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PURPOSE: To evaluate cumulative incidence of metastasis at specific timepoints after treatment of uveal melanoma in a large cohort of patients and to provide comparison of conditional outcomes in the youngest and oldest cohorts (extremes of age). METHODS: Retrospective analysis of 8091 consecutive patients with uveal melanoma at a single center over a 51-year period. The patients were categorized by age at presentation (0-29 years [n = 348, 4%], 30-59 years [n = 3859, 48%], 60-79 years [n = 3425, 42%], 80 to 99 years [n = 459, 6%]) and evaluated for nonconditional (from presentation date) and conditional (from specific timepoints after presentation) cumulative incidence of metastasis at five, 10, 20, and 30 years. RESULTS: For the entire population of 8091 patients, five-year/10-year/20-year/30-year nonconditional cumulative incidence of metastasis was 15%/23%/32%/36%, and the conditional incidence improved to 6%/15%/25%/30% for patients who did not develop metastasis in the first three years. For the extremes of age (0-29 years and 80-99 years), the nonconditional cumulative incidence of metastasis revealed the younger cohort with superior outcomes at 8%/15%/19%/27% and 21%/29%/29%/29%, respectively (P < 0.001). The conditional incidence (at one-year and two-year timepoints with metastasis-free survival) showed persistent superior younger cohort survival (P < 0.001, P = 0.001), but no further benefit for patients with three-year metastasis-free survival at 4%/12%/16%/24% and 7%/18%/18%/18%, respectively (P = 0.09). CONCLUSIONS: Non-conditional metastasis-free survival analysis for patients with uveal melanoma revealed the youngest cohort to have significantly better survival than the oldest cohort, and this persisted into one-year and two-year conditional metastasis-free survival but diminished at the three-year conditional timepoint.

Background: The first line definitive treatment for early-stage indolent B-cell lymphoma is radiation therapy (RT). Due to the sensitivity of orbital structures to radiation, ultra-low-dose RT (4 Gy in 2 fractions, "boom-boom") has and been utilized as an attractive option for orbital lymphoma. In this retrospective study, we evaluated the outcome and toxicity of "boom-boom" RT for indolent orbital lymphoma with an emphasis on ophthalmologic toxicity. Methods: This is a retrospective case series with 17 patients with orbital lymphoma who received boom-boom RT at a single tertiary referral center between January 2017 and June 2022. Medical records, imaging and radiation treatment plans were reviewed. Endpoints included response rate, progression, and ocular toxicity per oncologist and ophthalmology reports. Results: A total of 17 patients (12 female and 5 male) with 19 indolent orbital lymphomas were included. Median follow-up was 39 months. Complete, partial, and stable response was achieved in 65%, 24%, and 12% of patients, respectively. Only 1 patient developed local recurrent 47 month after radiation treatment, and was successfully salvaged with standard dose radiation (24 Gy). Five-year distant progression rate is 18%. Oncologist-reported Common Terminology Criteria for Adverse Events (CTCAE) toxicity rates were 6% grade 1 and 0% grade 2+. Ophthalmologist reported 33.3% new post-RT toxicities including dry eye, cataract, and chorioretinal atrophy. There is no significant vision acuity change after RT. Conclusions: "Boom-Boom" RT (4 Gy in 2 fractions) provides excellent control for indolent orbital lymphoma. While minimal toxicity was documented by radiation oncologists, higher rates were noted by ophthalmologists, highlighting the radiosensitivity of orbital structures and potentially underreported ocular toxicity in "boom-boom" and standard regimens. Further prospective randomized studies are needed to better define the outcome and toxicity of ultra-low-dose (4

