High-Risk Histopathological Features of Retinoblastoma following Primary Enucleation: A Global Study of 1426 Patients from 5 Continents.

PURPOSE: To evaluate high-risk histopathological features (HRHF) following primary enucleation of eyes with retinoblastoma (RB) and assess the patient outcomes across continents. METHODS: Retrospective study of 1426 primarily enucleated RB eyes from five continents. RESULTS: Of all, 923 (65%) were from Asia (AS), 27 (2%) from Australia (AUS), 120 (8%) from Europe (EUR), 162 (11%) from North America (NA), and 194 (14%) from South America (SA). Based on the continent (AS vs. AUS vs. EUR vs. NA vs. SA), the histopathology features included massive choroidal invasion (31% vs. 7% vs. 13% vs. 19% vs. 27%, p=0.001), post-laminar optic nerve invasion (27% vs. 0% vs. 16% vs. 21% vs. 19%, p=0.0006), scleral infiltration (5% vs. 0% vs. 4% vs. 2% vs. 7%, p=0.13), and microscopic extrascleral infiltration (4% vs. 0% vs. <1% vs. <1% vs. 4%, p=0.68). Adjuvant chemotherapy with/without orbital radiotherapy was given in 761 (53%) patients. Based on Kaplan-Meier estimates in different continents (AS vs. AUS vs. EUR vs. NA vs. SA), the 6-year risk of orbital tumor recurrence was 5% vs. 2% vs. 0% vs. 0% vs. 12% (p<0.001), systemic metastasis was reported in 8% vs. 5% vs. 2% vs. 0% vs. 13% (p=0.001), and death in 10% vs. 3% vs. 2% vs. 0% vs. 11% (p<0.001) patients. CONCLUSION: There is a wide variation in the infiltrative histopathology features of RB across continents, resulting in variable outcomes. SA and AS had a higher risk of orbital tumor recurrence, systemic metastasis, and death compared to AUS, EUR, and NA.

Iris and Ciliary Body Melanocytomas Are Defined by Solitary GNAQ Mutation Without Additional Oncogenic Alterations.

OBJECTIVE: To analyze the genetic features of melanocytomas and melanomas of the anterior uvea and assess the value of molecular testing for diagnosis and prognostication. DESIGN: Retrospective case-control study. SUBJECTS: Patients with melanocytoma (n = 16) and melanoma (n = 19) of the anterior uvea. METHODS: Targeted next-generation sequencing was performed on formalin-fixed, paraffin-embedded tumor tissue from anterior uveal melanocytic tumors and correlated with clinicopathologic features. MAIN OUTCOME MEASURES: Presence or absence of accompanying oncogenic alterations beyond GNAQ/GNA11 and their association with histologic features and local recurrence. RESULTS: Hotspot missense mutations in GNAQ/GNA11 were identified in 91% (32/35) of all cases. None of the melanocytomas with or without atypia demonstrated chromosomal imbalances or additional oncogenic variants beyond GNAQ mutation, and none recurred over a median follow-up of 36 months. Additional alterations identified in a subset of melanomas include mutations in BAP1 (n = 3), EIF1AX (n = 4), SRSF2 (n = 1), PTEN (n = 1), and EP300 (n = 1); monosomy 3p (n = 6); trisomy 6p (n = 3); trisomy 8q (n = 2); and an ultraviolet mutational signature (n = 5). Local recurrences were limited to melanomas, all of which demonstrated oncogenic alterations in addition to GNAQ/GNA11 (n = 5). A single melanoma harboring GNAQ and BAP1 mutations and monosomy 3 was the only tumor that metastasized. CONCLUSIONS: In this study, anterior segment uveal melanocytomas did not display oncogenic alterations beyond GNAQ/GNA11. Therefore, they are genetically similar to uveal nevi rather than uveal melanoma based on their molecular features known from the literature. Molecular testing can be performed on borderline cases to aid risk stratification and clinical management decisions.

Comparison of Subconjunctival Aflibercept and Betamethasone for the Treatment of Formed Corneal Neovascularization in a Rabbit Model.

