High-Dose Intravitreal Topotecan for Recurrent Retinoblastoma, Subretinal Seeds, and Vitreous Seeds in 13 Consecutive Cases.

PURPOSE: To evaluate the efficacy and safety of high-dose intravitreal topotecan (IvitTopo) for recurrent retinoblastoma. METHODS: There were 13 patients with recurrent retinoblastoma treated with high-dose IvitTopo (90 micrograms (µg)/0.18cc-100 µg/0.20cc). The primary outcome measures were tumor control, globe salvage, and treatment complications. RESULTS: At date first seen (DFS), median patient age was 9 months, and the affected eye was classified as International Classification of Retinoblastoma (ICRB) Group B (n=2, 15%), Group C (n=3, 23%), or Group D (n=8, 62%) retinoblastoma with initial therapy of intravenous chemotherapy (n=9, 69%) or intra-arterial chemotherapy (n=4, 31%). Recurrent tumor was detected at median 10 months as solid tumor (n=3), subretinal seeds (n=10), and/or vitreous seeds (n=3) and high-dose IvitTopo (median 3 injections) delivered at monthly intervals. Additional chemotherapy was delivered by intra-arterial (n=8, 62%) or intravenous (n=1, 8%) routes, and 1 eye received additional cryotherapy (n=1, 8%). In 3 cases (23%) there was no additional therapy. At mean follow-up of 9 months, regression of solid tumor, subretinal seeds and vitreous seeds was achieved in 12 cases (92%), and globe salvage was achieved in all cases (n=13, 100%). Of those 3 eyes treated with high-dose IvitTopo alone, tumor control was initially achieved in all cases (100%), but one case that previously demonstrated massive vitreous seeding showed late recurrence of a solitary vitreous seed at 8 months. There were no complications. CONCLUSIONS: High-dose IvitTopo is an effective and safe therapy for recurrent retinoblastoma, in conjunction with other therapy, and possibly as a stand-alone therapy.

Metastasis-free survival of uveal melanoma by tumour size category based on The Cancer Genome Atlas (TCGA) classification in 1001 cases.

BACKGROUND: Uveal melanoma (UM) can be classified by tumour size category and by The Cancer Genome Atlas (TCGA) groups (cytogenetic-based, 4-category prognostic classification into Groups A-D). This study was conducted to assess impact on metastasis-free survival (MFS) in UM by tumour size category based on correlation with TCGA classification. METHODS: Retrospective analysis of 1001 cases categorised as small (0.0-3.0 mm), medium (3.1-8.0 mm) and large (≥8.1 mm), grouped by TCGA classification. RESULTS: Of 1001 cases, TCGA Groups (A/B/C/D) included small (n = 270, 75%/11%/13%/1%), medium (n = 503, 46%/14%/27%/13%) and large (n = 228, 23%/19%/38%/20%) UM. The 5-and 10-year Kaplan-Meier MFS for small UM revealed Group A (98%, 98%), Group B (100%, 100%), Group C (86%, NA) and Group D (100%, NA). For medium UM, the values dropped with Group A (95%, 93%), Group B (90%, 90%), Group C (68%, 38%), and Group D (44%, NA). For large UM, the values dropped further with Group A (94%, 86%), Group B (85%, NA), Group C (40%, 28%), and Group D (23%, NA). Additionally, a comparison (small vs. medium vs. large tumour size category) revealed TCGA low-risk grouping (Groups A or B) in 86% vs. 60% vs. 58% cases with UM. CONCLUSION: By tumour size category, favourable cytogenetics (Groups A or B) is found in 86% of small tumours, 60% of medium tumours, and 58% of large tumours. The MFS at 10 years for favourable cytogenetics was 98% for small tumours, 92% for medium tumours, and 54% for large tumours. Tumour size category can serve as a surrogate for TCGA.

Conjunctival Melanoma in 430 Cases: Comparative Analysis of the Impact of Orbital Invasion on Tumor Recurrence, Metastasis, and Death.

PURPOSE: To compare the clinical features at presentation and treatment outcomes of conjunctival melanoma by absence/presence of orbital invasion. METHODS: A retrospective review of patients with conjunctival melanoma managed at a single tertiary referral center from April 18, 1974, to September 9, 2019. RESULTS: Of 430 patients with conjunctival melanoma, 21 (5%) had orbital invasion at presentation. A comparison between the 2 groups (orbital invasion absent vs. present) revealed that the orbital invasion group had a higher frequency of prior eyelid incisional biopsy (5% vs. 24%, P = 0.006), greater tumor basal diameter (12.2 vs. 17.3, P = 0.009), greater tumor thickness (2.4 vs. 7.0, P < 0.001), more quadrants involved (1.8 vs. 2.5, P = 0.002), and more clock hours involved (4.4 vs. 5.8, P = 0.037). In addition, those with orbital invasion were more likely to undergo exenteration as primary treatment (1% vs. 24%, P < 0.001). Multivariate relative risk regression analysis revealed that variables predictive of orbital invasion included greater tumor thickness (P < 0.001) and greater involvement of the fornix (P = 0.031) and tarsus (P = 0.033). Outcomes revealed orbital invasion group with greater 5-year/10-year distant metastatic rate (16%/21% vs. 63%/63%, P = 0.005), and greater melanoma-related death rate (7%/13% vs. 38%/53%, P = 0.001). CONCLUSIONS: Conjunctival melanoma with orbital invasion at presentation demonstrate larger, more extensive tumors involving the fornix or tarsus, and with greater rate of melanoma-related metastasis and death.

