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

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

Papillary cystadenocarcinoma of the lacrimal gland after radiation for bilateral retinoblastoma.

The authors report a case of papillary cystadenocarcinoma of the lacrimal gland after irradiation for bilateral retinoblastoma. A 32-year-old man with a history of bilateral retinoblastoma, diagnosed shortly after birth, was treated with enucleation of the OS and a single session of radiation to the OD. Over 30 years later, he presented with an orbital mass of the right lacrimal gland that on biopsy demonstrated papillary cystadenocarcinoma.

High-resolution images of retinal structure in patients with choroideremia.

PURPOSE: To study retinal structure in choroideremia patients and carriers using high-resolution imaging techniques. METHODS: Subjects from four families (six female carriers and five affected males) with choroideremia (CHM) were characterized with best-corrected visual acuity (BCVA), kinetic and static perimetry, full-field electroretinography, and fundus autofluorescence (FAF). High-resolution macular images were obtained with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SD-OCT). Coding regions of the CHM gene were sequenced. RESULTS: Molecular analysis of the CHM gene identified a deletion of exons 9 to 15 in family A, a splice site mutation at position 79+1 of exon 1 in family B, deletion of exons 6 to 8 in family C, and a substitution at position 106 causing a premature stop in family D. BCVA ranged from 20/16 to 20/63 in carriers and from 20/25 to 5/63 in affected males. FAF showed abnormalities in all subjects. SD-OCT showed outer retinal layer loss, outer retinal tubulations at the margin of outer retinal loss, and inner retinal microcysts. Patchy cone loss was present in two symptomatic carriers. In two affected males, cone mosaics were disrupted with increased cone spacing near the fovea but more normal cone spacing near the edge of atrophy. CONCLUSIONS: High-resolution retinal images in CHM carriers and affected males demonstrated RPE and photoreceptor cell degeneration. As both RPE and photoreceptor cells were affected, these cell types may degenerate simultaneously in CHM. These findings provide insight into the effect of CHM mutations on macular retinal structure, with implications for the development of treatments for CHM. (ClinicalTrials.gov number, NCT00254605.).

Expression of neurotrophin receptors by retinoinvasive uveal melanoma.

Retinoinvasive uveal melanoma demonstrates prominent diffuse retinal and optic nerve invasion, with little or no involvement of the adjacent choroid. Prior studies have advanced hypotheses on the potential role of molecular and cellular interactions in the pathogenesis of retinoinvasiveness and neuroinvasiveness, but the precise molecular events are not known. Here, we investigate the role of neutrotrophic factors in the pathogenesis of retinoinvasive uveal melanoma. The records of three ophthalmic pathology departments (The New York Eye and Ear Infirmary, Wills Eye Institute, and University of California San Francisco) were searched to identify all cases of retinoinvasive uveal melanoma, yielding four eyes (all previously irradiated). Eight eyes with nonretinoinvasive melanomas (four irradiated and four nonirradiated) were randomly selected as controls. All enucleated eyes were examined histopathologically and immunohistochemically for the expression of neurotrophic factor receptors [Pan-Trk, p75 neurotrophin receptor (p75(NTR) and ciliary neurotrophic factor receptor-α]. Histopathologic features were similar in both retinoinvasive and control melanomas with regard to choroidal tumor location and size, neovascular glaucoma, and cell type. The eyes with retinoinvasive melanoma showed diffuse retinal invasion beyond the choroidal tumor (n=4) and prelaminar (n=1) and retrolaminar (n=2) optic nerve invasion. The control melanomas showed focal retinal invasion over the tumor apices (n=6) and prelaminar optic nerve invasion (n=1). Nonirradiated melanomas demonstrated no trace immunoreactivity for neurotrophic factor receptors, whereas irradiated melanomas showed more prominent (trace to moderate) immunoreactivity. When controlled for irradiation, no difference in immunoreactivity for neurotrophin receptors nor tumor duration was observed between retinoinvasive and nonretinoinvasive melanomas. This study failed to demonstrate a direct causation between the expression of neurotrophin receptors and a retinoinvasive uveal melanoma growth pattern.

Intraocular coccidioidomycosis simulating a neoplasm.

Coccidioidomycosis can simulate an intraocular neoplasm. We reviewed a case report of a 10-year-old girl who was referred with an intraocular tumour. This tumour consisted of a coccidioidomycosis infection in the eye. The eye was blind and painful so it was removed.

