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OBJECTIVE: Giant cell arteritis (GCA) is the most common type of primary vasculitis. Matrix metalloproteinase 9 (MMP-9) is present in arterial lesions of GCA and may be involved in its pathogenesis. We investigated whether certain genotypes of 4 single-nucleotide polymorphisms (SNPs) of MMP-9 are overrepresented in patients with histologically confirmed GCA. METHODS: Four SNPs of MMP-9, rs3918242 in the promoter region and 3 nonsynonymous coding SNPs (rs3918252, rs17576, and rs2250889) were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis in 58 white patients for whom there was a clinical suspicion of GCA. Thirty of these patients had histologically confirmed GCA (group 1), and 28 patients had negative results of a temporal artery biopsy for GCA (group 2). Estimates of the genotype distributions of each of these SNPs in a white population were determined using publicly available genotype data for a panel of 23 individuals (group 3). RESULTS: Although 1 SNP was monomorphic in all 3 groups, we observed statistically significant differences in the genotype distributions for rs2250889 between group 1 and group 2 (P = 0.005) and between group 1 and group 3 (P = 0.009), but not between groups 2 and 3 (P = 0.965). CONCLUSION: These data derived from a sample of patients with GCA suggest that the G allele of MMP-9 polymorphism rs2250889 is overrepresented in patients with histologically confirmed GCA. Clearly, larger sample sizes will be necessary to confirm this suggestive association and better characterize a possible linkage disequilibrium structure among polymorphisms. [ABSTRACT FROM AUTHOR]

Report emphasizes the importance of systemic monitoring of germline retinoblastom patients for second malignant neoplasms [ABSTRACT FROM AUTHOR]

Purpose: To report the detailed histopathology of two enucleated eyes from two patients who developed severe visual loss associated with retinal hemorrhages, vessel sheathing and vascular nonperfusion after administration of an initial dose of intravitreal pegcetacoplan, and to propose, with supportive histopathology, the pathogenesis of the clinical syndrome previously termed hemorrhagic occlusive retinal vasculitis (HORV)., Design: Case series., Subjects: Two enucleated eyes from two patients treated with intravitreal pegcetacoplan., Methods: Retrospective, multicenter consecutive clinical-pathologic analysis., Main Outcome Measures: Histopathologic review and immunophenotypic characterization., Results: Both patients presented with inflammation and significant vision loss nine days following the initial injection of pegcetacoplan with no subsequent improvement and underwent enucleation for pain control. Histologic examination of the enucleated eyes (patient one at 4 months post-injection and patient two at 40 days) revealed extensive vascular thrombosis, retinal hemorrhages and necrosis, and a dense inflammatory infiltrate in the uvea and variably the optic nerve, episclera, and muscle tendons composed of predominantly of T-cells, macrophages, and eosinophils. Notably, the inflammatory infiltrate was absent from the retina. In addition, one eye demonstrated multiple foci of glomerular-like vascular proliferations in the uveal tract and thrombosis with focal recanalization of vessels in the optic nerve., Conclusion: Drug-induced, immune-mediated, retinal vasculopathy and choroiditis (DIRVAC) is a rare complication following pegcetacoplan injection. Although some limitations arise in interpretation of histopathologic findings due to compensatory changes in the eyes over time (prior to enucleation), the authors propose that the combined clinical, histopathologic, and immunohistochemical findings suggest a mixed-type, delayed hypersensitivity reaction as mechanism of initial injury., (Copyright © 2024. Published by Elsevier Inc.)

A 28-year-old male presented to the emergency room suffering an ocular burn injury from a welding rod. Given the mechanism of injury, severe delayed injury of the ocular adnexa occurred, requiring enucleation, partial exenteration of the superior orbit, and extensive reconstruction. Histopathology of the affected tissue was analyzed. This is the first report that details the clinical course of a patient with delayed high amperage and low voltage electrical burn injury.

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 nonmassive 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 ≤ .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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Ophthalmomyiasis is the result of fly larvae feeding on the tissues of the eye. Commonly associated with poor hygiene and open wounds, this condition is rare and often stigmatized. Treatment can be straightforward, and full recovery is common. Identifying the species responsible for ophthalmomyiasis is important for the medical, forensic, and entomological communities. Here, we present a case of ophthalmomyiasis where 30-40 blow fly (Diptera: Calliphoridae) larvae were removed from the eye of a human male. A representative subsample of five larvae was used for taxonomic identification via two approaches (a) DNA analysis, via sequencing of the complete mitochondrial genome (mtGenome) and comparison of the mtGenome and mitochondrial COI barcode region to GenBank, and (b) morphology, examination of the posterior spiracles using microscopy, and comparison to published larval descriptions of blow flies. Two species of blow flies were identified from the DNA analysis: Lucilia coeruleiviridis and Phormia regina . Morphological examination could only confirm L. coeruleiviridis as being present. To our knowledge, finding two blow fly species causing ophthalmomyiasis in a single individual has not been previously reported in the scientific literature. Neither P. regina nor L. coeruleiviridis prefers living tissue for larva development, but since they fill similar ecological niches, perhaps this was a show of competition rather than a normal feeding habit. Knowing these blow fly species can resort to this behavior, and that it can affect human populations, is valuable to the education of patients and providers., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Taylor B. Parker et al.)

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., (Copyright © 2024 Copyright: © 2024 Indian Journal of Ophthalmology.)