Mutational Landscape and Outcomes of Conjunctival Melanoma in 101 Patients.

PURPOSE: To evaluate targetable mutations and molecular genetic pathways in conjunctival melanoma with clinical correlation. DESIGN: Observational case series. PARTICIPANTS: Patients with conjunctival melanoma. MAIN OUTCOME MEASURES: Mutational profile of the tumor by next-generation sequencing (NGS), alternative lengthening of telomeres (ALT) by fluorescence in situ hybridization (FISH), and ATRX immunohistochemistry. Outcomes at 2 years and 5 years of tumor-related metastasis and death were recorded. RESULTS: Of the 101 patients, mean age at presentation was 60 years, 52% were male, and 88% were White. The NGS panels initially targeted BRAF only (n = 6, 6%), BRAF/NRAS (n = 17, 17%), and BRAF/NRAS/NF1 (n = 10, 10%). Sixty-eight tumors were tested with the expanded 592-gene panel. Next-generation sequencing identified high-frequency mutations in NF1 (29/74, 39%), BRAF (31/101, 31%), NRAS (25/95, 26%), and ATRX (17/68, 25%). Of those with an ATRX mutation, 12 (71%) had an additional NF1 mutation. A subset analysis of 21 melanomas showed that the ATRX mutation was associated with loss of ATRX protein expression and ALT. Loss of ATRX expression and ALT were present in both intraepithelial and invasive tumors, suggesting that an ATRX mutation is an early event in conjunctival melanoma progression. The NF1 and ATRX mutations were associated with tarsal (vs. nontarsal) tumors (NF1: 28% vs. 9%, P = 0.035, ATRX: 41% vs. 14%, P = 0.021) and orbital (vs. nonorbital) tumors (ATRX: 24% vs. 2%, P = 0.007). ATRXMUT (vs. ATRXWT) tumors were associated with a lower 2-year rate of metastasis (0% vs. 24%, P = 0.005). NRASMUT (vs. NRASWT) tumors were associated with a greater 2-year rate of metastasis (28% vs. 14%, P = 0.07) and death (16% vs. 4%, P = 0.04), with a 5-fold increased risk of death (relative risk, 5.45 [95% confidence interval, 1.11-26.71], P = 0.039). CONCLUSIONS: This study confirms the high frequency of previously documented BRAF and NRAS mutations and recently reported ATRX and NF1 mutations in conjunctival melanoma. An NRAS mutation implied increased risk for metastasis and death. Loss of ATRX and ALT may be early events in conjunctival melanoma development.

Usefulness of PAX8 Immunohistochemistry in Adult Intraocular Tumor Diagnosis.

PURPOSE: To evaluate the distribution of the PAX8 transcription factor protein in ocular tissues and to investigate if immunohistochemical stains for this biomarker are useful in the diagnosis of intraocular tumors. DESIGN: Observational case series. PARTICIPANTS: Excision and cytologic analysis specimens of 6 ciliary body epithelial neoplasms, 2 iris epithelial neoplasms, 3 retinal pigment epithelial neoplasms, 3 intraocular medulloepitheliomas, 15 uveal melanomas, and 5 uveal melanocytomas. METHODS: Hematoxylin-eosin and PAX8 immunohistochemical stains were performed on all specimens. In appropriate cases, bleached preparations and other immunohistochemical stains, including AE1/AE3 cytokeratin, Lin28A, and CD45, were performed. MAIN OUTCOME MEASURES: Distribution of PAX8 expression in normal and neoplastic tissue. RESULTS: Strong nuclear PAX8 expression was observed in the normal corneal epithelium, iris sphincter pupillae muscle, iris pigment epithelium and dilator muscle complex, nonpigmented and pigmented epithelia of the ciliary body, lens epithelium, and a subset of retinal neurons. The normal retinal pigment epithelium and uveal melanocytes did not stain for PAX8. The ciliary body epithelial and neuroepithelial tumors (adenoma, adenocarcinoma, and medulloepithelioma) showed uniform strong nuclear PAX8 immunoreactivity. All melanocytic tumors (iris melanoma, ciliary-choroidal melanoma, and melanocytoma) and retinal pigment epithelial neoplasms showed negative results for PAX8. A subset of tumor-associated lymphocytes, most prominent in uveal melanoma, showed positive results for PAX8. The uniformity of the PAX8 staining was superior to the variable cytokeratin staining in the ciliary epithelial neoplasms and the variable Lin28A staining in malignant medulloepithelioma. The veracity of PAX8 staining was equally as robust on cytologic analysis and open-flap biopsy specimens of ciliary epithelial and iris epithelial neoplasms, melanocytoma, and melanoma. CONCLUSIONS: PAX8 has proven to be a very useful diagnostic marker in a select group of adult intraocular tumors, and we highly recommend its inclusion in diagnostic antibody panels of morphologically challenging intraocular neoplasms.

