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Age-related macular degeneration (AMD) is a major cause of vision loss in the developed world and its pathogenesis is a topic of active research. To date, much study has been focused on the role of the retinal pigment epithelium (RPE) and Bruch's membrane (BrM) in AMD pathogenesis, but the role of the choroid has also been investigated. In this review, we focus on recent advancements in research in the role of the choroid in AMD, beginning with an exploration of the histopathologic, cellular and molecular changes that occur in the choroid in AMD and concluding by discussing new choroidal imaging techniques and patterns seen on fluorescein angiography, indocyanine green angiography, spectral-domain optical coherence tomography and optical coherence tomography angiography. Exploring these domains will lead to a better understanding of the factors at play beyond the outer retina in this important disease., Competing Interests: There are no conflicts of interest.

Aims: Cells have evolved a highly sophisticated web of cytoprotective systems to neutralize unwanted oxidative stress, but are challenged by unique modern day stresses such as cigarette smoking and ingestion of a high-fat diet (HFD). Age-related disease, such as age-related macular degeneration (AMD), the most common cause of blindness among the elderly in Western societies, develops in part, when oxidative stress overwhelms cytoprotective systems to injure tissue. Since most studies focus on the protection by a single protective system, the aim of this study was to investigate the impact of more than one cytoprotective system against oxidative stress., Results: Wingless (Wnt) and nuclear factor-erythroid 2-related factor 2 (Nrf2), two fundamental signaling systems that are vital to cell survival, decline after mice are exposed to chronic cigarette smoke and HFD, two established AMD risk factors, in a bidirectional feedback loop through phosphorylated glycogen synthase kinase 3 beta. Decreased Wnt and Nrf2 signaling leads to retinal pigment epithelial dysfunction and apoptosis, and a phenotype that is strikingly similar to geographic atrophy (GA), an advanced form of AMD with no effective treatment., Innovation: This study is the first to show that chronic oxidative stress from common modern day environmental exposures reduces two fundamental and vital cytoprotective networks in a bidirectional feedback loop, and their decline leads to advanced disease phenotype., Conclusion: Our data offer new insights into how combined modern oxidative stresses of cigarette smoking and HFD contribute to GA through an interactive decline in Wnt and Nrf2 signaling. Antioxid. Redox Signal. 29, 389-407.

Purpose: To identify changes in the outer retina in areas without atrophy or flecks of Stargardt disease (STGD) using spectral-domain optical coherence tomography., Methods: Twenty-three STGD patients and 26 control subjects were assessed for outer retina (from the outer border of Bruch membrane [BrM] to the inner border of the inner segment ellipsoid zone [EZ]), BrM-retinal pigment epithelium apex, the EZ thickness, and apical process interdigitation zone., Results: Patients with STGD had increased BrM-EZ thickness in areas without apparent disease versus control subjects at 1,000, 1,500, 2,000, and 2,500 μm superior and 1,500 μm, 2,000 μm, and 2,500 μm inferior to the fovea (P < 0.05 to P < 0.001), greatest difference (3.4 μm) at 2,500 μm superiorly. The BrM-retinal pigment epithelium segment showed larger fractional contribution of 0.48 to 0.51 to the overall BrM-EZ thickness compared with 0.35 to 0.42 in control subjects. The thickness of EZ and the interspace between the retinal pigment epithelium apex and EZ were smaller in the STGD patients (P < 0.05 to P < 0.001). Patients with STGD displayed an interrupted interdigitation zone in 16 (84.2%) of 19 eyes versus 6 (23.1%) of 26 eyes of the control subjects (P < 0.001). The BrM-EZ segment of the outer retina of STGD patients lacked the typical normal trilaminar pattern., Conclusion: Subtle changes are present within the BrM-EZ segment of the outer retina of STGD patients in areas that are devoid of atrophy and flecks. These findings suggest that pathologic changes in STGD are more widespread than that seen by clinical examination.