AIM: To compare the efficacy of aflibercept (Eylea®), a potent antivascular endothelial growth factor (VEGF) agent, with betamethasone (Celestone®) and placebo for the treatment of formed corneal neovascularization in a rabbit model. METHODS: A central corneal chemical burn was created in the right eye of 24 New Zealand albino rabbits. Four weeks later, the rabbits were randomly divided into 4 equal groups for subconjunctival injection of aflibercept, betamethasone, aflibercept+ betamethasone, or saline (control). Digital photographs taken at weekly intervals were rated by 2 masked observers for extent, centricity, and density of corneal neovascularization according to a predefined scale. The percentage of corneal surface involved by neovascularization was quantified by image analysis software (Fiji-J). The change in corneal neovascularization from treatment administration (4 weeks after injury) to 4 weeks later (8 weeks after injury) was assessed. The rabbits were then euthanized, and their eyes were enucleated and processed for histopathological and immunofluorescence studies. RESULTS: There was no significant difference in the change in corneal neovascularization after treatment among the 4 groups according to the digital images (p > 0.15) or histological evaluation with hematoxylin and eosin (p > 0.08). On immunofluorescence assay, a lower VEGF concentration was observed in all treatment groups compared to the control group. CONCLUSIONS: In this rabbit model, corneal neovascularization induced by chemical burn failed to regress with treatment with aflibercept, betamethasone, or their combination.

BRCA-associated protein1 (BAP1) immunohistochemical stain reliability in postbrachytherapy uveal melanoma enucleation specimens.

PURPOSE: The BRCA-associated protein1 (BAP1) immunohistochemical (IHC) stain has emerged as a powerful and inexpensive prognostic tool in uveal melanoma (UM), correlating with UM genetics and outcome. The data on the reliability of BAP1 immunohistochemistry in previously irradiated UM is scant. We aim to assess BAP1 IHC in post-Iodine-125 plaque brachytherapy-treated UM-enucleated eyes. METHODS: In a case-control study, the medical records of all patients who underwent enucleation for UM at a major Ocular Oncology Service from December 1 st , 2007 to December 31 st , 2014 were reviewed. All cases with either chromosome 3 (ch3) status or sufficient follow-up (>5 years or metastasis) were selected. Nuclear BAP1 (nBAP1) immunoreactivity was interpreted as intact (positive in >90% of nuclei), lost (positive in <5% of nuclei), or heterogeneous (positive in 5-90% of nuclei). Retina and intratumoral blood vessels served as internal positive controls. RESULTS: A comparison of 34 postbrachytherapy UM secondary-enucleated eyes with 47 nonbrachytherapy primary enucleated controls revealed no significant difference with respect to nBAP1 IHC (lost in 41% vs 51%, P = 0.19), ch3 status (ch3 monosomy in 59% vs 60%, P = 0.48), and outcome (metastatic disease in 44% vs 47%, P = 0.8). Association of nBAP1 IHC with ch3 status and outcome [intact nBAP1/(ch3 disomy and/or no metastasis) and lost nBAP1 (ch3 monosomy and/or metastasis)] in post-brachytherapy UM was significantly lower when compared with non-brachytherapy tumors [21/30 (70%) vs 41/44 (93%), P = 0.004*]. CONCLUSION: Although nBAP1 IHC stain is a strong prognostic tool in UM, its association with ch3 status, and outcome in postbrachytherapy UM was significantly lower compared with nonbrachytherapy tumors due to pitfalls in the interpretation of nBAP1 immunoreactivity in irradiated UM. This test should be used judiciously in the prognostication of postbrachytherapy-enucleated UM.

Familial retinoblastoma: variations in clinical presentation and management based on paternal versus maternal inheritance.

BACKGROUND: Several studies have demonstrated the effect of parent-of-origin on retinoblastoma penetrance. The purpose of the current study was to assess differences in clinical presentation of paternally versus maternally inherited retinoblastoma. METHODS: The clinical records of all children with familial retinoblastoma treated on a tertiary Ocular Oncology Service between December 1975 and May 2020 were reviewed retrospectively. RESULTS: A total of 179 patients with familial retinoblastoma were included. Paternal inheritance (PI) was identified in 109 (61%) patients and maternal inheritance (MI) in 70 patients (39%). A comparison (PI vs MI) revealed PI patients were older at presentation (57.2 vs 24.4 months [P = 0.002]) with no difference in patient sex (53% females vs 57% males [P = 0.606]) or number of family members affected (3.2 vs 3.0 family members [P = 0.255]). PI patients had more advanced classification according to the International Classification of Retinoblastoma (ICRB) (group E: 31% vs 8% [P = 0.012)] and greater largest tumor in basal diameter (9.0 vs 6.2 mm [P = 0.040]) and thickness (5.6 vs 4.0 mm [P = 0.038]); they were also less likely to be located in the macula (40% vs 60% [P = 0.004]). There was no difference in tumor laterality (69% vs 64% bilaterality [P = 0.530]). PI patients required enucleation more frequently (34% vs 14% [P = 0.007]). There was no difference in need for plaque radiotherapy (P = 0.86) or chemotherapy (P = 0.85). One PI patient developed metastatic retinoblastoma, and there were no retinoblastoma-related deaths. CONCLUSIONS: Patients with paternally inherited retinoblastoma presented at an older age, with larger, more peripheral tumors and more advanced ICRB group, and were more likely to require enucleation compared to those with maternally inherited retinoblastoma.