ASSOCIATION OF VITREORETINAL LYMPHOMA WITH SYSTEMIC LYMPHOMA.

PURPOSE: To determine the association between vitreoretinal lymphoma and systemic lymphoma (SL). METHODS: Single-center retrospective review of medical records. RESULTS: Of 95 patients with vitreoretinal lymphoma, 18 (19%) had associated SL (SL group) and 77 (81%) were not associated with SL (no SL group). The most common sites of SL were skin (n = 5), testis (n = 2), liver and breast (n = 2), and others (n = 9). A comparison (SL group vs. [vs.] no SL group) revealed no difference in demographic or ocular findings at initial visit. In the SL group, SL occurred before the onset of ocular symptoms in 14 (78%) patients with mean interval of 86 months (median 61, range 5-286 months) or after ocular symptoms in 4 (22%) patients with mean interval of 19 months (median 12, range 7-44 months). A comparison revealed no difference in overall frequency of pre-existing or eventual central nervous SL (50% vs. 53%, P = 0.99); however, the SL group demonstrated central nervous SL more often after onset of ocular symptoms (78% vs. 17%, P = 0.001). A comparison found no difference in treatment methods, response of vitreoretinal lymphoma to treatment, final visual outcome, or death rate. CONCLUSION: We found 19% of patients with vitreoretinal lymphoma demonstrate related SL, and there was no difference in demographics, clinical features, or response to treatment, compared to those not associated with SL.

SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY FEATURES OF VITREORETINAL LYMPHOMA IN 55 EYES.

PURPOSE: To evaluate spectral domain optical coherence tomography (SD-OCT) features of vitreoretinal lymphoma (VRL). METHODS: Review of records and SD-OCT images of vitreoretinal lymphoma evaluated at Ocular Oncology Service, Wills Eye Hospital between July 1, 2000, and April 1, 2019. RESULTS: There were 55 eyes of 32 patients included. At presentation, SD-OCT features included vitreous opacities (n = 36, 65%), preretinal deposits (n = 7, 13%), intraretinal deposits (n = 8, 15%), subretinal deposits (n = 20, 36%), retinal pigment epithelium abnormalities (n = 35, 64%), and subretinal pigment epithelium deposits (n = 35, 64%). Of 36 eyes with observed tumor progression, comparison (initial visit vs. time of progression) revealed more intraretinal deposits (17% vs. 50%, P = 0.005) at progression. Of 15 eyes with tumor recurrence, comparison (initial visit vs. time of recurrence) revealed more intraretinal deposits (7% vs. 47%, P = 0.04) at recurrence. At last visit, 39 eyes demonstrated tumor regression. By comparison (initial presentation vs. regression), there were less frequent vitreous opacities (67% vs. 0%, P < 0.001), intraretinal deposits (15% vs. 0%, P = 0.03), subretinal deposits (36% vs. 0%, P < 0.001), and subretinal pigment epithelium deposits (69% vs. 21%, P < 0.001) at regression. CONCLUSION: Using SD-OCT in patients with vitreoretinal lymphoma, local tumor regression correlated with a reduction in vitreous opacities, intraretinal deposits, subretinal deposits, and subretinal pigment epithelium deposits. SD-OCT is useful in judging vitreoretinal lymphoma response to therapy.

Lacrimal drainage apparatus melanoma remotely following treatment and resolution of conjunctival melanoma.

Lacrimal drainage apparatus melanoma is a rare entity that may arise primarily or, more commonly, as secondary involvement from melanoma originating elsewhere. Conjunctival melanoma may involve the lacrimal drainage apparatus (LDA) via spread along the canalicular epithelium, separate in situ processes, or direct invasion. Only seven cases exist in the literature where conjunctival melanoma remotely recurred in the LDA. We report three additional patients, two with invasive conjunctival melanoma and one with primary acquired melanosis (PAM) with severe atypia/melanoma in situ, who developed LDA melanoma at 5, 8, and 16 years after initial treatment of conjunctival melanoma. This report confirms the ability of conjunctival melanoma to give rise to spatially and temporally remote LDA melanoma despite adequate local treatment, and reviews the proposed mechanisms and associated characteristics of LDA recurrence in conjunctival melanoma.

Conjunctival 'mucoepidermoid carcinoma' revisited: a revision of terminology, based on morphologic, immunohistochemical and molecular findings of 14 cases, and the 2018 WHO Classification of Tumours of the Eye.