Pathological findings in poststrabismus surgery endophthalmitis.

Bacterial entry into the vitreous cavity via inadvertent scleral perforation is one postulated mechanism for poststrabismus surgery endophthalmitis. In a review of 746 cases, we identified 2 pediatric enucleation specimens related to complications of strabismus surgery. In both cases, the patients developed postoperative endophthalmitis and no light perception vision, and the eyes were enucleated when they became phthisical or painful. In both submitted cases, pathology showed a thick band of scar tissue emanating focally from the sclera into the vitreous. Although no needle tracts were visualized, pathological findings were consistent with scleral perforation.

Clinicopathologic review of pediatric enucleations during the last 50 years.

PURPOSE: To evaluate diagnoses leading to enucleations in the pediatric age group over time. METHODS: All pathology reports of enucleation specimens at the University of California-San Francisco eye pathology laboratory from children (ages 0 to 18 years) from 1960 to 2008 were reviewed. The main outcome measures were the frequency of pediatric enucleation specimens in each diagnostic category as compared with total pathological laboratory volume over time, and the age and gender distribution of histopathological diagnostic categories over time. RESULTS: Specimens of 746 eyes from 729 pediatric patients were analyzed. Pediatric enucleated eyes constituted 2.7% of all specimens received at the pathology laboratory. The overall frequency of pediatric enucleation specimens did not change over time. Retinoblastoma specimens increased by a factor of 2.9 over time (p < 0.0001). The increase in retinoblastoma was offset by a decrease in nonretinoblastoma enucleations, which decreased by a factor of 3.8 between the 1960s and 2000s (p < 0.0001), driven by a decrease in enucleations caused by trauma (p < 0.0001). Beginning in the 1980s, pediatric enucleations caused by nonrhegmatogenous retinal detachment, nematode and non-nematode endophthalmitis, and congenital glaucoma decreased significantly. Retinoblastoma was the most common diagnosis overall (45%), in girls (60%), and in ages <5 years (78%). Trauma was the second most common diagnosis (32%) and the most common in boys (42%) and in children ages 6-12 (58%) and 13-18 (72%) years. CONCLUSIONS: A decrease in pediatric nonretinoblastoma enucleations was observed over time, possibly attributable to better diagnostic capabilities, surgical techniques, and public health interventions. The increase in retinoblastoma enucleations over time was likely due to the result of institutional referral bias.

Analysis of clinical misdiagnoses in children treated with enucleation.

OBJECTIVE: To evaluate discordant clinical and pathological diagnoses leading to pediatric enucleations over time. METHODS: All pathology reports of pediatric enucleation specimens (subjects aged 0 to 18 years) from 1960 to 2008 were reviewed. Specimens with discordant clinical and pathologic diagnoses were further analyzed. Formalin-fixed, paraffin-embedded sections of enucleated eyes of any misdiagnosed cases were reevaluated. RESULTS: Of 729 pediatric patients (746 eyes) who had enucleation from 1960 to 2008, 29 patients (4.0%) and 30 eyes (4.0%) had discordant clinical and pathological diagnoses. The misdiagnosis enucleation rate decreased with each respective decade studied, with the highest rate of 6.5% (18 of 276 eyes) in the 1960s and no misdiagnoses from 1990 to 2008. Of the 369 eyes enucleated for the clinical indication of malignancy, 22 eyes (6.0%) were misdiagnosed in that no evidence of malignancy was found on histopathological examination. Of the 377 eyes enucleated for benign clinical indications, 7 cases (1.9%) were found to be malignant by histopathology. CONCLUSIONS: Misdiagnoses leading to pediatric enucleation have decreased during the past 5 decades, likely owing to improved diagnostic techniques. Benign and malignant intraocular conditions can simulate each other, especially retinoblastoma, Coats disease, nematode and bacterial endophthalmitis, panuveitis, and persistent hyperplastic primary vitreous.

Crystal-storing histiocytosis and crystalline keratopathy caused by monoclonal gammopathy of undetermined significance.