PurposeTo characterize the optic nerve head (ONH) structure in patients with non-arteritic anterior ischemic optic neuropathy (NAION) compared to healthy control subjects using spectral domain optical coherence tomography (SD-OCT) via the enhanced depth imaging method.MethodsIn this prospective, cross-sectional, comparative study, we assessed 66 eyes of 33 patients with unilateral NAION and 31 eyes of 31 healthy normal subjects in an academic institution. The peripapillary nerve fiber layer thickness, disc area, and quantitative parameters of the ONH structures, including the Bruch's membrane opening (BMO) area, anterior laminar depth, and prelaminar thickness and depth were compared between the three groups.ResultsLinear mixed model analysis after adjusting for age, sex, and axial length showed that the BMO area was similar in eyes with NAION (1.89±0.33 mm 2 ), their fellow eyes (1.85±0.35 mm 2 ), and control eyes (1.88±0.37 mm 2 ; all P>0.99). Anterior laminar depth was also similar in the three groups. The mean prelaminar tissue thickness of the NAION eyes was 445±176 μm, which was thinner than the prelaminar tissue of their unaffected fellow eyes (mean, 539±227 μm, P=0.004), but both were thicker than the prelaminar tissue of the normal subjects (mean 243±145 μm, P=0.001 and P<0.001, respectively).ConclusionsThe thick prelaminar thickness is associated with unilateral NAION in the affected and unaffected eyes.

The discovery that genetic abnormalities in complement factor H (FH) are associated with an increased risk for age-related macular degeneration (AMD), the most common cause of blindness among the elderly, raised hope of new treatments for this vision-threatening disease. Nonetheless, over a decade after the identification of this important association, how innate immunity contributes to AMD remains unresolved. Pentraxin 3 (PTX3), an essential component of the innate immunity system that plays a non-redundant role in controlling inflammation, regulates complement by interacting with complement components. Here, we show that PTX3 is induced by oxidative stress, a known cause of AMD, in the retinal pigmented epithelium (RPE). PTX3 deficiency in vitro and in vivo magnified complement activation induced by oxidative stress, leading to increased C3a, FB, and C3d, but not C5b-9 complex formation. Increased C3a levels, resulting from PTX3 deficiency, raised the levels of Il1b mRNA and secretion of activated interleukin (IL)-1β by interacting with C3aR. Importantly, PTX3 deficiency augmented NLRP3 inflammasome activation, resulting in enhanced IL-1β, but not IL-18, production by the RPE. Thus, in the presence of PTX3 deficiency, the complement and inflammasome pathways worked in concert to produce IL-1β in sufficient abundance to, importantly, result in macrophages accumulating in the choroid. These results demonstrate that PTX3 acts as an essential brake for complement and inflammasome activation by regulating the abundance of FH in the RPE, and provide critical insights into the complex interplay between oxidative stress and innate immunity in the early stages of AMD development. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Purpose: To compare the pattern of macular ganglion cell plus inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (RNFL) thickness changes in moderate to severe primary open-angle glaucoma (POAG) with nonarteritic anterior ischemic optic neuropathy (NAION) using optical coherence tomography (OCT) auto-segmentation., Methods: A total of 138 eyes (42 eyes with chronic unilateral NAION and their 42 unaffected fellow eyes, 32 eyes of 32 moderate to severe glaucoma patients, and 22 eyes of 22 healthy normal subjects) underwent neuro-ophthalmologic examinations and spectral-domain OCT in a cross-sectional study at a single academic institution. GCIPL and total retinal thicknesses were obtained from 20° by 20° cube scans of the macula centered around the fovea. The scanned region was divided into two concentric regions (inner and outer, with diameters of 3 and 6 mm, respectively) and eight sectors (four sectors in each of the inner and outer regions). Peripapillary RNFL thickness was also measured., Results: Peripapillary RNFL, total macula, and GCIPL were significantly thinner in NAION and POAG eyes compared to unaffected fellow eyes of NAION and to age-matched healthy control eyes in all eight sectors (P < 0.001). There was no significant difference in peripapillary RNFL, total macula, and outer region GCIPL thicknesses between the affected eyes of the patients with NAION and glaucoma patients. However, the inner region GCIPL was significantly thinner in NAION eyes compared to POAG eyes after adjusting for age, sex, and mean deviation of the visual field (P = 0.001). Also, the GCIPL sector thicknesses were more strongly correlated with visual acuity than were the macular sectors in all patients (most sectors P ≤ 0.001)., Conclusions: Patients with NAION show differences in the tissue damage with greater loss of parafoveal GCIPL tissue thickness compared to patients with POAG.