Purpose: To report an atypical presentation of an epibulbar simple cartilaginous choristoma with a unique pigmented multicystic component., Case Description: A 69-year-old African American female presented for evaluation of a right nasal epibulbar lesion that had progressed over the prior year. Slit-lamp evaluation revealed an immobile, mildly pigmented multicystic lesion measuring 6.0 × 4.5 mm that involved the nasal bulbar conjunctiva and the plica semilunaris. The lesion appeared benign, without feeder vessels or features of epithelial dysplasia. Given its recent growth and the patient's cosmetic concerns, the lesion was excised with ocular surface reconstruction. Histopathological evaluation disclosed a well-circumscribed nodule of well-differentiated cartilage in the substantia propria, consistent with a simple cartilaginous choristoma. The overlying conjunctival stroma contained multiple cysts lined by focally pigment epithelium. The patient recovered well from surgery, with satisfactory cosmetic results., Conclusions: Our case of epibulbar simple cartilaginous choristoma includes a prominent superficial component of pigmented epithelial cysts, which has not been previously reported in the literature. This augments our knowledge on the spectrum of presentations of cartilaginous choristomas and underscores the importance of histopathological evaluation for definitive diagnosis., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: The aim of this study was to report a novel PRDM5 pathologic variant and ophthalmic findings in a family with 3 children diagnosed with brittle cornea syndrome (BCS). Histopathologic findings and surgical outcome of a child with BCS who underwent full-thickness corneal transplant are described., Methods: This is an observational case report of a nonconsanguineous Laotian family with 3 siblings diagnosed with BCS. Data collected included visual acuity, cycloplegic refraction, slit-lamp biomicroscopy, dilated fundus examination, corneal pachymetry, corneal topography, and general medical findings. Targeted testing through PRDM5 gene sequencing with copy number variation detection was conducted., Results: The 3 siblings included a 12-year-old boy and 8- and 6-year-old sisters, all of whom presented with myopia, blue-tinted sclerae, thin corneas, and variable corneal scarring. All 3 affected children were found to be homozygous for the PRDM5 gene variant c.1117&#95;1123delinsTTTAATGCTTACAAATGTTTG p.Asp373Phefs*57. Coding sequences of PRDM5 and ZNF469 genes were sequenced in their entirety, and this was the only pathologic variant present in this family. The youngest affected sister developed persistent hydrops with severely decreased vision and underwent penetrating keratoplasty. Histopathology revealed severe corneal thinning, diffuse absence of Bowman layer, and ruptured Descemet membrane scrolls., Conclusions: Three siblings with clinical signs of BCS, including corneal thinning, myopia, and blue sclerae, were found to have a novel PRDM5 gene pathologic variant. This pathologic variant has not been previously reported, although 1 downstream nonsense pathologic variant has been reported as pathogenic. The similar phenotypes in all affected patients support the pathogenicity of this variant. Surgical management of BCS presents unique challenges due to severe tissue fragility., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

A 53-year-old Caucasian male presented with an inflamed-appearing limbal nodule in his OD, clinically compatible with nodular episcleritis, that was unresponsive to topical corticosteroid therapy. Excisional biopsy of the lesion was performed and histopathological examination revealed foci of necrotizing vasculitis and granulomatous inflammation in a background of intense actinic elastosis. Infectious stains for organisms were negative. A comprehensive systemic evaluation for vasculitides was negative. Three years later, the patient returned with a clinically and histopathologically identical lesion in his OS. Systemic evaluation was noncontributory again, and a diagnosis of bilateral conjunctival actinic granuloma with necrobiotic vasculitic pattern was made., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2023 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Exogenous ochronosis refers to accumulation of homogentisic acid metabolites in tissues, manifesting as pigmentation of affected tissues. Phenolic compounds are most commonly implicated, including hydroquinone, quinine, phenol, resorcinol, mercury, and picric acid. The affected connective tissues exhibit brownish discoloration when heavily pigmented and the histopathological appearance is characteristic with "banana-shaped" ochre-colored pigment deposits. Herein, the authors describe a rare case of exogenous ochronosis involving the conjunctiva, sclera and skin, as a result of chronic use of Teavigo (94% epigallocatechin gallate), a polyphenol compound with postulated antioxidant and antiapoptotic activity., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