PURPOSE: The purpose of this study was to report the occurrence of crystalline keratopathy and of orbital infiltrative disease resulting from crystal-storing histiocytosis (CSH) in a patient with monoclonal gammopathy of undetermined significance. METHODS: The authors conducted a review of a medical record and immunohistopathologic studies. RESULTS: A 66-year-old man presented with a 3-year history of unilateral progressive ptosis, proptosis, and external ophthalmoplegia. Magnetic resonance imaging showed orbital fat expansion and extraocular muscle thickening with gadolinium enhancement. The patient also had bilateral crystalline keratopathy and had undergone penetrating keratoplasty in one eye. The urine and serum showed elevated levels of immunoglobulin, but the bone marrow aspirate was normal. The systemic evaluation was consistent with monoclonal gammopathy of undetermined significance. An orbital fat biopsy revealed histiocytes engorged with lambda light chain crystals. The corneal stroma also showed positive immunostaining for lambda light chains. The patient was diagnosed with orbital CSH and with lambda light chain crystalline keratopathy. CONCLUSIONS: CSH is characterized by the accumulation of reactive histiocytes filled with immunoglobulin crystals in various tissues and is frequently associated with systemic hyperglobulinemic states. For unknown reasons, in this patient, a systemic immunologic disorder led to lambda light chain abnormalities with histiocyte infiltration of the orbit and corneal deposition. Although CSH is rare, it should be part of the differential diagnosis of orbital infiltrative disease with or without crystalline keratopathy.

Orbital invasion despite topical anti-metabolite therapy for conjunctival carcinoma.

BACKGROUND: Two cases of conjunctival carcinoma developed orbital invasion during treatment with topical medication. METHODS: This was a retrospective study from a tertiary ophthalmic oncology unit, performed after informed consent was obtained. The main outcome measurement was orbital invasion. RESULTS: Two patients treated with topical agents developed orbital invasion. CONCLUSION: While topical agents are important in treatment of conjunctival neoplasia, recurrence or deep invasion require careful monitoring.

Metaplastic squamous epithelial downgrowth after clear corneal cataract surgery.

PURPOSE: To report a case of metaplastic squamous epithelial downgrowth after cataract surgery. DESIGN: Interventional case report. METHODS: Clinical, laboratory, and histologic findings are presented. Our study is in compliance with institutional review board guidelines. RESULTS: A 76-year-old man developed anterior chamber inflammation five months after uncomplicated clear corneal cataract surgery. Despite antimicrobial and anti-inflammatory therapies, the inflammation persisted. An extensive examination failed to demonstrate an infectious etiology or lymphoma. Subsequently, the patient developed an incipient limbal lesion and iris mass. Immunostaining of a biopsy specimen from the iris mass indicated an epithelial-derived tumor. The prephthisical and painful eye was enucleated; histopathology of the globe revealed a contiguous lesion extending from the limbal mass to the iris tumor through the surgical incision site, a finding consistent with metaplastic squamous epithelial downgrowth. Systemic evaluation was negative. CONCLUSIONS: After intraocular surgery, metaplastic epithelial downgrowth may occur as a consequence of occult ocular surface squamous neoplasia and masquerade as chronic inflammation; clinicians should be aware of this rare complication.

Ophthalmic manifestations of infections caused by the USA300 clone of community-associated methicillin-resistant Staphylococcus aureus.

PURPOSE: To report the microbiological, clinical, and pathological characteristics of community-associated methicillin-resistant Staphylococcus aureus (CAMRSA) infections of the eye and orbit. DESIGN: Prospective case series. PARTICIPANTS: Nine patients with CAMRSA infections of the eye and orbit were identified during a 6-month period at 2 tertiary care hospitals in San Francisco. METHODS: Case identification was by prospective case selection and retrospective laboratory review of 549 MRSA cultures collected in the 2 hospitals. Ophthalmic microbial isolates were analyzed by pulsed-field gel electrophoresis and compared with a control CAMRSA clone (USA300). Clinical characteristics of patients infected with CAMRSA were reviewed, and all surgical specimens underwent pathological examination. MAIN OUTCOME MEASURES: Pulsed-field gel electrophoresis banding patterns of MRSA isolates, antibiotic sensitivity profiles, patient demographics, systemic and ocular complications of infection, and posttreatment visual acuities. RESULTS: Nine ophthalmic isolates were CAMRSA clone USA300. The infections included orbital cellulitis, endogenous endophthalmitis, panophthalmitis, lid abscesses, and septic venous thrombosis. Patients were treated with trimethoprim-sulfamethoxazole, rifampin, clindamycin, or vancomycin based on microbial sensitivity studies and severity of infection. Eight of the 9 patients had no history of hospitalization. Seven patients required hospitalization, 3 required surgery, and an additional 4 required invasive procedures. Eight patients had good visual outcomes, but 1 deteriorated to no light perception. Pathological analyses showed extensive necrosis in eyelid and orbital specimens, and disorganized atrophy bulbi in an enucleated eye. CONCLUSION: The USA300 CAMRSA clone, which carries Panton-Valentine leukocidin genes, can cause aggressive infections of the eye and orbit in hospital-naive patients. Treatment of infections often required debridement of necrotic tissues in addition to non-beta-lactam class antibiotics. In communities where CAMRSA is prevalent, ophthalmologists should obtain microbial cultures and sensitivity studies to help guide antibiotic therapy for severe ophthalmic infections.