Treatment of conjunctival palpebral lesions using ruthenium plaque brachytherapy "Sandwich Technique".

OBJECTIVE: Treatment of palpebral conjunctival lesions is problematic due to late diagnosis, difficult surgical approach, and the need to preserve eyelid integrity. We describe our treatment experience using plaque brachytherapy in the "sandwich technique." DESIGN: A retrospective study. PARTICIPANTS: We reviewed the medical records of patients treated by plaque brachytherapy for conjunctival lesions at the Hadassah Medical Center between January 1, 2013, and January 1, 2024, and included in the analysis patients treated for palpebral conjunctival lesions. METHODS: Ruthenium plaque was sutured to the palpebral conjunctiva. The matching nonradioactive "dummy" plaque was sutured to the external eyelid to flip the tarsal's curvature. RESULTS: The study cohort included 5 patients, 2 men (40%) and 3 women (60%) at a median age of 68.11 years (range: 47-79.7 years). Three patients had conjunctival melanoma (60%), 1 had sebaceous carcinoma (20%), and 1 had extensive carcinoma in situ (20%). All lesions were in the left upper eyelid. Median follow-up was 37.6 months (range: 18.7-110.6 months). Four patients demonstrated a complete response (80%), while one had a partial response (20%). There was local recurrence in 1 patient (20%), and 1 patient had new foci elsewhere (20%). All patients had full local control after adding local treatments. One patient developed metastatic disease and died (20%). All patients had manageable madarosis and conjunctival scars. CONCLUSIONS: Treatment of palpebral conjunctival lesions using "sandwich" plaque brachytherapy is safe and effective. To the best of our knowledge, this treatment was never described before, and we believe it should be added to our armamentarium.

Treatment Outcomes and Definition Inconsistencies in High-Risk Unilateral Retinoblastoma: Outcomes and Definition Variances in High-Risk Rb.

PURPOSE: To compare the clinical outcomes of children with unilateral retinoblastoma (Rb) and high-risk histopathology features (HRHF) following upfront enucleation with/without adjuvant chemotherapy, and investigate cases locally considered non-HRHF but converted to a standardized HRHF definition. DESIGN: Retrospective multinational clinical cohort study. METHODS: Children with Rb who presented to 21 centers from 12 countries between 2011-2020, and underwent primary enucleation were recruited. Centers retrieved clinical data and were asked to report detailed histopathology findings, as well as indicate cases defined locally as high-risk. For analysis, only unilateral cases with standardized HRHF, defined as retrolaminar optic nerve invasion, massive choroidal invasion, scleral invasion, anterior-segment involvement, and/or combined non-massive choroidal and prelaminar/laminar optic nerve invasion, were included. Main Outcome Measures included orbital tumor recurrence, systemic metastasis, survival and number and outcome of cases converted to standardized HRHF. RESULTS: A total of 600 children presenting to 14 centers in 9 countries were included. Of these, 505 (84.2%) were considered locally as HRHF and received adjuvant chemotherapy. After a median follow-up period of 39.2±1.6 months (range: 0.8-60.0 months), 36 (6.0%) had orbital tumor recurrence, 49 (8.2%) metastasis, and 72 (12.0%) children died. Children not receiving adjuvant chemotherapy were at significantly increased risk of orbital tumor recurrence, metastasis, and death (p ≤0.002). Of the study children, 63/600 (10.5%) were considered locally non-HRHF, but converted to standardized HRHF and included in the analysis. Of these, 6/63 (9.5%) had orbital tumor recurrence, 5/63 (7.9%) metastasis, and 6/63 (9.5%) children died. Isolated minor choroidal invasion with prelaminar/laminar optic nerve invasion was reported in 114 (19.0%) children, but considered locally as HRHF only in 68/114 (59.6%). Of these, 6/114 (5.3%) children developed metastasis and subsequently died, yielding a number needed to treat of 15. CONCLUSION: Based on this multinational cohort of children with Rb, we recommend the use of adjuvant chemotherapy following upfront enucleation and diagnosis of HRHF. Variation exists worldwide among centers when defining HRHF, resulting in adverse patient outcomes, warranting standardization.