In 2018, the consensus meeting for the WHO Classification of Tumours of the Eye decided that conjunctival mucoepidermoid carcinoma should be reclassified as adenosquamous carcinoma, as this represented a better morphological fit. To examine the applicability of this terminology, we studied the clinical, histopathological, immunohistochemical and molecular pathology of 14 cases that were originally diagnosed as conjunctival mucoepidermoid carcinoma. There were 7 (50%) females and 7 (50%) males. The median age was 64 years. The left eye was affected in 8 and the right eye in 6 patients. In-situ carcinoma was present in 11/14 (79%) cases and comprised in-situ squamous cell carcinoma (SCC) and conjunctival intraepithelial neoplasia with mucinous differentiation (CIN-Muc). Invasive carcinoma was present in 11/14 (79%) cases. Group 1 (1/11 cases, 9%) comprised invasive SCC only. Group 2 (6/11 cases, 55%) comprised SCC with mucinous differentiation, manifesting as scattered intracellular mucin, occasionally together with intercellular mucin, with no evidence of true glandular differentiation. Group 3 (3/11 cases. 27%) comprised true adenosquamous carcinoma. Group 4 (1/11 cases, 9%) comprised pure adenocarcinoma. Thirteen of 14 cases (93%) underwent FISH for MAML2 translocation and none were rearranged. Two cases harboured high-risk HPV (type 16 and 18). The combined findings confirm that all lesions in our study were not mucoepidermoid carcinoma, but represented predominantly SCC with mucinous differentiation and adenosquamous carcinoma. We, therefore, recommend future revision of the WHO classification to include SCC with mucinous differentiation alongside adenosquamous carcinoma.

Focal Scleral Nodule: A New Name for Solitary Idiopathic Choroiditis and Unifocal Helioid Choroiditis.

PURPOSE: To evaluate multimodal imaging findings of solitary idiopathic choroiditis (SIC; also known as unifocal helioid choroiditis) to clarify its origin, anatomic location, and natural course. DESIGN: Multicenter retrospective observational case series. PARTICIPANTS: Sixty-three patients with SIC in 1 eye. METHODS: Demographic and clinical data were collected. Multimodal imaging included color fundus photography, OCT (including swept-source OCT), OCT angiography (OCTA), fundus autofluorescence, fluorescein and indocyanine green angiography, and B-scan ultrasonography. MAIN OUTCOME MEASURES: Standardized grading of imaging features. RESULTS: Mean age at presentation was 56 ± 15 years (range, 12-83 years). Mean follow-up duration in 39 patients was 39 ± 55 months (range, 1 month-25 years). The lesions measured a mean of 2.4 × 2.1 mm in basal diameter, were located inferior (64%) or nasal to the optic disc, and appeared yellow (53%). No systemic associations were found. The lesions all appeared as an elevated subretinal mass, with OCT demonstrating all lesions to be confined to the sclera, not the choroid. On OCT, the deep lesion margin was visible in 12 eyes with a mean lesion thickness of 0.6 mm. Overlying choroidal thinning or absence was seen in 95% (mean choroidal thickness, 28 ± 35 µm). Mild subretinal fluid was observed overlying the lesions in 9 patients (14%). Retinal pigment epithelial disruption and overlying retinal thinning was observed in 56% and 57%, respectively. OCT angiography was performed in 13 eyes and demonstrated associated choroidal and lesional flow voids. Four lesions (6%) were identified at the macula, leading to visual loss in 1 patient. One lesion demonstrated growth and another lesion showed spontaneous resolution. CONCLUSIONS: In this largest series to date, multimodal imaging of SIC demonstrated a scleral location in all patients. The yellow and white clinical appearance may be related to scleral unmasking resulting from atrophy of overlying tissues. Additional associated features included documentation of deep margin on swept-source OCT, trace subretinal fluid in a few patients, and OCTA evidence of lesional flow voids. Because of the scleral location of this lesion in every patient, a new name, focal scleral nodule, is proposed.

UVEAL METASTASIS BASED ON PATIENT AGE IN 1,111 PATIENTS: Comparison of Clinical Features and Outcomes Per Age Category.