p62/sequestosome-1 is a multidimensional protein that interacts with many signaling factors, and regulates a variety of cellular functions including inflammation, apoptosis, and autophagy. Our previous work has revealed in the retinal pigment epithelium (RPE) that p62 promotes autophagy and simultaneously enhances an Nrf2-mediated antioxidant response to protect against acute oxidative stress. Several recent studies demonstrated that p62 contributes to NFkB mediated inflammation and inflammasome activation under certain circumstances, raising the question of whether p62 protects against or contributes to tissue injury. Herein, we will review the general characteristics of p62, focusing on its pro- and anti-cell survival roles within different physiological/pathological contexts, and discuss the potential of p62 as a therapeutic target for AMD.

Age-related macular degeneration (AMD) is a major disease affecting central vision, but the pathogenic mechanisms are not fully understood. Using a mouse model, we examined the relationship of two factors implicated in AMD development: oxidative stress and the immune system. Carboxyethylpyrrole (CEP) is a lipid peroxidation product associated with AMD in humans and AMD-like pathology in mice. Previously, we demonstrated that CEP immunization leads to retinal infiltration of pro-inflammatory M1 macrophages before overt retinal degeneration. Here, we provide direct and indirect mechanisms for the effect of CEP on macrophages, and show for the first time that antigen-specific T cells play a leading role in AMD pathogenesis. In vitro, CEP directly induced M1 macrophage polarization and production of M1-related factors by retinal pigment epithelial (RPE) cells. In vivo, CEP eye injections in mice induced acute pro-inflammatory gene expression in the retina and human AMD eyes showed distinctively diffuse CEP immunolabeling within RPE cells. Importantly, interferon-gamma (IFN-γ) and interleukin-17 (IL-17)-producing CEP-specific T cells were identified ex vivo after CEP immunization and promoted M1 polarization in co-culture experiments. Finally, T cell immunosuppressive therapy inhibited CEP-mediated pathology. These data indicate that T cells and M1 macrophages activated by oxidative damage cooperate in AMD pathogenesis.

Genetic and immunohistochemical studies have identified the alternative complement pathway as an important component of age-related macular degeneration (AMD). The objective of this chapter is to review the impact of complement regulators on complement activation in the macula as it relates to AMD. Our laboratory and other investigators have identified CD46 and CD59 as important retinal pigment epithelium (RPE) cell membrane complement regulators, which are decreased in AMD. Using oxidized low-density lipoproteins (oxLDLs), which are found in Bruch's membrane in AMD, we found that CD46 and CD59 were decreased in RPE cells in part, by their release in exosomes and apoptotic particles. The release of complement regulators could potentially impair complement regulation on RPE cells and contribute to lesion formation in the outer retina and Bruch's membrane during the development of AMD.

Activation of inflammatory cells and the RhoA signaling pathway may contribute to optic nerve damage following non-arteritic anterior ischemic optic neuropathy (NAION). We induced an optic nerve infarct with a photothrombotic mechanism in a rat model of AION (rAION). Immunohistochemistry and Western blot were performed to detect activation of RhoA signaling and inflammation. The extent of Rho activity, inflammation, retinal ganglion cell (RGC) loss and extent of axon regeneration were determined at 8 and 14 days after infarct. Eight days after stroke, we observed significant inflammation and RhoA activity at the site of infarction as well as loss of cells in the RGC layer. RhoA activity had decreased and inflammation had decreased at day 14 compared with day 8; however, loss of RGCs was greater at 14 days than at 8 days. Stroked eyes showed minor axon regeneration around the optic nerve lesion site at both 8 and 14 days. These results demonstrate that inflammation and RhoA activation occur in rAION at the site of infarction., (© 2013 Elsevier B.V. All rights reserved.)