PURPOSE: To characterize demographic, clinical, and histopathologic features of ocular adnexal lymphoma (OAL) at a single institution. METHODS: Retrospective review of all patients with pathologic diagnosis of OAL between 2015 and 2020. RESULTS: There were 133 patients with OAL, with a median age of 65 years (range 23-97) and a slight female predominance (male: female = 1:1.46), (n = 79, 59%). The majority of tumors were non-Hodgkin B-cell lymphomas (n = 131, 99%), most frequently Extranodal Marginal Zone B-Cell Lymphoma (EMZL, n = 93, 70%), followed by follicular lymphoma (n = 21, 16%), chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 7, 5%), diffuse large B-cell lymphoma (n = 5, 4%), and mantle cell lymphoma (n = 5, 4%). The most frequently involved sites included the orbit (n = 85, 64%) and conjunctiva (n = 43, 32%). Information was available on oncologic staging in 78 (59%), treatment in 82 (62%), and follow-up in 75 (56%) patients. By the Ann-Arbor classification system, patients were classified as IE (54/78, 69%), IIE (9/78, 12%), IIIE (6/78, 8%), and IVE (9/78, 12%). The most common treatments included external beam radiotherapy (standard and ultra-low-dose) (48/82, 59%), biologics (22/82, 27%), and surgical excision with cryotherapy (14/82, 17%) (some patients had >1 therapy). Median follow-up time was 24 months (range 0-221 months). Recurrence was observed in 13% (10/75) with a median time to recurrence of 60 months (95% confidence interval 47-73 months). Excision with cryotherapy as a sole treatment modality was associated with earlier recurrence (P = 0.003). CONCLUSION: In this largest single-center study of OAL, we found that most OAL were Ann-Arbor Stage IE EMZL, occurring in older patients with a female predominance. Early recurrence was noted in tumors treated with excision and cryotherapy alone.

Purpose: To discuss the evolution of noninvasive diagnostic methods in the identification of choroidal nevus and determination of risk factors for malignant transformation as well as introduce the novel role that artificial intelligence (AI) can play in the diagnostic process. Methods: White paper. Results: Longstanding diagnostic methods to stratify benign choroidal nevus from choroidal melanoma and to further determine the risk for nevus transformation into melanoma have been dependent on recognition of key clinical features by ophthalmic examination. These risk factors have been derived from multiple large cohort research studies over the past several decades and have garnered widespread use throughout the world. More recent publications have applied ocular diagnostic testing (fundus photog-raphy, ultrasound examination, autofluorescence, and optical coherence tomography) to identify risk factors for the malignant transformation of choroidal nevus based on multimodal imaging features. The widespread usage of ophthalmic imaging systems to identify and follow choroidal nevus, in conjunction with the characterization of malignant transformation risk factors via diagnostic imaging, presents a novel path to apply AI. Conclusions: AI applied to existing ophthalmic imaging systems could be used for both identification of choroidal nevus and as a tool to aid in earlier detection of transformation to malignant melanoma. Translational Relevance: Advances in AI models applied to ophthalmic imaging systems have the potential to improve patient care, because earlier detection and treatment of melanoma has been proven to improve long-term clinical outcomes.

Purpose: To understand the prognostic value of The Cancer Genome Atlas (TCGA) for uveal melanoma metastasis, using a simplified 4-category classification, based on tumor DNA. Methods: A retrospective cohort study of 1001 eyes with uveal melanoma at a single center, categorized according to TCGA as Group A, B, C, or D (by fine-needle aspiration biopsy for DNA analysis), and treated with standard methods, was studied for melanoma-related metastasis at 5 and 10 years. Results: Of 1001 eyes with uveal melanoma, the TCGA categories included Group A (n = 486, 49%), B (n = 141, 14%), C (n = 260, 26%), and D (n = 114, 11%). By comparison, increasing category (A vs. B vs. C vs. D) was associated with features of older age at presentation (56.8 vs. 52.8 vs. 61.1 vs. 63.5 years, P < 0.001), less often visual acuity of 20/20-20/50 (80% vs. 67% vs. 70% vs. 65%, P = 0.001), tumor location further from the optic disc (P < 0.001) and foveola (P < 0.001), and greater median tumor basal diameter (10.0 vs. 13.0 vs. 14.0 vs. 16.0 mm, P < 0.001) and tumor thickness (3.5 vs. 5.2 vs. 6.0 vs. 7.1 mm, P < 0.001). The Kaplan-Meier (5-year/10-year) rate of metastasis was 4%/6% for Group A, 12%/20% for Group B, 33%/49% for Group C, and 60%/not available for Group D. Conclusion: A simplified 4-category classification of uveal melanoma using TCGA, based on tumor DNA, is highly predictive of risk for metastatic disease.