In Vivo Effects of Prostaglandin Analogues Application by Topical Drops or Retrobulbar Injections on the Orbital Fat of a Rat Model.

PURPOSE: To assess the in vivo effects of bimatoprost 0.03% (Lumigan®) on the orbital fat in a rat model. METHODS: Twenty rats were randomly divided into two groups: bimatoprost was administrated to the right eye by topical drops (group 1) or retrobulbar injection (group 2), and saline was administrated to the left eye by similar administration routes (controls). Four weeks later, all rats were sedated and euthanized, both orbits exenterated, and thin sections through the intraconal orbital fat were obtained. RESULTS: Average adipocyte cell count was significantly lower in the bimatoprost treated orbits (drops or retrobulbar injection, 29.5 vs. 67.5 cells per slide in the control globes, p=0.046). Fat cells were not detected in 9/20 (45%) bimatoprost treated orbits     . CONCLUSIONS: Orbits treated with bimatoprost by drops or retrobulbar injection demonstrated significant decrease in adipocytes cell count compared with controls. Bimatoprost could be an effective treatment for inactive thyroid eye disease.

Risk factors for the development of macular edema in children with uveitis.

Aim: To determine the risk factors for macular edema (ME) in children with uveitis. Methods: A retrospective study was conducted of 150 pediatric patients (264 eyes) with uveitis attending 2 tertiary medical centers. Data were collected from the medical files on demographics, type of uveitis, etiology, clinical findings, treatment, and time to development of ME. Risk factors for the development of ME were identified. Results: ME developed in 63 eyes (23.9%) over a mean period of 15.3 ± 2.95 months from diagnosis of uveitis, at a rate of 0.08 eyes per eye-year. On univariate analysis, risk factors for the development of ME were the non-anterior location of the inflammation (p=0.002), band keratopathy (p <0.0001), posterior synechiae (p=0.003), cataract (p=0.002), and vision impairment at presentation (p <0.0001). On multivariate analysis, non-anterior uveitis, which includes intermediate, pan, and posterior-uveitis, and vision impairment retained significance as independent risk factors of ME. Conclusion: Within the pediatric population with uveitis, non-anterior location is associated with the highest risk of ME, followed by the presence of complications, such as band keratopathy and posterior synechiae. These findings indicate a need for close follow-up in children with uveitis for early detection of ME.

Iodine-125 Plaque Radiotherapy for Retinoblastoma Recurrence Following Intra-arterial Chemotherapy.

PURPOSE: To assess the efficacy and toxicity of Iodine-125 (I-125) plaque radiotherapy for retinoblastoma following intra-arterial chemotherapy (IAC). METHODS: Clinical records of patients with retinoblastoma who received I-125 plaque radiotherapy after IAC at the Ocular Oncology Service at Wills Eye Hospital between December 1, 2009 and April 30, 2020, were retrospectively reviewed. RESULTS: Forty-one retinoblastomas in 41 eyes of 41 patients were treated with I-125 plaque radiotherapy after IAC at a median age of 32 months. The indication for plaque radiotherapy was solid tumor recurrence with or without overlying subretinal/vitreous seeds (n = 33, 80%), subretinal seeds alone (n = 6, 15%), and vitreous seeds alone (n = 2, 5%). The median irradiated basal diameter and thickness was 9 and 4 mm, respectively. Mean radiation dose to tumor apex was 3,483 centigray (cGy) delivered at mean rate of 35 cGy/hr. The irradiated site was controlled in 39 eyes (95%) at a median of 20 months after plaque radiotherapy for solid tumor (31 of 33, 94%), subretinal (6 of 6,100%), and vitreous seeds (2 of 2, 100%). A subgroup of tumors occurring within an ischemic retinal/choroidal field was identified on fluorescein angiography (n = 24) and demonstrated control in 22 of 24 (92%). Using Kaplan-Meier analysis, radiation complications at 2 years included vitreous hemorrhage (37%), retinopathy (28%), papillopathy (18%), and cataract (18%). Five eyes (12%) were enucleated for recurrence outside the irradiated area, chronic vitreous hemorrhage, and/or total retinal detachment. CONCLUSIONS: Iodine-125 plaque radiotherapy provided 95% control for retinoblastoma tumors that failed IAC, including those in ischemic fields untreatable with further chemotherapy. Radiation complications should be anticipated in eyes exposed to substantial chemotherapy. [J Pediatr Ophthalmol Strabismus. 2022;59(3):164-171.].