Purpose: To compare the diagnostic value of magnetic resonance (MR) imaging and ophthalmoscopy for staging of retinoblastoma., Methods: MR and ophthalmoscopic images of 36 patients who underwent enucleation were evaluated retrospectively following institutional review board approval. Histopathology being the standard of reference, the sensitivity and specificity of both diagnostic modalities were compared regarding growth pattern, iris neoangiogenesis, retinal detachment, vitreous seeds and optic nerve invasion. Data were analysed via McNemar's test., Results: Both investigations showed no significant difference in accuracy for the detection of different tumour growth patterns (P = 0.80). Vitreous seeding detection was superior by ophthalmoscopy (P < 0.001). For prelaminar optic nerve invasion, MR imaging showed similar sensitivity as ophthalmoscopy but increased specificity of 40 % (CI 0.12-0.74) vs. 20 % (0.03-0.56). MR detected optic nerve involvement past the lamina cribrosa with a sensitivity of 80 % (0.28-0.99) and a specificity of 74 % (0.55-0.88). The absence of optic nerve enhancement excluded histopathological infiltration, but the presence of optic nerve enhancement included a high number of false positives (22-24 %)., Conclusions: Ophthalmoscopy remains the method of choice for determining extent within the globe while MR imaging is useful for evaluating extraocular tumour extension. Thus, both have their own strengths and contribute uniquely to the staging of retinoblastoma., Key Points: • Ophthalmoscopy: method of choice for determining extent of retinoblastoma within the globe. • MR imaging provides optimal evaluation of extrascleral and extraocular tumour extension. • Positive enhancement of the optic nerve on MRI does not necessarily indicate involvement.

Dysregulated complement is thought to play a central role in age-related macular degeneration (AMD) pathogenesis, but the specific mechanisms have yet to be determined. In maculae of AMD specimens, we found that the complement regulatory protein, CD59, was increased in regions of uninvolved retinal pigmented epithelium (RPE) of early AMD, but decreased in the RPE overlying drusen and in geographic atrophy, an advanced form of AMD. While CD46 immunostaining was basolaterally distributed in the RPE of unaffected controls, it was decreased in diseased areas of early AMD samples. Since oxidized low-density lipoproteins (oxLDL) collect in drusen of AMD and are a known complement trigger, we treated ARPE-19 cells with oxLDL and found that cellular CD46 and CD59 proteins were decreased by 2.9- and nine-fold (p < 0.01), respectively. OxLDLs increased complement factor B mRNA and Bb protein, but not factor D, I or H. OxLDLs increased C3b, but not C3a, C5 or C5b-9. C5b-9 was increased by 27% (p < 0.01) when the medium was supplemented with human serum, which was sufficient to induce poly(ADP-ribose) polymerase cleavage, a marker of apoptosis. The decreased levels of CD46 and CD59 were in part explained by their release in exosomal and apoptotic membranous particles. In addition, CD59 was partially degraded through activation of IRE1α. Collectively, these results suggest that a combination of impaired complement regulators results in inadequately controlled complement by the RPE in AMD that induces RPE damage., (Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Retinoblastoma is the most common intraocular childhood malignancy, with a prevalence of one in 18,000 children younger than 5 years old in the United States. In 80% of patients, retinoblastoma is diagnosed before the age of three, and in 95% of patients, retinoblastoma is diagnosed before the age of five. Although reports exist of retinoblastoma in adults, onset beyond 6 years of age is rare. Broadly, retinoblastoma may be classified into two groups: sporadic and heritable. In either case, the origin of the tumor is a biallelic mutation in primitive neuroepithelial cells. Although their details vary, several staging schemes are used to describe the extent of retinoblastoma according to the following four general criteria: intraocular location, extraocular (extraorbital) location, central nervous system disease, and systemic metastases. In the past decade, substantial changes have taken place in terms of staging and monitoring treatment in patients with retinoblastoma. Diagnosis and treatment of retinoblastoma involve a multidisciplinary approach, for which imaging is a vital component. Increasing awareness and concerns about the effects of radiation in patients with retinoblastoma have led to a shift away from external-beam radiation therapy and toward chemotherapy and locoregional treatment, as well as the establishment of magnetic resonance imaging as the most important imaging modality for diagnosis, staging, and treatment monitoring.