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., (Published by Elsevier Inc.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To present the clinicopathologic correlation of indolent nonprogressive multifocal choroidal lesions, clinically presumed to be lymphoid in nature, using multimodal imaging and histopathological analysis of a donor eye., Design: Case study and clinicopathological correlation., Participants: A 77-year-old man of Caucasian ancestry with indolent, nonprogressive, multifocal, choroidal infiltration of his right eye, presumed to be lymphocytic in nature based on the appearance of the lesions, was followed up for 19 years., Methods: Multimodal imaging, including fundus photography, B-scan ultrasonography, OCT, fluorescein angiography, and indocyanine green angiography, was performed throughout the 19 years of follow-up before the patient's death. The involved eye was preserved 21 hours postmortem and analyzed using standard histopathological and immunohistochemical techniques., Main Outcome Measures: Correlation of findings on multimodal imaging with histopathological and immunohistochemical findings in the involved eye., Results: Clinical examination over the course of 19 years showed no deterioration in the visual acuity of the involved eye. Multimodal imaging revealed yellow-orange choroidal lesions that showed no appreciable progression during the 19 years of follow-up. These areas stained minimally on fluorescein angiography. Indocyanine green angiography revealed tortuous choroidal vessels and fluorescence blockage. Enhanced-depth imaging OCT revealed hyporeflective, homogenous choroidal thickening. Light microscopy, histopathology, and immunohistochemistry showed that the lesions were composed of small, mature-appearing B cells that spared the choriocapillaris. The findings were most consistent with extranodal marginal-zone lymphoma of the mucosa-associated lymphoid tissue (MALT)., Conclusions: Indolent, nonprogressive, multifocal, choroidal lymphoid lesions in this patient remained confined to the choroid, as determined based on the clinical examination and imaging for almost 2 decades, with no clinical evidence of extension into the retina. Light microscopy, histopathology, and immunohistochemistry postmortem showed that the lesions were composed of small, mature-appearing B cells that spared the choriocapillaris. The findings were consistent with extranodal marginal-zone lymphoma of the MALT. This entity is distinct from more aggressive uveal and choroidal lymphomas and is expected to remain relatively stationary on long-term clinical follow-up, with a good visual prognosis., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to describe the genotypic and phenotypic characteristics of an infant with a SLC4A11 mutation associated with bilateral corneal edema, hearing loss, and hydronephrosis present since birth., Methods: This was a case report. Ophthalmic and systemic examination of the proband, histopathologic and ultrastructural characteristics of bilateral corneal discs, and molecular genetic evaluation by whole-exome sequencing are described., Results: A male infant was born with bilateral corneal opacities, sensorineural hearing loss, and hydronephrosis to healthy parents after an uneventful pregnancy. Penetrating keratoplasty of the left eye at age 10 months demonstrated minimal corneal edema with normal thickness Descemet membrane and cellular endothelium with intracytoplasmic vacuoles and degenerative changes in rare cells. Penetrating keratoplasty of the right eye 6 months later disclosed prominent corneal edema with a thickened posterior banded layer of Descemet membrane and severe endothelial atrophy. Whole-exome sequencing of the proband and parents' blood demonstrated a homozygous mutation in SLC4A11 gene (c.1735&#95;1737delCTC,p.Leu579del). The combined clinical, histopathologic, and molecular genetic findings raised consideration of an unusual phenotype of Harboyan syndrome manifesting as congenital hereditary endothelial dystrophy with a prelingual rather than, as previously described, postlingual hearing loss., Conclusions: We report a novel homozygous SLC4A11 variant with a previously undocumented phenotype of CHED in association with prelingual sensorineural hearing loss and hydronephrosis, thus broadening our understanding of the spectrum of genotypic and phenotypic findings of Harboyan syndrome., Competing Interests: Conflicts of interest statement: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The purpose of this study was to report a large series of patients with peripheral hypertrophic subepithelial corneal degeneration (PHSCD) and differentiate the condition from Salzmann nodular degeneration (SND)., Methods: We retrospectively reviewed the charts of 49 patients diagnosed with PHSCD and reported their clinical, refractive, and topographic/tomographic findings., Results: Most of the eyes were white and quiet. Minimal variable injection was present in a few eyes usually in the presence of pseudopterygium. Typical corneal involvement consists of peripheral circumferential-elevated whitish subepithelial opacities with fine superficial vessels along the limbus and linear deposits of iron in the epithelium along the central edge of the opacification. The typical topographic/tomographic findings consist of flattening directly over the corneal opacification with central flattening aligning with the axis of the opacification. In all subjects, the mean refractive astigmatism was significantly less than the mean topographic/tomographic Sim K astigmatism. Thirty-five eyes underwent surgical excision. The surgical eyes demonstrated significantly less astigmatism and better best-spectacle corrected visual acuity than pre-op. Moreover, all the eyes that underwent surgery for discomfort experienced significant improvement in their symptoms. Histopathology of the keratectomy specimens demonstrated paucicellular subepithelial fibrosis with overlying epithelium that was variable in caliber., Conclusions: PHSCD is distinct from SND, primarily occurring in middle-aged women, bilateral and fairly symmetric with larger more peripheral opacities than SND, and absence of inflammatory signs and symptoms., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: High-risk histopathologic features of retinoblastoma are useful to assess the risk of systemic metastasis. In this era of globe salvage treatments for retinoblastoma, the definition of high-risk retinoblastoma is evolving., Objective: To evaluate variations in the definition of high-risk histopathologic features for metastasis of retinoblastoma in different ocular oncology practices around the world., Design, Setting, and Participants: An electronic web-based, nonvalidated 10-question survey was sent in December 2020 to 52 oncologists and pathologists treating retinoblastoma at referral retinoblastoma centers., Intervention: Anonymized survey about the definition of high-risk histopathologic features for metastasis of retinoblastoma., Main Outcomes and Measures: High-risk histopathologic features that determine further treatment with adjuvant systemic chemotherapy to prevent metastasis., Results: Among the 52 survey recipients, the results are based on the responses from 27 individuals (52%) from 24 different retinoblastoma practices across 16 countries in 6 continents. The following were considered to be high-risk features: postlaminar optic nerve infiltration (27 [100%]), involvement of optic nerve transection (27 [100%]), extrascleral tissue infiltration (27 [100%]), massive (≥3 mm) choroidal invasion (25 [93%]), microscopic scleral infiltration (23 [85%]), ciliary body infiltration (20 [74%]), trabecular meshwork invasion (18 [67%]), iris infiltration (17 [63%]), anterior chamber seeds (14 [52%]), laminar optic nerve infiltration (13 [48%]), combination of prelaminar and laminar optic nerve infiltration and minor choroidal invasion (11 [41%]), minor (<3 mm) choroidal invasion (5 [19%]), and prelaminar optic nerve infiltration (2 [7%]). The other histopathologic features considered high risk included Schlemm canal invasion (4 [15%]) and severe anaplasia (1 [4%]). Four respondents (15%) said that the presence of more than 1 high-risk feature, especially a combination of massive peripapillary choroidal invasion and postlaminar optic nerve infiltration, should be considered very high risk for metastasis., Conclusions and Relevance: Responses to this nonvalidated survey conducted in 2020-2021 showed little uniformity in the definition of high-risk retinoblastoma. Postlaminar optic nerve infiltration, involvement of optic nerve transection, and extrascleral tumor extension were the only features uniformly considered as high risk for metastasis across all oncology practices. These findings suggest that the relevance about their value in the current scenario with advanced disease being treated conservatively needs further evaluation; there is also a need to arrive at consensus definitions and conduct prospective multicenter studies to understand their relevance.