Cyclin D1 Expression and Molecular Genetic Findings in Periocular Histiocytoses and Neoplasms of Macrophage-Dendritic Cell Lineage.

PURPOSE: Frequent activating mutations in the mitogen-activated protein kinase (MAPK) pathway genes have been identified in histiocytoses. MAPK signaling consistently upregulates cyclin D1. The goal of this study was to determine whether cyclin D1 expression by immunohistochemistry is a useful diagnostic marker for periocular histiocytoses and to further characterize their genetic basis. DESIGN: Retrospective observational case series. METHODS: Pathology records were searched for all patients with histiocytoses diagnosed between 1995 and 2020. Eleven histiocyte-rich inflammatory lesions and 10 xanthelasma served as controls. Cyclin D1 immunohistochemistry was performed on all tissues. A subset of histiocytoses was evaluated by next-generation sequencing (NGS) and droplet digital PCR (ddPCR). RESULTS: There were 36 patients, 15 males (42%) and 21 females (58%), with histiocytoses: 9 juvenile xanthogranuloma (25%), 8 adult-onset asthma and periocular xanthogranuloma (22%), 7 Langerhans cell histiocytosis (19%), 5 Rosai-Dorfman disease (14%), 5 xanthogranuloma-not otherwise specified (14%), 1 Erdheim-Chester disease (3%), and 1 histiocytic sarcoma (3%). Moderate to strong nuclear cyclin D1 expression was present in ≥50% of lesional cells in histiocytoses (23/36, 64%), significantly more when compared to histiocyte-rich inflammatory lesions (0/11, 0%, P<.001) and xanthelasma (0/10, 0%, P<.001). Cyclin D1 was expressed in <10% of lesional cells in all 11 histiocyte-rich inflammatory lesions (P<.001) and all 10 xanthelasma lesions (P<.001). MAPK pathway gene mutations were detected in 12 of 14 (86%) histiocytoses successfully assayed by NGS and/or ddPCR. CONCLUSIONS: Our study confirms that the cyclin D1 immunohistochemical stain is a useful diagnostic marker for periocular histiocytoses, correlating with underlying mutations in MAPK pathway genes.

Validation of the Newly Proposed World Health Organization Classification System for Conjunctival Melanocytic Intraepithelial Lesions: A Comparison with the C-MIN and PAM Classification Schemes.

PURPOSE: We sought to compare the sensitivity, specificity, accuracy, and interobserver agreement of the two most commonly used classification systems for conjunctival melanocytic intraepithelial lesions with the new World Health Organization (WHO) classification. DESIGN: Retrospective case series and evaluation of classification systems. METHODS: We reviewed the pathology and medical records of all patients who underwent a primary biopsy procedure for conjunctival primary acquired melanosis (PAM) at Wills Eye Hospital between 1974 and 2002 who had ≥36 months of follow-up. Data collected included age, sex, clinical findings, recurrence, and progression to melanoma. Twelve ophthalmic pathologists analyzed scanned hematoxylin and eosin-stained virtual microscopic slides using 3 classification systems: PAM, conjunctival melanocytic intraepithelial neoplasia, and the WHO 4th edition classification of conjunctival melanocytic intraepithelial lesions. Observer agreement, sensitivity, specificity, and diagnostic accuracy of each classification system were assessed. RESULTS: There were 64 patients who underwent 83 primary excisions with cryotherapy for conjunctival PAM who had adequate tissue for histopathologic evaluation. The interobserver agreement in distinction between the low- and high-grade lesions was 76% for PAM, 67% for conjunctival melanocytic intraepithelial neoplasia, and 81% for WHO classification system. Low-grade lesions provided the greatest interpretative challenge with all 3 classification systems. The 3 classification systems had comparable accuracy of 81%-83% in their ability to identify lesions with potential for recurrence. CONCLUSIONS: This study highlights the comparable strengths and limitations of the 3 classification systems for conjunctival melanocytic intraepithelial lesions and suggests that the simplified WHO classification scheme is appropriate for evaluation of these lesions.

Muir-Torre Syndrome Associated Periocular Sebaceous Neoplasms: Screening Patterns in the Literature and in Clinical Practice.