PURPOSE: To evaluate clinical features and survival outcomes of uveal metastasis based on patient age. METHODS: Retrospective analysis of all patients with uveal metastasis evaluated on the Ocular Oncology Service, Wills Eye Hospital, Philadelphia, PA, USA between February 1, 1974 and June 1, 2017. The features and outcomes were analyzed based on patient age classified as children (0-20 years), young adults (21-40 years), middle [aged] adults (41-60 years), older adults (61-80 years) and senior adults (81-100 years). RESULTS: There were 1111 consecutive patients, including children (n = 3, <1%), young adults (n = 77, 7%), middle adults (n = 472, 42%), older adults (n = 509, 46%), and senior adults (n = 50, 4%). At uveal metastasis diagnosis, demographics included mean patient age of 60 years, Caucasian race (88%), and female gender (64%). Compared to the largest cohort (older adults), there were significant differences (age group versus [vs.] older adults) in Caucasian race (senior adult 98% vs. 89%, p = 0.042), male sex (young adults: 22% vs. 43%, p < 0.001) (middle adults: 29% vs. 43%, p < 0.001), unilateral tumor (young adult: 70% vs. 86%, p < 0.001) (middle adult: 79% vs. 86%, p = 0.003) (senior adults: 96% vs. 86%, p = 0.045), and cancer origin in breast (young adults: 51% vs. 32%, p = 0.002) (middle adults: 44% vs 32%, p < 0.001), lung (young adults: 14% vs. 30%, p = 0.004), kidney (young adults: 0% vs. 5%, p = 0.043), prostate (middle adults: 1% vs. 4%, p = 0.001), gastrointestinal tract (senior adults: 8% vs. 2%, p = 0.028), and others (children: 100% vs. 4%, p < 0.001) (young adults: 10% vs. 4%, p = 0.044). Kaplan-Meier survival (children, young, middle, older, and senior adults) at 1 year was 33%, 48%, 60%, 62%, and 76% and at 5 years was 0%, 22%, 29%, 25%, and 40%, respectively, with no difference per age category. The mean overall survival was 17.2 months and children demonstrated hazard ratio (HR) for death at 1 year of 2.1 relative to older adults. CONCLUSION: Uveal metastasis is found in all age groups. Compared to older adults, primary cancer site was more often breast and less likely lung in young and middle adults. Other rare sites were more often seen in children. Survival outcomes at 1 and 5 years were most favorable for senior adults and least favorable for children.

Impact of uveal melanoma thickness on post-plaque radiotherapy outcomes in the prophylactic anti-vascular endothelial growth factor era in 1131 patients.

IMPORTANCE: The impact of tumour thickness on radiation complications following plaque radiotherapy for uveal melanoma in the anti-vascular endothelial growth factor (VEGF) era remains unknown. BACKGROUND: To evaluate treatment outcomes following plaque radiotherapy and prophylactic intravitreal bevacizumab for uveal melanoma based on initial tumour thickness. DESIGN: This was a retrospective, interventional case series. PARTICIPANTS: Patients with uveal melanoma were included in this study. METHODS: A review of medical records was conducted of patients with uveal melanoma treated with plaque radiotherapy and prophylactic intravitreal bevacizumab from 7 July 2000 to 2 November 2018. MAIN OUTCOMES MEASURES: Radiation-related outcomes of cystoid macular oedema (CME), radiation maculopathy, papillopathy, retinopathy, iris neovascularization (NVI) and neovascular glaucoma (NVG) were compared based on tumour thickness (small [<3.0 mm] vs medium [3.1-8.0 mm] vs large [>8.0 mm]). RESULTS: Of 1131 eyes, 341 (30%) had small, 633 (56%) medium and 157 (14%) large melanoma. Comparison (small vs medium vs large) at 4 years following radiotherapy revealed large melanoma with greater Kaplan-Meier estimated risk of CME (37% vs 37% vs 63%, P < .001), earlier onset of CME (33 vs 26 vs 19 months, P < .001) and greater development of NVI (<1% vs 2% vs 13%, P < .001) and NVG (1% vs 2% vs 12%, P < .001). Radiation-induced maculopathy, papillopathy and retinopathy were not associated with tumour thickness. CONCLUSIONS AND RELEVANCE: Compared with small and medium uveal melanoma, large uveal melanoma demonstrated greater 48-month risk for CME, shorter time to CME onset and greater development of NVI and NVG following plaque radiotherapy and prophylactic intravitreal bevacizumab.

Conjunctival Melanoma: Features and Outcomes Based on the Fitzpatrick Skin Type in 540 Patients at a Single Ocular Oncology Center.

PURPOSE: To determine the association of Fitzpatrick skin type (FST) with conjunctival melanoma. METHODS: Retrospective case series of 540 patients with conjunctival melanoma to assess clinical features and outcomes per FST. RESULTS: The FST was Type I (n = 126, 23%), II (n = 337, 62%), III (n = 56, 10%), IV (n = 8, 2%), V (n = 12, 2%), and VI (n = 1, <1%). A comparison (FST I vs. II vs. III, IV, V, and VI) revealed Types I and II associated with older mean patient age (63.9 vs. 60.7 vs. 51.1 years, p < 0.001), greater percentage of female patients (68% vs. 44% vs. 42%, p < 0.001), lower frequency of complexion associated melanosis (1% vs. 2% vs. 13%, p < 0.001), smaller tumor thickness (2.1 vs. 2.8 vs. 3.6 mm, p = 0.01), and less eyelid involvement (13% vs. 13% vs. 28%, p = 0.02). Kaplan-Meier estimates for 5-year risk showed no difference by Types for visual acuity loss ≥3 lines, local tumor recurrence, exenteration, metastasis, or death. CONCLUSION AND RELEVANCE: Most patients with conjunctival melanoma show FST I or II, and this demonstrated no association with 5-year rate of vision loss, tumor recurrence, exenteration, metastasis, or death.