Purpose: To determine whether uveal melanoma, the most common primary intraocular malignancy in adults, requires Notch activity for growth and metastasis., Experimental Design: Expression of Notch pathway members was characterized in primary tumor samples and in cell lines, along with the effects of Notch inhibition or activation on tumor growth and invasion., Results: Notch receptors, ligands, and targets were expressed in all five cell lines examined and in 30 primary uveal melanoma samples. Interestingly, the three lines with high levels of baseline pathway activity (OCM1, OCM3, and OCM8) had their growth reduced by pharmacologic Notch blockade using the γ-secretase inhibitor (GSI) MRK003. In contrast, two uveal melanoma lines (Mel285 and Mel290) with very low expression of Notch targets were insensitive to the GSI. Constitutively active forms of Notch1 and Notch2 promoted growth of uveal melanoma cultures and were able to rescue the inhibitory effects of GSI. MRK003 treatment also inhibited anchorage-independent clonogenic growth and cell invasion and reduced phosphorylation levels of STAT3 and extracellular signal-regulated kinase (Erk)1/2. Suppression of canonical Notch activity using short hairpin RNA targeting Notch2 or CBF1 was also able to reduce tumor growth and invasion. Finally, intraocular xenograft growth was significantly decreased by GSI treatment., Conclusion: Our findings suggest that Notch plays an important role in inducing proliferation and invasion in uveal melanoma and that inhibiting this pathway may be effective in preventing tumor growth and metastasis.

The authors describe the optical coherence tomography (OCT) findings and the therapeutic approach of a patient with metastatic neoplastic disease of the retina. A patient with a history of brain cancer of undetermined origin underwent imaging and surgery to investigate a suspected metastatic retinal lesion of the right eye. Retinal thinning with cordon-like hyperreflective structures was seen on OCT. Neoplastic cells consistent with small cell carcinoma were identified in the vitreous sample. Those cells were thought to be similar to the previous biopsied cerebellar tumor specimen. OCT imaging, along with vitrectomy and retinal biopsy, may be useful in the evaluation of patients with suspected metastatic lesions of the retina., (Copyright 2011, SLACK Incorporated.)

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. While excellent treatment has emerged for neovascular disease, treatment for early AMD is lacking due to an incomplete understanding of the early molecular events. A prominent age-related change is the accumulation of neutral lipid in normal Bruch's membrane (BrM) throughout adulthood and also disease-related BrM accumulations called basal deposits and drusen. AMD lesion formation has thus been conceptualized as sharing mechanisms with atherosclerotic plaque formation, where low-density lipoprotein (LDL) retention within the arterial wall initiates a cascade of pathologic events. However, we do not yet understand how lipoproteins contribute to AMD. This paper explores how systemic and local production of lipoproteins might contribute to the pathogenesis of AMD.

Purpose: The efficacy of radiation therapy in orbital xanthogranuloma in patients who fail medical therapy is unclear. The purpose of this study was to ascertain its effectiveness., Methods: The records of 11 cases were reviewed retrospectively for histopathologic findings, age, gender, site of involvement, clinical manifestations, and outcomes of treatment. The case histories of the 4 patients treated with radiation, all of whom had failed medical treatment, were described., Results: Of 11 patients, 5 were female, and all were white. The age range at the time of presentation was 25 to 85 years. Nine patients had bilateral involvement. Five patients, all of whom had bilateral disease, had systemic manifestations or autoimmune disease thought to be related to their orbital disease. In general, patients treated with systemic corticosteroids had at least a partial response of their lesion. However, none of the 4 patients treated with orbital radiation (3 of whom had not responded to steroid treatment and 1 of whom had responded only to high-dose steroids) experienced improvement, and at least 3 experienced exacerbation of their disease. The histologic features before treatment in all cases were similar and consistent with xanthogranuloma., Conclusion: Orbital xanthogranuloma may be a unilateral or bilateral condition. Particularly when bilateral, it may be associated with similar lesions elsewhere or with systemic autoimmune disorders. The results of this study suggest that fractionated radiotherapy not only may be ineffective but also may exacerbate the progression of the orbital lesions in patients who do not respond to medical therapy or who are steroid dependent on intolerable doses of medication.

Purpose: To characterize the clinical and histologic features of primary graft failure after Descemet's stripping and automated endothelial keratoplasty (DSAEK)., Design: Retrospective observational case series., Participants: Sixteen cases of DSAEK graft failure from 15 patients, all with detailed histologic examination of failed graft tissue., Methods: Hematoxylin-eosin, periodic acid-Schiff staining, and light microscopy were used to examine the failed DSAEK graft tissue from all patients., Main Outcome Measures: Examination of specimens for corneal endothelial cell viability and host-donor interface characteristics., Results: Clinical history revealed that 88% (14/16) of studied DSAEK grafts detached before failure, and pathologic examination found that 75% (12/16) of failed grafts had atrophic corneal endothelium. Examples of residual host Descemet's membrane in the graft site and improper donor trephination were also identified., Conclusions: Marked loss of the corneal endothelium is the prominent feature of primary DSAEK graft failure. Examples of surgical features, such as incomplete Descemet's stripping and residual full-thickness cornea with a DSAEK graft, are shown.