BACKGROUND: Muir-Torre syndrome (MTS) is defined clinically as the association of cutaneous sebaceous neoplasm and visceral malignancy. Ancillary tests are considered crucial for diagnosis. Although screening guidelines for MTS, including the Mayo MTS scoring system, have been proposed, there are no ophthalmic site-specific guidelines. SUMMARY: A literature review conducted by PubMed search for articles describing patients with periocular sebaceous neoplasm and MTS disclosed 31 publications describing 60 patients, 36 (60%) of whom fulfilled clinical criteria for MTS, 6 (10%) whose diagnosis was based on screening ancillary studies, 14 (23%) who fulfilled clinical criteria and had supporting screening ancillary studies, and 4 (7%) who fulfilled clinical criteria and had supporting diagnostic genetic testing. Most patients were male (34 vs. 15 females), with a median age of 59 years (range 37-79 years). The most common diagnosis was sebaceous carcinoma (40/60, 67%), followed by sebaceous adenoma (16/60, 27%), followed by other tumors with sebaceous differentiation (4/60, 6%). The periocular lesions were identified prior to visceral malignancy in 10 out of 45 (22%) cases, after visceral malignancy in 34 out of 45 (76%) cases, and concurrently with visceral malignancy in 1 out of 45 (2%) cases. Immunohistochemistry for mismatch repair proteins was performed in 41 out of 60 (68%) and 14 out of 38 (37%) of the tumors had lost MSH2. Based on Mayo-MTS scores of 2 or greater, and after removing visceral malignancies not included in their scoring algorithm, 26 out of 30 of patients (87%) with complete data were considered to be appropriate candidates for further work-up. A survey of current practice was conducted by questionnaires, distributed to ophthalmic pathologists, ocular oncologists, and oculoplastic surgeons from national and international professional societies. Of the 103 physicians who participated in the survey, 91 (88%) felt that MTS evaluation guidelines were not sufficiently clear. KEY MESSAGES: Our findings suggest that Mayo MTS screening guidelines may be applicable to periocular sebaceous neoplasms. The uncertainty of ophthalmic specialists about optimal screening guidelines for MTS reflects the heterogeneity of defining criteria for MTS and limited molecular genetic data. Larger studies with detailed clinical, histopathologic, and molecular genetic data are required to formally assess screening guidelines for MTS in patients with periocular sebaceous neoplasms.

Conjunctival Melanocytic Nevi With Granular Cell Change.

CONTEXT.­: Granular cell change in melanocytic nevus is underrepresented in the literature with only 4 well-documented cases, 1 described in the conjunctiva. Unfamiliarity with the clinical and pathologic features of these lesions contributes to the diagnostic difficulty. OBJECTIVE.­: To delineate the clinical and histopathologic features of conjunctival nevi with granular cell change. DESIGN.­: In a retrospective observational case series, the medical records of all patients with conjunctival nevi and granular cell change diagnosed between December 2016 and October 2018 were reviewed. Data collected included age, sex, clinical presentation, pathologic findings, and follow-up. RESULTS.­: Twelve patients, 6 males and 6 females, with a median age of 14 years (range, 8-82 years) were identified. The nevus manifested as a pigmented, well-circumscribed nodule (7 of 9; 78%) or patch (2 of 9; 22%) in the bulbar and limbal conjunctiva (7 of 9; 78%) or in the plica semilunaris/caruncle (2 of 9; 22%). Cysts were noted in 7 of 9 lesions (78%). Features prompting surgical excision included atypical pigmentation (8 of 9; 89%), growth (7 of 9; 78%), and atypical vascularity (4 of 9; 44%). Microscopically, all lesions comprised a conventional melanocytic nevus with focal granular cell change and immunoreactivity for Melan-A, SOX10, and HMB-45, with Ki-67 proliferative index of less than 2%. Of the 9 lesions with follow-up information, there were no recurrences over mean follow-up of 11.2 months (range, 1-23 months). CONCLUSIONS.­: Granular cell change in melanocytic nevi is an underrecognized finding that can simulate melanoma clinically and histopathologically. Young age at diagnosis, lack of associated conjunctival melanosis, bulbar location, cysts, and the absence of mitotic figures with a low Ki-67 proliferative index are helpful clinical and pathologic diagnostic clues.

Prostaglandin analogue drops for the treatment of soft tissue expansion and exophthalmos in patients with inactive thyroid eye disease.