Small choroidal melanoma: detection with multimodal imaging and management with plaque radiotherapy or AU-011 nanoparticle therapy.

PURPOSE OF REVIEW: To explore risk factors for choroidal nevus transformation into melanoma using multimodal imaging and review current treatment options. RECENT FINDINGS: A recently published longitudinal study of 3806 choroidal nevi, imaged with optical coherence tomography (OCT), ultrasonography, and standard wavelength autofluorescence, revealed transformation into melanoma in 5.8% at 5 years and 13.9% at 10 years, using Kaplan-Meier analysis. Multivariate factors predictive of transformation included thickness more than 2 mm (by ultrasonography), fluid subretinal (by OCT), symptoms vision loss (by Snellen acuity), orange pigment (by autofluorescence), melanoma hollow (by ultrasonography), and DIaMeter more than 5 mm (by photography). These important factors can be recalled by the mnemonic 'To Find Small Ocular Melanoma Doing IMaging' (TFSOM-DIM). The mean 5-year estimate of nevus growth into melanoma was 1.1% for those with 0 risk factor, 11% with one factor, 22% with two factors, 34% with three factors, 51% with four factors, and 55% with five risk factors. Management of small choroidal melanoma typically involves plaque radiotherapy with 5 and 10-year rates of tumor recurrence at 7 and 11%, visual acuity loss (≥3 Snellen lines) at 39 and 49%, and melanoma-related metastasis at 4 and 9%. A novel infrared dye-conjugated virus-like nanoparticle (AU-011) is currently under investigation for treatment of small choroidal melanoma, with a goal to induce tumor regression and minimize vision loss. SUMMARY: The mnemonic, TFSOM-DIM, can assist the clinician in detection of small choroidal melanoma. Treatment of small melanoma with plaque radiotherapy offers tumor control but with potential vision loss. A novel nanoparticle therapy using AU-011 is currently under trial.

VON HIPPEL-LINDAU DISEASE: Update on Pathogenesis and Systemic Aspects.

PURPOSE: To provide an update summarizing the biologic pathways governing von Hippel-Lindau (VHL) disease pathogenesis and to provide an overview of systemic manifestations as well as screening recommendations. METHODS: A PubMed search of the English language literature was reviewed using the following search terms: von Hippel-Lindau, von Hippel-Lindau disease, and VHL. Of 6,696 publications, the most current and pertinent information related to the pathogenesis and systemic aspects of VHL disease were included in this review. RESULTS: von Hippel-Lindau disease is one of the most frequently occurring multisystem familial cancer syndromes. The disease results from germline mutation in the VHL tumor suppressor gene on the short arm of chromosome 3. Mutation in the VHL gene affects multiple cellular processes including transcriptional regulation, extracellular matrix formation, apoptosis, and, in particular, the cellular adaptive response to hypoxia. As a result, there is widespread development of vascular tumors affecting the retina, brain, and spine, as well as a spectrum of benign and malignant tumors and/or cysts in visceral organs. CONCLUSION: The ophthalmologist plays a key role in VHL disease diagnosis, as retinal hemangioblastoma is frequently the first disease manifestation. Screening guidelines for individuals with known VHL disease, and those at risk of VHL disease, help to ensure early detection of potentially vision-threatening and life-threatening disease.

CHOROIDAL NEVUS IMAGING FEATURES IN 3,806 CASES AND RISK FACTORS FOR TRANSFORMATION INTO MELANOMA IN 2,355 CASES: The 2020 Taylor R. Smith and Victor T. Curtin Lecture.