Purpose: To characterize the clinical and histopathologic features of actinic granuloma of the conjunctiva., Design: Retrospective observational case series METHODS: Institutional pathology records between 2014 and 2020 were searched for all cases of conjunctival actinic granuloma. Information collected included age, sex, ocular and medical history, clinical findings, laboratory workup, treatment, follow-up, pathologic diagnosis, and histopathologic inflammation pattern., Results: Eight eyes of 8 patients, 5 men and 3 women, with a median age of 43 years (mean 49, range 24-83) were identified. Clinical diagnosis was pterygium (n = 4, 50%), inflamed pterygium (n = 1, 13%), pterygium vs conjunctival squamous cell carcinoma (n = 1, 13%), episcleritis vs inflamed pinguecula (n = 1, 13%), and scleritis vs keratoacanthoma (n = 1, 13%). Of 5 lesions with follow-up information, none recurred following excision with a median follow-up of 9 weeks (mean 19 weeks, range 1-61 weeks). Allergy/atopy was documented in 4 of 7 (57%) patients with available medical information. There were no other systemic associations. Histopathologically, actinic granuloma was associated with pterygium (n = 6, 75%) and pinguecula (n = 2, 25%). All lesions were composed predominantly of histiocytes and a variable number of foreign body-type giant cells associated with a focus of severe actinic elastosis. The inflammatory pattern was giant cell (n = 4, 50%), sarcoidal (n = 2, 25%), histiocytic (n = 1, 13%), and combined histiocytic and sarcoidal (n = 1, 13%)., Conclusion: Conjunctival actinic granuloma has diverse clinical and histopathologic manifestations, which need to be distinguished from other autoimmune, neoplastic, and infectious etiologies. This lesion frequently occurs in pre-existing pterygium and pinguecula and may be associated with allergy and atopy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To find immunohistochemical markers that distinguish adenocarcinoma of the nonpigmented ciliary epithelium (NPCE) from metastatic carcinoma, especially metastatic renal cell carcinoma., Design: Retrospective case series., Methods: Three cases of adenocarcinoma of the NPCE were examined histologically with hematoxylin-eosin stain and immunohistochemical stains including vimentin, AE1/AE3, Cam 5.2, CK7, PAX2, PAX8, AMACR, and CAIX. We also reviewed previously reported cases of this tumor., Results: We found that the immunohistochemical profile of adenocarcinoma of the NPCE can overlap with renal cell carcinoma. Both tumors can express vimentin, cytokeratin AE1/AE3, Cam 5.2, PAX2, PAX8, and AMACR. One of the adenocarcinomas of the NPCE in our series also expressed CD10 and the renal cell carcinoma marker (RCC Ma). Carbonic anhydrase IX (CAIX) was not detected in any of the 3 tumors., Conclusions: Adenocarcinomas arising in phthisic eyes can be diagnostically challenging. We have found it particularly difficult to distinguish adenocarcinoma of the NPCE from metastatic carcinoma, especially metastatic clear cell renal cell carcinoma and papillary renal cell carcinoma. Because of the immunophenotypic overlap, most patients will require systemic workup including imaging of the kidneys to be certain of the diagnosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe a patient with orbital adult T-cell leukemia/lymphoma (ATLL) and to review the literature on presentation, diagnostics, management, and clinical course of this rare disease., Methods: A systematic literature review. PubMed/MEDLINE and Google Scholar databases were searched for all well-documented cases of orbital/ocular adnexal ATLL., Results: Sixteen patients were included in the final analysis. The median age at diagnosis was 47 years (range, 20-85), 9/16 patients (56%) were male, and patients were of Japanese (10/16, 63%), Caribbean (5/16, 31%), or African (1/16, 6%) origin. Proptosis (6/15, 40%) and visual loss (5/15, 33%) were the most common presenting signs. Involvement of adjacent structures was documented in 8 of 16 (50%) patients. All patients had evidence of systemic ATLL, which was identified concurrently with orbital/ocular adnexal disease in 9 of 15 (60%) patients. Management included multi-agent chemotherapy with steroids (9/13, 69%), antivirals (2/13, 15%), biologic agents (4/13, 31%), and umbilical cord blood transplantation (1/13, 8%). Most patients (8/12, 67%) experienced at least partial remission with disease relapse occurring in 6 of 8 patients (75%). The median survival time was 28 months (95% CI, 5.5-50.5 months)., Conclusions: Adult T-cell leukemia/lymphoma should be considered in the differential diagnosis of orbital and ocular adnexal space-occupying lesions, particularly in male patients from endemic regions. Orbital disease is frequently locally aggressive and presents concurrently with systemic ATLL, highlighting the importance of comprehensive multimodal work-up and multidisciplinary management. Emerging targeted therapies and hematopoietic stem cell transplant may prolong survival., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2021 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Purpose: To evaluate PAX8 expression by immunohistochemistry in the normal pediatric and adult crystalline lens and to assess the usefulness of PAX8 immunohistochemical stain in the diagnosis of morphologically challenging lesions of lenticular origin., Design: Retrospective, observational case series., Participants: Fourteen congenital and acquired lens-derived lesions and 10 control crystalline lenses., Methods: Hematoxylin-eosin and periodic acid-Schiff stains and an immunohistochemical panel of PAX8, vimentin, S100, smooth muscle actin, AE1/AE3, cytokeratin 7, and cytokeratin 5/6 antibodies were performed on all tissues., Main Outcome Measures: Distribution of PAX8 expression in normal crystalline lens and in lens-derived lesions., Results: Records search identified 10 normal pediatric and adult crystalline lenses, 1 phakomatous choristoma, 1 Peters anomaly with adherent leukoma, 1 lens capsule with congenital pyramidal cataract formation, 2 lenses with anterior and posterior subcapsular cataract formation, 3 postsurgical cataractous lenses (Soemmerring ring cataract and capsular fibrosis), and 6 retrocorneal membranes that incorporated various components of metaplastic corneal endothelium, metaplastic lens epithelium, corneal stroma, and epithelial downgrowth. Strong nuclear PAX8 expression was observed in the lens epithelium and in the equatorial lens bow of normal pediatric and adult lenses. Nuclear PAX8 expression also was observed in the lesions that retained some of the epithelial morphologic features, such as phakomatous choristoma, adherent leukoma, congenital pyramidal cataract, and components of intraocular membranes with lens epithelial differentiation. PAX8 expression was lost in lens epithelial lesions that had undergone mesenchymal transition, such as anterior subcapsular cataract and capsular fibrosis., Conclusions: PAX8 antibody may be a useful adjunct to the immunohistochemical panels in morphologically challenging lens epithelial-derived lesions that retain epithelial morphologic features. PAX8 is not useful in the diagnosis of lens-derived lesions that feature epithelial-mesenchymal transition., (© 2021 by the American Academy of Ophthalmology.)