Bilateral endogenous Scedosporium prolificans endophthalmitis after lung transplantation.

PURPOSE: To report a case of bilateral endogenous fungal endophthalmitis resulting from disseminated Scedosporium prolificans. DESIGN: Observational case report. METHODS: A 56-year-old woman with cystic fibrosis status post dual lung transplantation on chronic immunosuppressive therapy presented with acute graft rejection. Cultures of bronchial brushings revealed S. prolificans. Three weeks after admission, the patient noted increased blurriness and a central scotoma in her right eye. Dilated fundus examination revealed profound vitritis in the right eye with hemorrhagic retinitis involving the macula. A peripheral, yellow choroidal infiltrate with overlying retinitis and localized vitritis was present in the left eye. RESULTS: Intravitreal antibiotics were initiated, and vitreous cultures revealed S. prolificans. The patient ultimately succumbed to her disseminated disease. Pathologic examination of the eyes confirmed bilateral endogenous fungal endophthalmitis. CONCLUSION: S. prolificans is an opportunistic infection resistant to standard antifungal therapy that can result in endogenous endophthalmitis in immunocompromised individuals.

Analysis of melanoma cell type in uveal melanoma following treatment failure.

PURPOSE: To determine whether an increase (or progression) in the degree of malignancy according to cytologic or histopathologic criteria corresponded with failure of intraocular melanoma control. DESIGN: Retrospective case control study from a single institution. METHODS: Uveal melanoma patients had either fine-needle aspiration biopsy followed by irradiation and later enucleation or an eyewall resection followed by enucleation. The observation procedures were serial histology or cytopathology and histology, reanalyzed in a masked manner. The main outcome measures were change in the predominant tumor cell type, local tumor control, and metastases. RESULTS: There was not a significant correlation between a change in melanoma cell type and failure to control intraocular melanoma. Similarly, the latency between treatment and enucleation was actually less (but not statistically so) in tumors that showed no increase in melanoma malignancy cell type compared with those that had a more malignant cell type on serial examination. CONCLUSIONS: There was no correlation between a change to more a malignant cell type and local control failure in patients treated either with radiation or eyewall resection for uveal melanoma.

A new mutation (Leu569Arg) within exon 13 of the TGFBI (BIGH3) gene causes lattice corneal dystrophy type I.

PURPOSE: To describe an American family with lattice corneal dystrophy type I, which associates with a novel mutation, Leu569Arg, of the TGFBI (BIGH3) gene. DESIGN: Experimental study. METHODS: Genomic DNA was extracted from buccal epithelial cells of four affected members of an American family with lattice corneal dystrophy type I. All 17 exons of the TGFBI gene were evaluated by PCR amplification and direct sequencing. Clinical and histologic data were also collected. RESULTS: Three generations of this family have been positively diagnosed with lattice corneal dystrophy, indicating autosomal dominant inheritance. We identified a heterozygous point mutation that associates with the disease phenotype. The single base-pair substitution (T1753G) results in an amino acid substitution (Leu569Arg) in exon 13 of the TGFBI gene. CONCLUSIONS: Substitution of arginine for leucine at position 569 of the TGFBI gene results in a form of lattice corneal dystrophy that is phenotypically similar to other genetically distinct forms of type I disease. This is the first report of disease correlated with changes in exon 13 of the TGFBI gene.