Purpose: To report a case of host-donor interface calcification after Descemet membrane stripping with automated endothelial keratoplasty (DSAEK)., Methods: Review of the patient's clinical records and histopathologic examination of the donor corneal lamella from repeat DSAEK performed subsequent to the original DSAEK., Results: Review of the clinical record of the patient revealed an ocular history of Fuchs dystrophy and pseudophakic bullous keratoplasty that was treated with DSAEK. She later developed corneal edema and a partially detached donor lamella and underwent repeat DSAEK. Histopathologic and transmission electron microscopic evaluations of the corneal lamella revealed calcium deposits in the host-donor interface., Conclusions: Calcareous degeneration of the host-donor interface after DSAEK is reported as a novel postoperative complication of DSAEK. Calcium deposits in the host-donor interface after DSAEK should be considered in the differential diagnosis of interface opacity after this procedure, particularly in patients with predisposing systemic or local risk factors such as retained phosphate-containing viscoelastic material, excessive postoperative inflammation, or use of phosphate-buffered, postoperative topical medications.

Background: Acanthamoeba scleritis is an uncommon but severe complication of acanthamoeba keratitis. We report the clinical and histopathologic features of a patient with acanthamoeba sclerokeratitis., Methods: Review of the patient's clinical records and histopathologic examination of the globe including light microscopy and transmission electron microscopy., Results: Review of the clinical record of the patient revealed a past ocular history of penetrating keratoplasty for persistent acanthamoeba keratitis. Later in the course of treatment, the patient developed nodular necrotizing scleritis with culture-proven viable acanthamoeba in this area. She underwent enucleation of the eye for persistent acanthamoeba sclerokeratitis. Histopathologic examination of the globe revealed no acanthamoeba cysts or trophozoites at the site of crotherapy., Conclusion: Our study provides evidence for the invasion of acanthamoeba organisms into the sclera in a case of acanthamoeba keratitis. The presence of trophozites in scleral tissue may exacerbate the immune response leading to nodular scleritis.

Purpose: Orbital pleomorphic lipoma has been rarely reported in the literature. Although floretlike cells are characteristic of pleomorphic lipoma, they are not pathognomonic. We reviewed cases of prolapsed orbital fat and exenteration specimens to determine the significance of presence of these cells in the diagnosis of orbital pleomorphic lipoma., Design: Retrospective interventional case series with clinicopathologic correlation., Participants: Seventy-two specimens of 45 patients with prolapsed orbital fat and 74 exenteration specimens as controls., Intervention: Histologic review of the specimens including light microscopy, Masson trichrome staining, immunostaining for S100, CD34, CD68, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay, and transmission electron microscopy and review of clinical records and analysis of the data with generalized estimation equation., Main Outcome Measure: Evidence of histologic abnormalities in histologic specimens and clinical and demographic data., Results: Floretlike cells were present in 31 of 72 (43%) specimens of prolapsed orbital fat and in 12 of 74 (16%) orbital exenterations. Fewer than 6 florets were present in twenty 40x high-power fields in 15 (48%), 6 to 10 in 9 (29%), and >10 in 7 (23%) specimens. The florets stained positive for CD34 but not for S100 or CD68. TUNEL assay revealed significant nuclear pyknosis, and transmission electron microscopy disclosed spindle-shaped cells with abundant rough endoplasmic reticulum and no basement membrane. The mean age of patients with prolapsed orbital fat with florets was 67 years (range, 52-86). Of 31 samples, 29 (94%) were from males. Of 30 samples, 29 (97%) were located in the superotemporal conjunctiva; only one was located in the lower lid. There was significant association between the presence of florets and location of the prolapsed orbital fat (P = 0.0013) and gender (P = 0.0015)., Conclusion: Floretlike cells may be present in in situ and prolapsed orbital fat as a degenerative process. What some have called "orbital pleomorphic lipoma" is in fact only age-related orbital fat prolapse.