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To determine the usefulness of melan-A, SOX10, HMB45, and p16 immunohistochemical stains in the distinction between the low-grade and high-grade conjunctival melanocytic intraepithelial lesions, either independently or as components of an immunohistochemical panel., Design: Retrospective observational case series., Methods: Institutional pathology records between 2014 and 2018 were searched for all patients with conjunctival melanocytic intraepithelial lesions. Biopsies without supporting clinical history or tissue available for review and immunohistochemical analysis were excluded. Clinical, histopathologic, and immunohistochemical (p16, SOX10, HMB45, and Ki-67) findings were recorded., Results: Thirty-one patients underwent 47 biopsies for conjunctival melanocytic lesions between 2014 and 2018. Pathologic diagnoses were low-grade conjunctival melanocytic intraepithelial lesion (n = 18, 38%) and high-grade conjunctival melanocytic intraepithelial lesion/melanoma in situ (n = 29, 62%). The addition of melan-A and SOX10 immunohistochemical stains resulted in an upgrade of conjunctival melanocytic intraepithelial lesion from low-grade to high-grade in 2 (4%) of 47 cases. The addition of melan-A and SOX10 immunohistochemical stains did not downgrade any of the histomorphologically high-grade lesions. In a clinical-pathologic multivariable model, the parameters most predictive of high-grade melanocytic intraepithelial lesion/melanoma in situ were involvement of the caruncle (odds ratio [OR] = 19, confidence interval [CI] 1.6-212; P = .02] and p16 cytoplasmic H-score >30 (OR = 81, CI 2.7 to >999; P = .01) CONCLUSION: Although the stains for melanocytic markers melan-A and SOX10 facilitate assessment of melanocytic intraepithelial lesions, the current immunohistochemical panels have limited value in distinction between the low-grade and high-grade intraepithelial melanocytic proliferations and need to be used judiciously., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To highlight the increasing importance of gene fusions in the diagnosis, prognosis, and therapy of ocular adnexal tumors., Design: Perspective., Methods: A focused review of gene fusions, their pathogenic mechanism, and gene fusion detection methods in lacrimal gland and primary orbital and ocular adnexal soft tissue tumors; reappraisal of diagnostic, prognostic, and therapeutic approach to ocular adnexal tumors in light of emerging molecular genetic data., Results: The widespread implementation of fluorescence in situ hybridization and next-generation sequencing methods in pathology practice has led to identification of recurrent gene rearrangements and fusions in a variety of tumors. As a result, molecular genetic methods have become the gold standard for diagnosis of tumors with overlapping histology and immunophenotype, such as small round blue cell tumors. Identification of canonic gene fusions has led to development of sensitive and specific immunohistochemical markers, such as STAT6 in solitary fibrous tumor. In addition to diagnostic accuracy, gene fusions have prognostic implications, such as unfavorable prognosis of PAX3-FOXO1 fusion in alveolar rhabdomyosarcoma. Finally, recognition of gene fusions as a driving mechanism in neoplasia has led to development of U.S. Food and Drug Administration-approved targeted therapies, such as TRK inhibitors for NTRK fusion-positive cancers., Conclusion: The discovery of recurrent gene fusions in various tumors, including those involving ocular adnexa, has led to a deeper insight into the molecular mechanisms of these neoplasms, revolutionizing our approach to their diagnosis, prognostication, and therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Since the original description of "dacryadenoma" by Jakobiec and associates, the data on this unusual epibulbar lacrimal gland lesion remain sparse. The aim of this study was to characterize clinically, morphologically, and immunohistochemically this isolated epibulbar lacrimal gland lesion., Design: Retrospective observational case series., Methods: Institutional pathology records between 2000 and 2019 were searched for all cases of isolated epibulbar lacrimal gland lesions. Tissue from 3 normal lacrimal glands and 1 complex choristoma were included for comparative analysis. Clinical, histopathologic, and immunohistochemical findings were recorded., Results: Four patients with isolated epibulbar lacrimal gland lesions, 2 male and 2 female, with a median age of 18 years (range, 12-57) were identified. All patients presented with recent onset of unilateral pink-to-orange, well-circumscribed subepithelial juxtaforniceal (3/4, 75%), or nasal (1/4, 25%) bulbar conjunctival nodules, which were asymptomatic (3/4, 75%) or associated with foreign body sensation (1/4, 25%). When compared with the normal lacrimal gland and complex choristoma, all isolated epibulbar lacrimal gland lesions were composed predominantly of variably dilated, branching tubular structures with pseudo-apocrine snouts, and either totally absent (2/2, 50%) or rare (2/2, 50%) ducts and rare acinar zymogen granules (3/4, 75%)., Conclusion: Our study confirms that a subset of isolated epibulbar lacrimal gland lesions differs morphologically and immunohistochemically from normal lacrimal gland tissue and the lacrimal gland in a complex choristoma. These differences range from subtle to overt, suggesting that isolated epibulbar lacrimal gland lesions may have originated from precursor cellular elements indigenous to the conjunctiva (hamartia) and grew into disorganized lacrimal gland tissue., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The role of p16 in the diagnosis and prognosis of conjunctival melanocytic lesions in the context of other clinical and immunohistochemical parameters has not been systematically explored. This study was conducted to determine whether p16 is a useful parameter in the diagnosis and prognosis of conjunctival melanocytic nevi and melanoma, either independently or as a component of immunohistochemical panels. Sixty-one patients underwent 61 biopsies for conjunctival melanocytic lesions between 2014 and 2018. Pathologic diagnoses were melanoma (n = 25, 41%), nevus (n = 21, 34%), and conjunctival melanocytic lesion of uncertain malignant potential (n = 15, 25%). The biopsies were assessed for expression of p16, SOX10, HMB45, and Ki-67. In a multivariable model, the parameters most predictive of melanoma versus nevus were diffuse HMB45 staining (odds ratio [OR] = 45, confidence interval [CI] = 4.4-457, P = .02] and p16 nuclear H-score≤115 (OR = 9.5, CI = 1.2-77; P = .04). There was no association of p16 expression with melanoma thickness. Next-generation sequencing identified no CDKN2A mutations or copy number alterations in 12 conjunctival melanomas, including the tumors with absent p16 expression. This study demonstrates that p16 immunohistochemical stain is useful in distinguishing conjunctival melanocytic nevi from melanoma, particularly in combination with HMB45. P16 expression does not appear to correlate with CDKN2A status and melanoma thickness., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors have no conflict of interest to disclose., (Copyright © 2020 by S. Karger AG, Basel.)