PURPOSE: To use multimodal imaging for identification of risk factors for choroidal nevus transformation into melanoma. METHODS: Retrospective chart review of 3806 consecutive choroidal nevi with imaging and 2355 choroidal nevi with additional follow up to identify factors predictive of transformation of choroidal nevus into melanoma. RESULTS: The median patient age was 62.5 years and Caucasian race in 3167 (95%). The choroidal nevus demonstrated median basal diameter of 4.0 mm and thickness of 1.4 mm. Imaging included optical coherence tomography (OCT) showing subretinal fluid (SRF) in 312 (9%), ultrasonography (US) with acoustic hollowness in 309 (9%), and hyper-autofluorescence (AF) in 100 (3%). Of those 2355 choroidal nevi with follow up, Kaplan-Meier estimates of nevus transformation into melanoma at 1, 5, and 10 years were 1.2%, 5.8%, and 13.9%, respectively. Multivariate analysis, using multimodal imaging for detection of factors predictive of nevus transformation into melanoma, included thickness >2 mm on US (hazard ratio (HR) 3.80, p < 0.0001), SRF on OCT as cap over nevus (HR 3.00, p < 0.0001) or SRF ≤3 mm from nevus margin (HR 3.56, p = 0.0003), symptomatic vision loss ≤20/50 on Snellen visual acuity (VA) (HR 2.28, p = 0.005), orange pigment (lipofuscin) hyperautofluorescence on AF (HR 3.07, p = 0.0004), acoustic hollowness on US (HR 2.10, p = 0.0020), and tumor diameter >5 mm on photography (HR 1.84, p = 0.0275). These factors can be recalled by the mnemonic "To Find Small Ocular Melanoma Doing IMaging" (TFSOM-DIM) representing Thickness >2 mm (US), Fluid subretinal (OCT), Symptoms vision loss (VA), Orange pigment (AF), Melanoma hollow (US), and DIaMeter >5mm (photography). The mean 5-year estimates of nevus growth into melanoma were 1% (HR 0.8) for those with 0 risk factor, 11% (HR 3.09) with 1 factor, 22% (HR 10.6) with 2 factors, 34% (HR 15.1) with 3 factors, 51% (HR 15.2) with 4 factors, 55% (HR 26.4) with 5 risk factors, and not-estimable with all 6 risk factors. CONCLUSION: In this analysis, multimodal imaging was capable of detecting risk factors for nevus transformation into melanoma, including thickness >2 mm (US), fluid subretinal (OCT), symptoms vision loss (Snellen acuity), orange pigment (AF), melanoma hollowness (US), and diameter >5 mm (photography). Increasing number of risk factors imparts greater risk for nevus transformation into melanoma, including thickness >2 mm (US), fluid subretinal (OCT), symptoms vision loss (Snellen acuity), orange pigment (AF), melanoma hollowness (US), and diameter >5 mm (photography). Increasing number of risk factors imparts greater risk for transformation.

CHOROIDAL NEVUS TRANSFORMATION INTO MELANOMA PER MILLIMETER INCREMENT IN THICKNESS USING MULTIMODAL IMAGING IN 2355 CASES: The 2019 Wendell L. Hughes Lecture.

PURPOSE: To analyze risk of nevus transformation into melanoma per millimeter increment. METHODS: Retrospective analysis of 3,806 choroidal nevi for transformation into melanoma per incremental millimeter thickness (flat [≤1.0 mm], thin [1.1-2.0 mm], thicker [2.1-3.0 mm], and thickest [>3.0 mm]) RESULTS:: The median nevus thickness was 1.4 mm, and nevi were categorized (flat, thin, thicker, and thickest) in 1,140 (30%), 2052 (54%), 555 (15%), and 59 (<1%), respectively. There were differences in tumor diameter (2.5, 4.8, 7.5, and 9.3 mm; P < 0.01), optical coherence tomography detection of overlying subretinal fluid (<1, 4, 15, and 11%; P < 0.01), overlying retinal edema (<1, 3, 14, and 25%; P < 0.01), overlying drusen (23, 49, 64, and 64%; P < 0.01), overlying retinal pigment epithelial detachment (1, 4, 4, and 9%; P < 0.01), and overlying lipofuscin hyperautofluoresence (<1, 3, 6, and 7%; P < 0.01). Choroidal nevus transformation into melanoma (n = 90/2,355 cases, 3.8%) was found by Kaplan-Meier 7-year estimates (2.2, 6.1, 31.7, and 34.5%; P < 0.0001) and by hazard ratio (HR) compared with nevus ≤1.0 mm (not available, 4.7 [P = 0.01], 35.7 [P < 0.0001], and 52.0 [P < 0.0001]). For all thicknesses, those with growth displayed increase in mean basal diameter of 2.4 mm and thickness of 1.1 mm, optical coherence tomography increase in subretinal fluid (65%), autofluorescence increase in lipofuscin (40%), and ultrasonography increase in hollowness (30%). Multivariable risk factors, recalled by the mnemonic "To Find Small Ocular Melanoma Doing IMaging" (TFSOM-DIM) representing Thickness >2 mm (ultrasonography), Fluid subretinal (optical coherence tomography), Symptom vision loss (Va), Orange pigment (autofluorescence), Melanoma hollow (ultrasonography), and DIaMeter >5 mm, revealed factors per incremental thickness category (compared with flat) including thin (Fluid overlying, HR 6.1; DIaMeter >5 mm, HR 3.3), thicker (Fluid subretinal ≤3 mm from nevus, HR 5.7; Melanoma acoustic hollowness, HR 2.7), and thickest (Orange pigment, HR 9.1). CONCLUSION: Each incremental increase in choroidal nevus thickness demonstrated risk of growth into melanoma with HR (compared with flat) 4.7 for thin, 35.7 for thicker, and 52.0 for thickest. The increase from ≤2.0 mm to >2.0 mm thickness conferred the greatest rise for transformation.

Adjuvant Sunitinib in High-Risk Patients with Uveal Melanoma: Comparison with Institutional Controls.

