistent with a choroidal hemangioma. A closer external examination demonstrated a subtle reddish hue of the eyelids and cheek, consistent with a nevus flammeus. MRI of the brain revealed a T2 enhancing vascular mass. Collectively, these findings were consistent with Sturge-Weber Syndrome. This case highlights the need for a high degree of suspicion for Sturge-Weber Syndrome in dark-skinned individuals that can otherwise mask the nevus flammeus. Physical exam findings and radiographic evidence can be used to guide the diagnosis. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:183-186.].

PURPOSE/OBJECTIVE:To investigate and characterize the clinical features of subtype-specific orbital lymphoma. DESIGN/METHODS:Retrospective, interventional case series. METHODS:The study included 7 international eye cancer centers. Patient data were collected from January 1, 1980 through December 31, 2017. A total of 797 patients with a histologically verified orbital lymphoma were included. The primary end points were overall survival, disease-specific survival and progression-free survival. RESULTS:The median age was 64 years, and 51% of patients were male. The majority of lymphomas were of B-cell origin (98%, n = 779). Extranodal marginal zone B-cell lymphoma (EMZL) was the most frequent subtype (57%, n = 452), followed by diffuse large B-cell lymphoma (DLBCL) (15%, n = 118), follicular lymphoma (FL) (11%, n = 91), and mantle cell lymphoma (MCL) (8%, n = 66). Localized Ann Arbor stage IE EMZL and FL were frequently treated with external beam radiation therapy. DLBCL, MCL and disseminated EMZL and FL were primarily treated with chemotherapy. EMZL and FL patients had a markedly better prognosis (10-year disease-specific survival of 92% and 71%, respectively) than DLBCL and MCL patients (10-year disease-specific survival of 41% and 32%, respectively). CONCLUSIONS:and Relevance: Four lymphoma subtypes were primarily found in patients with orbital lymphoma: EMZL, DLBCL, FL, and MCL. The histological subtype was found to be the main predictor for outcome, with EMZL and FL patients having a markedly better prognosis than DLBCL and MCL.

Purpose/UNASSIGNED:The purpose of this study is to describe the clinical characteristics, multimodality imaging findings, and clinical course of iris varices. Methods/UNASSIGNED:Retrospective, noncomparative, observational case series of 28 eyes of 26 patients with iris varices, diagnosed between 2007 and 2017, has been used. Results/UNASSIGNED:The mean (±SD) age was 58.3 ± 12.5 years (median 57.5, range 37-81). Patients were 57.7% male and 27% hypertensive. Varices were bilateral in two patients. The mean and median visual acuities were both 20/20 (range 20/16-20/40). Intraocular pressures were 16 mmHg (10-23 mmHg). Secondary glaucoma did not occur. The inferotemporal iris quadrant was affected in 75%. A single varix was seen in 64% and 36% appeared multiple. Varix orientation was radial in 57% and circumferential in 21%. Combined radial and circumferential varix orientation was noted in 18%. One had independent radial and circumferential varices in separate quadrants. A single episcleral sentinel blood vessel directed to the varix was present in 36%. Ultrasound biomicroscopy (UBM) showed a slightly increased mean iris thickness of 0.8 mm and multiple echolucent iris stromal vascular channels. Iris angiography showed no leakage of dye. Managed by observation over a mean follow-up of 37.7 months (range, 3-129), 96.4% eyes were stable and one (3.6%) regressed. No corectopia, ectropion uveae, hyphema, or metachronous anterior segment benign or malignant tumors occurred. Conclusion/UNASSIGNED:Iris varix is primarily located in the inferotemporal quadrant and not associated with dysmorphic pupillary findings, progression, secondary glaucoma, or malignancy. Iris varices were benign vasculopathies with no associated ocular or vision-related morbidity.