Purpose: To describe the clinical and imaging characteristics, pathologic features, and management options of retinal pigment epithelium (RPE) adenoma/adenocarcinoma., Design: Retrospective case series., Participants: Fifty-one patients with RPE adenoma/adenocarcinoma., Methods: Treatment options for the patients included observation, partial lamellar sclerouvectomy (PLSU), enucleation, and others., Main Outcome Measures: Factors related to visual acuity (VA) outcomes (>2 Snellen lines loss, poor final VA [≤20/200], good final vision [≥20/40]), tumor growth, and need for enucleation., Results: The mean patient age at diagnosis was 51 years, and the majority of patients were white (40/51, 78%) and female (34/51, 67%). Primary management included observation (29/51, 57%), PLSU (9/51, 18%), enucleation (4/51, 8%), or others (9/51, 18%). Outcomes revealed decreased VA (10/32, 31%), poor final VA (17/32, 53%), good final VA (11/32, 34%), tumor growth (12/25, 48%), and need for enucleation (7/51, 14%). By multivariable analysis, features predictive of decreased VA included increasing baseline tumor thickness (P = 0.01) and presence of vitreous hemorrhage (P = 0.05). Factors predictive of poor final VA included presence of exudative retinal detachment (P = 0.004), baseline VA 20/50 to 20/150 (P = 0.008), and baseline VA ≤20/200 (P = 0.01). Absence of feeding and/or draining vessel was predictive of good VA (P = 0.004). Tumor growth was associated with multiple treatments (P = 0.02). Increased tumor thickness (P = 0.03) and presence of exudative retinal detachment (P = 0.01) were predictive of enucleation., Conclusion: RPE adenoma/adenocarcinoma can simulate choroidal melanoma. Greater tumor thickness, vitreous hemorrhage, exudative retinal detachment, and poor baseline VA predict worse visual outcome and greater risk for enucleation., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to investigate an enlarged dacryoadenotic lacrimal gland and normal lacrimal glands for the presence of goblet cells (mucocytes)., Design: Retrospective clinicopathologic series., Methods: An enlarged lacrimal gland (dacryoadenosis) without obvious histopathologic alterations was extensively evaluated histochemically, immunohistochemically, and ultrastructurally to detect the presence of goblet cells and to compare the findings with those in five normal lacrimal glands., Results: Granular, zymogen-rich pyramidal acinar cells in normal glands predominated over a previously not reported subpopulation of nongranular, pale-staining cells in both dacryoadenotic and normal lacrimal glands. These cells histochemically stained positively with mucicarmine and Alcian blue. Immunohistochemical and electron microscopic evaluations established that there was a displacement or replacement of cytoplasmic gross cystic disease fluid protein-15 and CK 7-positive tonofilaments in the pale acinar cells by myriad mucus granules. The goblet cells constituted approximately 2% of the normal acinar cells and 5% of dacryoadenotic acinar cells. A depletion of myoepithelial cells and ectopic intra-acinar ductular cells were also observed in dacryoadenosis., Conclusion: Dacryoadenosis is caused by an increase in the number of acini without individual acinar cell hyperplasia. A normal cytologic feature of the lacrimal gland is the presence of acinar goblet cells that had been long overlooked; they are increased in number in dacryoadenosis. Intra-acinar ductular cells and the scattered loss of myoepithelial cells are other abnormalities in dacryoadenosis. The presence of lacrimal gland goblet cells may have physiologic implications for the precorneal tear film and its derangements as well as for the histogenesis of mucus-producing carcinomas., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