PURPOSE: To compare overall survival in high-risk patients with primary uveal melanoma who received adjuvant sunitinib with institutional controls. DESIGN: Retrospective cohort. PARTICIPANTS: Selection criteria were (1) monosomy 3 and 8q amplification by cytogenetic or DecisionDx-UM Class 2 and (2) monosomy 3 and large tumor size (T3-4 by American Joint Committee on Cancer classification). Exclusion criteria were date of diagnosis before 2007 or after 2013 and age <18 years. METHODS: A cohort of patients who intended to receive adjuvant sunitinib for 6 months was compared with institutional historical controls with the same risk factors. Kaplan-Meier and Cox proportional hazards models were used to analyze the outcome. Propensity score was used to adjust for nonrandom assignment to sunitinib. MAIN OUTCOME MEASURES: Overall survival. RESULTS: From the Wills Eye Hospital Oncology Service Uveal Melanoma Cytogenetic Database (N = 1172), 128 patients fulfilled the selection and exclusion criteria. Median follow-up was 52.7 months (range, 0.26-108 months). A total of 54 patients received sunitinib. Their median age was 56 years (range, 29-81 years), and 48% were men. A total of 74 historical controls in the same risk category were identified. Their median age was 62 years (21-80 years), and 48% were men. Patients in the sunitinib group had worse cytogenetic or molecular features (monosomy 3 and 8q amplification or class 2 87% vs. 57%; P < 0.001), had smaller tumor sizes (T3-4 56% vs. 83%; P = 0.001), and were younger. There were 51 deaths, 14 (26%) in the sunitinib group and 37 (50%) in the control group. In the univariate analysis, the sunitinib group had longer overall survival (hazard ratio, 0.53; 95% confidence interval, 0.29-0.99; P = 0.041). In multivariate Cox regression analysis, interaction between use of sunitinib and age as a dichotomous variable was highly significant (P = 0.003). The following variables were statistically associated with prediction of overall survival: cytogenetic/molecular status (P = 0.015), T-size category (P = 0.022), gender (P = 0.040), and adjuvant sunitinib in patients aged <60 years (P = 0.004). Results were confirmed by propensity score analysis. CONCLUSIONS: In this retrospective study, the use of sunitinib in the adjuvant setting was associated with better overall survival.

Iris Melanoma Outcomes Based on the American Joint Committee on Cancer Classification (Eighth Edition) in 432 Patients.

PURPOSE: The American Joint Committee on Cancer (AJCC) classification was updated to the eighth edition in January 2017, providing staging for iris melanoma. This study evaluated outcomes of iris melanoma per the AJCC classification, eighth edition. DESIGN: Retrospective case series. PARTICIPANTS: Four hundred thirty-two patients with iris melanoma. METHODS: Management including tumor resection, plaque radiotherapy, or enucleation. MAIN OUTCOME MEASURES: Local tumor recurrence, melanoma-related systemic metastasis, and melanoma-related death. RESULTS: Of 432 patients with iris melanoma, AJCC classification was category T1 (n = 324 [75%]), T2 (n = 83 [19%]), T3 (n = 2 [<1%]), and T4 (n = 23 [5%]). There was no difference in age, race, gender, eye, or iris color among T categories. Overall, Kaplan-Meier analysis of outcomes (at 5 and 10 years) revealed visual acuity reduction by 3 lines or more (42% and 54%, respectively), secondary glaucoma (29% and 33%, respectively), local recurrence (8% and 17%, respectively), secondary enucleation (12% and 19%, respectively), lymph node metastasis (1% and 1%, respectively), melanoma-related systemic metastasis (5% and 10%, respectively), and melanoma-related death (3% and 4%, respectively). Compared with T1 category, the hazard ratio (HR) for local recurrence in nonenucleated eyes was 1.31 for T2, not evaluable (NE) for T3 (because of small cohort), and 6.61 for T4; the HR for metastasis was 3.41 for T2, NE for T3 (because of small cohort), and 25.6 for T4; the HR for death was 7.51 for T2, NE for T3 (because of small cohort), and 26.5 for T4; and the odds ratio for enucleation was 1.23 for T2, 3.63 for T3, and 4.72 for T4. Features predictive of melanoma-related metastasis (multivariate analysis) included secondary glaucoma (P < 0.001; HR, 4.51), T2 category (vs. T1; P = 0.01; HR, 4.09), and T4 category (vs. T1; P < 0.001; HR, 30.8). Features predictive of melanoma-related death (multivariate analysis) included older age (P = 0.008; HR, 2.16 per 10-year increase), T2 category (vs. T1; P = 0.005; HR, 8.07), and T4 category (vs. T1; P < 0.001; HR, 20.3). CONCLUSIONS: The AJCC eighth edition classification provides prognostic stratification of iris melanoma. By multivariate analysis, the ratio for melanoma-related metastasis was 4 times greater in category T2 and 31 times greater in T4 compared with T1. The ratio for melanoma-related death was 8 times greater in category T2 and 20 times greater in T4 compared with T1. The cohort size for T3 was too small to provide useful information.