Purpose: To report clinical features, pathology characteristics, and treatment outcomes of five patients with Rosai-Dorfman disease (RDD). Methods: A retrospective case series of patients with RDD from the Ocular Oncology Service of Wills Eye Hospital between 1974 and 2018. Results: There were six eyes of five patients (3 males, 2 females) with ophthalmic manifestations of RDD. The mean age at the initial presentation was 33 years (median 35, range 10-52 years). Before referral, the tumor was initially suspected to be lymphoma (n = 3), idiopathic orbital inflammation (n = 2), or pterygium (n = 1). The disease was unilateral (n = 4) or bilateral (n = 1). The mean duration of symptoms was 9 months (median 8, range 5-24 months). The disease produced nodules in the conjunctiva (n = 4) or orbit (n = 2). Two patients with conjunctival involvement had corneal involvement. One patient with bilateral conjunctiva lesions demonstrated bilateral orbital involvement and bilateral anterior uveitis. The mean tumor basal dimension was 13 mm (median 9, range 6-27 mm) for conjunctiva lesions and 37 mm (median 37, range 34-40 mm) for orbital lesions. The main symptom (per patient) included proptosis (n = 2), palpable mass (n = 1), and foreign body sensation (n = 2). No patient experienced pain or tenderness. Palpable, nontender lymphadenopathy was detectable in two patients in the cervical and inguinal lymph nodes. Systemic involvement with paranasal sinusitis and mediastinal/pulmonary lymphadenopathy occurred in two patients, both with orbital involvement. Surgical resection was performed for all patients. At a mean follow-up of 31 months (median 12, range, 10-76 months) after the surgery, tumor control was achieved in all six eyes without local recurrence. Conclusion: In this series of six eyes with RDD, patients with orbital and/or intraocular disease were more likely to demonstrate lymphadenopathy and systemic involvement, while those with unilateral perilimbal conjunctival tumors

A 60-year-old Caucasian female was referred for biopsy-proven amelanotic orbito-conjunctival melanoma. Map biopsies revealed residual invasive melanoma on the deep tarsal margin at the site of previous surgery. Repeat excisions were required after recurrence was detected following 3 months and 7 months. Positron emission tomography scan detected liver metastasis and additional orbito-conjunctival melanoma recurrence. Biomarker testing showed NRAS mutation without BRAF or c-KIT mutations and without PD-L1 expression. Systemic checkpoint inhibitor therapy was initiated with regression of both the orbito-conjunctival melanoma and liver metastasis. Invasive, non resectable orbito-conjunctival melanoma with liver metastasis can demonstrate a response to systemic checkpoint inhibitor therapy.

Two asymptomatic elderly women who underwent cataract extraction 7 or more years previously and with intraocular lens placement presented with a linear bead-like white multinodular mass in the inferior angle simulating iris metastasis versus large inflammatory precipitates. There was no iris infiltration. In the first case, the posterior lens capsule was intact and there was no evidence of gelatinous vitreous in the anterior chamber, whereas in the second case, the capsule was open and there was gelatinous vitreous prolapse. In both cases, there was asteroid hyalosis in the vitreous. Both patients were diagnosed with prolapsed vitreous asteroid hyalosis into the anterior chamber and managed with observation. Vitreous asteroid hyalosis can prolapse into the anterior chamber of pseudophakic elderly patients with or without capsular opening and can simulate an intraocular tumor.

PURPOSE/BACKGROUND: To report the clinical and radiographic features and treatment outcome of neuroendocrine tumor (carcinoid) metastasis to the orbit. MATERIALS AND METHODS: Retrospective chart review of four cases. RESULTS: Mean patient age at the time of diagnosis of the primary neuroendocrine tumor and orbital metastasis was 58 and 66 years, respectively, with a mean duration of 8 years between diagnosis of primary tumor and orbital metastasis. Primary neuroendocrine tumor sites were gastrointestinal tract (n = 2), lung (n = 1), and testicle (n = 1). The most common presenting symptom was diplopia (three cases). Magnetic resonance imaging revealed orbital tumor in all cases. Octreotide scan was positive in one case. Treatment was tumor excision in three cases followed by external beam radiotherapy in two cases and one patient was followed without treatment. Tumor cells showed immunoreactivity to chromogranin, synaptophysin, and neuron-specific enolase in all cases. Mean follow-up after orbital tumor diagnosis was 39 months. Three patients had known systemic extraorbital metastasis before orbital involvement (mean interval of 5.9 years) and one case had immediately after development of orbital metastasis. One patient had multiple recurrences of orbital metastasis and eventually underwent exenteration. Two patients died of disseminated metastasis between 2 and 3 years after diagnosis of orbital metastasis. CONCLUSION: All four patients with orbital metastasis from neuroendocine tumor had evidence of systemic extraorbital metastasis. Aggressive metastatic neuroendocine tumors of orbit can lead to local recurrence even after surgical excision and radiation. Imaging tests were helpful in allowing early diagnosis and for monitoring after treatment.