OBJECTIVE: Thyroid eye disease (TED) is characterized by an inflammatory response leading to soft tissue expansion within the bony orbit, which may cause exophthalmos. Studies of glaucoma patients reported periorbital fat atrophy after treatment with prostaglandin analogue drops. We hypothesize that owing to this side effect, prostaglandin analogue drops may benefit patients with TED-induced exophthalmos. DESIGN: Interventional prospective pilot study. PARTICIPANTS: Five adults with inactive TED and exophthalmos treated with a single daily drop of bimatoprost to both eyes for 6 months. METHODS: The effect of treatment was evaluated by clinical examinations, Hertel exophthalmometry, marginal reflex distance (MRD), and comparison of digital photographs from before and after treatment by 3 masked oculoplastic surgeons. Patients' subjective satisfaction was recorded as well. RESULTS: Hertel exophthalmometry showed an improvement in exophthalmos after treatment in 3 patients and no change in 2. Both MRD1 and MRD2 increased (for MRD2 p = 0.007). Two observers correctly identified the photograph taken after treatment in 4 patients, and the third observer correctly identified 2 patients and was indecisive about the others. Four patients reported an improvement in their appearance, although additional eyelid retraction was observed. Adverse effects were minimal. CONCLUSION: Topical prostaglandin analogue treatment of TED-associated exophthalmos appears safe. Although this pilot study was statistically underpowered to show positive results, our findings suggest a treatment-related reduction in periorbital fat volume in most cases and a subjective improvement in appearance. These findings have potential implications for the treatment of exophthalmos in the clinical setting, but more research is required.

Complications in Intermediate Uveitis: Prevalence, Time of Onset, and Effects on Vision in Short-Term and Long-Term Follow-Up.

Purpose: To study the prevalence and time of onset of ocular complications in intermediate uveitis (IU) and to assess their effects on visual outcome in short-term and long-term follow-up. Methods: A retrospective cohort study of patients with IU who had a minimal follow-up of one year. Results: 96 patients (174 eyes, 70% females) were included with a mean age at presentation of 30 years. Children constituted 38% of all patients. Mean follow- up was 64.9 months. Pars planitis was the most common form followed by sarcoidosis and multiple sclerosis. Cystoid macular edema (CME), cataract, epiretinal membrane and posterior synechiae were the most prevalent complications. Posterior synechiae, band keratopathy, cataract and papillitis at presentation were associated with worse presenting visual acuity (VA). Of the late-onset complications, glaucoma/ocular hypertension (OHT) was the most significantly associated with worse long-term VA. Most sight-threatening complications (namely CME and glaucoma) were diagnosed at presentation while late complications predominantly affected the posterior segment and included among others peripheral retinal elevations, vasoproliferative tumors, and vitreous hemorrhage. Median LogMAR VA improved at short-term and long-term follow-up, from 0.2 to 0.1 (p<0.001). Subgroup analysis revealed significant VA improvement for eyes with all the different complications except for eyes with glaucoma/OHT. Conclusion: IU is a chronic low-grade uveitis that may be associated with protean early and late complications of the anterior or posterior segments or both. Optimal treatment regimens are imperative for the strict control of inflammation and proper management of complications thus allowing a favorable long-term prognosis.

Visual and Clinical Outcome of Macular Edema Complicating Pediatric Noninfectious Uveitis.

PURPOSE: To investigate the clinical course and visual outcome of macular edema (ME) in pediatric patients with chronic noninfectious uveitis. DESIGN: Retrospective case series. METHODS: The databases of the uveitis clinics of 4 tertiary medical centers in Israel and the UK were searched for all children treated for uveitic ME in the years 2005-2015. Data were collected from the medical records as follows: demographics, diagnosis, visual acuity, clinical and imaging findings, and treatment given specifically for ME. Findings at baseline and at 3, 6, 12, and 24 months were evaluated. RESULTS: The cohort included 25 children (33 eyes) of mean age 8.5 ± 3.4 years. The most common diagnosis was intermediate uveitis, in 14 children (7 idiopathic, 7 pars planitis). Uveitis was active at ME diagnosis in 28 eyes (84.8%). Median duration of follow-up was 48 months. Median time to resolution of ME was 6 months, with complete resolution in 25 eyes (75.8%) by 24 months. Baseline visual acuity was ≥20/40 in 8 eyes (24.2%), increased to 57.6% at 3 months (P < .0001), and remained stable thereafter. Treatment regimens included corticosteroids (systemically and/or locally), immunosuppression, and biologic therapies. No correlation was found between outcome and either structural characteristics of ME or specific treatment strategy. CONCLUSIONS: The prognosis of pediatric uveitic ME is favorable despite its chronic course. Larger randomized controlled trials are needed to define differences among treatment regimens.

Tubular apocrine adenoma of the eyelid - A case report and literature review.