Pediatric-type follicular lymphoma is an uncommon B-cell lymphoma that primarily involves the lymph nodes of the head and neck of children and young adults. Ocular involvement is rare, with only 5 well-documented cases in the literature, all occurring in the conjunctiva. The authors describe a 20-year-old African American man with enlarging bilateral medial conjunctival nodules. Excisional biopsy of the larger left conjunctival lesion, clinically presumed to be pyogenic granuloma, revealed pediatric-type follicular lymphoma composed of expansile follicles with germinal centers containing mitotically active blastoid cells, which coexpressed CD20, CD10, and BCL6 and lacked expression of BCL2. Polymerase chain reaction for immunoglobulin heavy chain rearrangement identified a monoclonal B-cell population. Fluorescence in situ hybridization studies failed to demonstrate BCL2, BCL6, and MALT1 gene rearrangements. Next-generation sequencing revealed a pathogenic MAP2K1 mutation, known to be enriched in pediatric-type follicular lymphoma. This report summarizes the clinical and pathologic diagnostic findings, biologic behavior, and management of conjunctival pediatric-type follicular lymphoma.

Purpose: The aim of this study was to assess whether mucoepidermoid carcinoma of the lacrimal sac is a counterpart of CRTC1/3-MAML2 gene fusion-related salivary gland mucoepidermoid carcinoma., Methods: In this retrospective observational case series, pathology records were searched for all cases of lacrimal sac mucoepidermoid carcinoma diagnosed between 1990 and 2018. Data collected included demographics, clinical findings, management, and follow-up. Pathologic parameters assessed included tumor morphology, immunohistochemistry, and MAML2 and EGFR fluorescence in situ hybridization (FISH) studies., Results: Six patients with mucoepidermoid carcinoma of the lacrimal sac, 5 males and 1 female, with a median age of 63 years (range 24-66) were identified. Five tumors were managed with radical resection and 1 patient underwent orbital exenteration. None of the patients developed recurrence or metastases with an average follow-up of 18 months (range 13-23). All tumors had morphologic and immunohistochemical features of mucoepidermoid carcinoma and overexpressed EGFR. MAML2 FISH was negative for MAML2 rearrangement in all tumors. EGFR FISH demonstrated EGFR amplification in 1 tumor., Conclusions: Mucoepidermoid carcinoma of the lacrimal sac is not a lacrimal sac counterpart of CRTC1/3-MAML2 gene fusion-related salivary gland mucoepidermoid carcinoma. EGFR pathway activation and EGFR amplification in a subset of these neoplasms suggest the potential role for anti-EGFR agents., Competing Interests: The authors have no conflicts of interest to declare. None of the authors have relevant financial relationships with commercial interests., (Copyright © 2019 by S. Karger AG, Basel.)

A 4-month-old male infant with frontometaphyseal dysplasia and de novo FLNA gene mutation died of complications of disease. Post-mortem examination revealed accessory iris membranes. This is the first report in the literature of accessory iris membranes in a confirmed case of FLNA mutation and phenotypic anomalies consistent with frontometaphyseal dysplasia. [J Pediatr Ophthalmol Strabismus. 2020;57:e8-e11.]., (Copyright 2020, SLACK Incorporated.)

This is a retrospective case description of a single male patient found to have multiple endocrine neoplasia syndrome type 2B (MEN 2B). At the age of 14, he presented for evaluation of ocular irritation and eyelid thickening. Intraoperative assessment revealed mucosal lesions on the anterior dorsum of his tongue and biopsy of multiple eyelid lesions disclosed bilateral submucosal neuromas, leading to the diagnosis of MEN 2B. MEN 2B is a potentially life-threatening syndrome due to the risk of developing medullary thyroid carcinoma (MTC) and pheochromocytoma. The patient was found to have MTC requiring thyroidectomy. We hope to highlight the clinical and histopathologic findings of MEN 2B in an effort to emphasize the importance of its identification in the absence of a family history.

Melanocytoma is a deeply pigmented variant of melanocytic nevus that classically occurs in the optic disk, sometimes with contiguous involvement of the adjacent retina or choroid. Historically, this tumor was often confused with malignant melanoma both clinically and histopathologically. Today, however, it is generally recognized by its typical clinical features that differ from most melanomas and erroneous enucleation is rarely done. Histopathologically, melanocytoma is composed of intensely pigmented round to oval nevus cells with benign features. Although traditionally believed to be a relatively stationary lesion, it is now known to exhibit minor enlargement in 10--15% of cases and can cause minor visual loss by a variety of mechanisms. In rare instance, it can induce severe visual loss due to spontaneous necrosis of the lesion or compressive optic neuropathy. More importantly, it can exhibit malignant transformation into melanoma in 1--2% of cases. Ophthalmologists should be familiar with melanocytoma of the optic disk and affected patients should be followed periodically., Competing Interests: None

Purpose: To describe four pediatric cases in which isolated orbital pseudotumor preceded the development of a systemic inflammatory disease by months to years., Methods: The medical records of all patients with the clinical diagnosis of orbital pseudotumor seen at the Ocular Oncology Service of Wills Eye Hospital and Northern Virginia Ophthalmology Associates from 2010 to 2015 were reviewed retrospectively, and those associated with systemic inflammatory disease were selected for further study. Data were retrospectively collected from medical record review regarding patient demographics and clinical features, time to development of systemic inflammatory disease, and medical management., Results: In four pediatric patients, isolated orbital pseudotumor preceded the development of a systemic inflammatory disease, including pauciarticular juvenile idiopathic arthritis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), granulomatosis with polyangiitis (Wegener's granulomatosis), and Crohn's disease., Conclusions: Orbital pseudotumor may be an antecedent to systemic inflammatory disease in children. Because this was a small case series, the authors are not ready to suggest that a full systemic work-up for systemic inflammatory disease is warranted for every patient with orbital pseudotumor. However, close observation and suspicion for systemic inflammatory conditions may be reasonable in children who present with idiopathic orbital pseudotumor. [J Pediatr Ophthalmol Strabismus. 2019;56(6):373-377.]., (Copyright 2019, SLACK Incorporated.)