Tubular apocrine adenoma is a rare benign adnexal neoplasm most commonly identified in the scalp, composed of a dermal proliferation of apocrine tubules in a background of hyalinized stroma. Tubular apocrine adenoma can be a component of various sweat gland tumors and can also morphologically overlap with other sweat gland neoplasms. Isolated tubular apocrine adenoma arising in the glands of Moll is exceedingly rare, with only 4 previously reported cases. We present a 63-year-old male with tubular apocrine adenoma of the left upper eyelid, which recurred following initial incomplete excision. Although the lesion showed focal morphologic similarity to the apocrine variant of pleomorphic adenoma (chondroid syringoma), the diagnosis of tubular apocrine adenoma was supported by fluorescence in situ hybridization studies, which demonstrated absence of PLAG1 and HMGA2 gene rearrangements seen in pleomorphic adenoma. This case illustrates the clinical, microscopic and immunohistochemical features of tubular apocrine adenoma. The recent advances in our understanding of the molecular genetics of tubular apocrine adenoma and related tumors, and how these advances shape the evolving classification of sweat gland tumors are reviewed.

Efficacy of Vismodegib for the Treatment of Orbital and Advanced Periocular Basal Cell Carcinoma.

PURPOSE: To evaluate the effectiveness of vismodegib, a Hedgehog pathway inhibitor, in treating orbital and advanced periocular basal cell carcinoma (BCC) in Israeli multidisciplinary medical centers. DESIGN: Retrospective case series. METHODS: Background, treatment, and outcome data were retrospectively collected from the medical records of all patients with locally advanced and metastatic orbital or periocular BCC treated with vismodegib in 2012-2017 at 2 tertiary medical centers. RESULTS: The cohort included 21 patients (16 male) of median age 76 years with periocular (n=6) or orbital (n=15) BCC. Median duration of treatment was 9 months, with follow-up of 26 months (range 9-60 months) overall and 17 months after treatment cessation. Clinical response was complete in 10 patients, partial in 10 patients, and stable in 1 patient. Among the complete responders, 5 maintained a complete response at 16 months, and 3 who stopped treatment had a recurrence 8 months later. Almost all treatment-related adverse reactions were graded 1 or 2 (low-grade). The most common grade 1 or 2 complications were muscle spasm (76%), followed by dysgeusia (57%), alopecia (47%), weight loss (47%) and decreased appetite (19%). The only grade 3 or 4 adverse event was hepatotoxicity (10%). Eight patients discontinued treatment because of side effects. Five patients died, most from reasons unrelated to vismodegib therapy, except for 1 patient who died from possibly treatment-related sepsis (grade 5 adverse event). CONCLUSIONS: To our knowledge, this is the only study generated outside the United States and Europe, and it represents the largest study to date on vismodegib therapy for locally advanced periocular BCC. Treatment according to an individualized maximally tolerated dose may achieve a comparable response to the ERIVANCE protocol. Longer-term studies are needed to assess prognosis.

Horizontal Deviations in Congenital Brown Syndrome.

PURPOSE: To report the incidence of horizontal deviations requiring surgical correction in patients with congenital Brown syndrome. METHODS: In a retrospective study, the medical records of all children who underwent a surgical correction of congenital Brown syndrome at Schneider Children's Medical Center of Israel from 1998 to 2016 were reviewed, analyzing the presence of preoperative primary position horizontal misalignment. RESULTS: Overall, 19 eyes (8 right and 11 left eyes) of 16 patients (7 males, 9 females; mean age: 4.2 ± 2.6 years) were included in this study. Fourteen patients (88%) had surgery for correction of a compensatory head position, including 8 patients (50%) with a head tilt and 6 patients (38%) with a chin-up position, and 2 patients had surgery for primary position hypotropia. All of them underwent a weakening procedure of the superior oblique tendon, by either Z-tenectomy (81%, n = 13) or suture elongation of the superior oblique tendon (19%, n = 3). Fifty-six percent of patients (n = 9) had primary position horizontal deviation before surgery, including 50% (n = 8) exodeviations, ranging from exophoria of 4 prism diopters (PD) to exotropia of 30 PD, and one esotropia of 14 PD. Fifty percent of patients (n = 8) had surgery to correct the horizontal deviation by a recession of either one (31%, n = 5) or two (19%, n = 3) muscles. Mean preoperative horizontal deviation (9.3 ± 3.4 PD) decreased significantly following surgery (1.7 ± 1 PD, P = .001) (paired t test). CONCLUSIONS: Significant horizontal misalignment is often present in patients with congenital Brown syndrome and its correction should be considered at the time of surgery. [J Pediatr Ophthalmol Strabismus. 2018;55(2):113-116.].