Purpose: To prospectively determine the prevalence of high-risk histopathologic features (HRFs) in patients with unilateral retinoblastoma who undergo enucleation and to evaluate the role of chemotherapy in preventing recurrences., Patients and Methods: Children newly diagnosed with enucleated unilateral retinoblastoma were enrolled prospectively. After central histopathology review, patients with specific HRFs received chemotherapy; others were observed. Primary end points were event-free survivals (EFS)., Results: Of the 331 patients enrolled during 2005 to 2010, 321 eligible patients had central histopathologic review. Discordance between central review and contributing institutions occurred in 23% of patients with HRFs and in 17% of patients without HRFs. Postlaminar optic nerve involvement was present in 53 patients; 42 had massive posterior uveal invasion (≥ 3 mm); 15 had concomitant peripapillary 3 mm or greater choroid and postlaminar optic nerve involvement; and 15 had focal (< 3 mm) choroidal concomitant with lamina or prelamina optic nerve involvement. Two-year EFS for patients with HRFs requiring adjuvant chemotherapy was 0.96 (95% CI, 0.89 to 0.98), and 2-year EFS for patients without HRFs for which observation was indicated was 0.99 (95% CI, 0.96 to 1.0). The 2-year EFS for all patients was 0.98 (95% CI, 0.96 to 0.99)., Conclusion: Adequate handling and interpretation of histopathology of eyes with retinoblastoma is necessary to assign metastatic risk. Concomitant less than 3 mm choroidal and any prelaminar/laminar optic nerve invasion show no recurrence and may warrant no adjuvant chemotherapy. In contrast, concomitant greater than 3 mm peripapillary choroidal invasion and 1.5 mm or greater of postlaminar optic nerve invasion have the poorest outcomes, supporting the need for a more intensive adjuvant chemotherapy regimen for this subgroup. Strict criteria for adjuvant therapy may improve outcomes of children who undergo enucleation at diagnosis and may avoid unnecessary adjuvant chemotherapy for those who are not at risk for recurrence.

Purpose: To demonstrate vitreoretinal traction as a mechanism for perimacular folds in abusive head trauma., Methods: We performed gross and histopathologic examination of eyes of children with suspected abusive head trauma and identified those with typical perimacular folds. Information was collected regarding the incident that led to the child's death and systemic manifestations noted at autopsy. Eyes were prepared in a fashion that allowed for demonstration of the vitreoretinal interface., Results: Ten eyes of five patients (2-13 months) were examined. All patients had systemic manifestations of abusive trauma including intracranial injury. All cases provided evidence of vitreoretinal traction producing perimacular folds. Condensed vitreous was seen attached to the apices of the retinal folds, and the detached internal limiting membrane comprising the inner surfaces of the schisis cavity. Four cases showed severe bilateral multilayered symmetric retinal hemorrhages extending to the ora serrata. All cases showed optic nerve sheath subdural hemorrhage and subarachnoid hemorrhage. Orbital hemorrhage was unilateral in two cases and bilateral in three cases. Four cases showed orbital fat hemorrhage. One case showed extraocular muscle sheath and cranial nerve sheath hemorrhage. Two cases showed juxtapapillary intrascleral hemorrhage., Conclusion: Vitreoretinal traction is the likely mechanism of perimacular folds in abusive head trauma.

Purpose: To evaluate the clinical and pathologic characteristics of conjunctival myxoid lesions, with specific focus on PRKAR1A studies, in order to distinguish neoplastic conjunctival myxoma from other myxoid conjunctival lesions., Methods: A retrospective, interventional, multicenter study of all patients with conjunctival myxoma, conjunctival stromal tumor, or reactive fibromyxoid proliferation diagnosed during 1988-2018. Patient and family medical histories and clinical and pathologic characteristics of excised lesions were assessed., Results: There were 28 patients with conjunctival myxoid lesions diagnosed as myxoma (16/28), conjunctival stromal tumor (10/28), or reactive fibromyxoid proliferation (2/28). The patients with abundant myxoid matrix lesions (14/28, 50%) were younger (mean 49 [range 23-68] years) than those with scant-to-moderate myxoid matrix lesions (14/28, mean 61 [range 18-82] years; P = .04). Abundant myxoid matrix lesions more likely contained predominantly stellate cells (6/14 [43%] vs 0/14 [0%]; P = .05) and fibrillar collagen (13/14 [93%] vs 2/14 [14%]; P < .0001), conforming to the standard morphologic definition of myxoma. Absence of PRKAR1A protein expression was found in 2 lesions with morphologic features of myxoma (2/14, 14%), 1 of which demonstrated a pathogenic mutation in the PRKAR1A gene. There was no difference between the lesions with respect to other clinical and pathologic parameters., Conclusions: PRKAR1A plays a role in the development of a subset of conjunctival myxomas, particularly in tumors fulfilling stringent morphologic criteria for myxoma. With the exception of PRKAR1A studies, current immunohistochemical panels cannot reliably distinguish between neoplastic conjunctival myxomas and other myxoid lesions, underscoring the importance of morphology in establishing accurate diagnosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)