The Pediatric and Young Adult Choroidal and Ciliary Body Melanoma Genetic Study, A Survey by the European Ophthalmic Oncology Group.

Purpose: To explore the genetic background of choroidal and ciliary body melanoma among children and young adults, with special focus on BAP1 germline variants in this age group. Methods: Patients under the age of 25 and with confirmed choroidal or ciliary body melanoma were included in this retrospective, multicenter observational study. Nuclear BAP1 immunopositivity was used to evaluate the presence of functional BAP1 in the tumor. Next-generation sequencing using Ion Torrent platform was used to determine pathogenic variants of BAP1, EIF1AX, SF3B1, GNAQ and GNA11 and chromosome 3 status in the tumor or in DNA extracted from blood or saliva. Survival was analyzed using Kaplan-Meier estimates. Results: The mean age at diagnosis was 17 years (range 5.0-24.8). A germline BAP1 pathogenic variant was identified in an 18-year-old patient, and a somatic variant, based mainly on immunohistochemistry, in 13 (42%) of 31 available specimens. One tumor had a somatic SF3B1 pathogenic variant. Disomy 3 and the absence of a BAP1 pathogenic variant in the tumor predicted the longest metastasis-free survival. Males showed longer metastasis-free survival than females (P = 0.018). Conclusions: We did not find a stronger-than-average BAP1 germline predisposition for choroidal and ciliary body melanoma among children and young adults compared to adults. Males had a more favorable survival and disomy 3, and the absence of a BAP1 mutation in the tumor tissue predicted the most favorable metastasis-free survival. A BAP1 germline pathogenic variant was identified in one patient (1%), and a somatic variant based mainly on immunohistochemistry in 13 (42%).

Subconjunctival Ocular Argyrosis following Treatment with Ruthenium 106 Brachytherapy for Choroidal Melanoma.

Introduction: Ruthenium-106 (Ru-106) brachytherapy is one of the commonest eye-sparing treatments for choroidal melanoma. These patients require long-term surveillance of the treated tumour remnant to ensure there is no local recurrence. New or progressive pigmented lesions in treated eyes are often regarded as suspicious - especially if there are concerns of extra-scleral extension. Case Presentations: We present two cases of posterior choroidal melanoma treated five and 10 years previously with Ru-106. Both cases developed subconjunctival dark/black lesions on the anterior surface of the eye in the quadrant of the conjunctival peritomy during Ru-106 treatment. Both had similar findings on histopathology: black, non-organic, particulate foreign material of varying confluence deposited on elastin and collagen fibres. Energy dispersive X-ray microanalysis confirmed the material contained silver. Discussion: The Ru-106 applicator consists of a radioactive core of Ru-106 encapsulated within pure silver as a radiation shield. During surgical insertion, stainless steel suture needles and forceps can occasionally scratch the applicator's silver eyelets and scatter microscopic particles of elemental silver into the operative field. These particles were likely deposited within the subconjunctival tissues of these patients during brachytherapy administration, leading to localised ocular argyrosis. Iatrogenic ocular argyrosis should be considered in the differential diagnosis of new pigmented lesions in patients treated with Ru-106 brachytherapy. This study is the first to unequivocally identify the cause of some post-brachytherapy ocular surface pigmentation as caused by silver.

LOCALIZED CONJUNCTIVAL AL-AMYLOID DEPOSITS SECONDARY TO A RETINAL DETACHMENT SURGERY RADIAL EXPLANT.

PURPOSE: To describe a hitherto unreported late ocular surface complication of retinal detachment surgery around a radial segment explant. METHODS: A single case report of a 72-year-old white man, with a previous history of right scleral buckling surgery for retinal detachment surgery 25 years ago, presented with right-sided ptosis of 6 months duration. RESULTS: Ocular surface examination showed a prominent right supero-nasal quadrant radial segment explant, around which there was bulky pink conjunctival mass, extending from the supero-medial fornix down to the medial canthal area and inferior medial fornix with similar changes seen on the upper medial tarsal conjunctiva. The clinical differential diagnosis was either inflammation from an exposed radial explant or lymphoma. Biopsies of the conjunctival mass showed perivascular and interstitial solid eosinophilic deposits of amyloid, with scattered giant cells; the amyloid was of AL type. There was no morphological or immunohistochemical evidence of lymphoma or a plasma cell neoplasm in the specimen. CONCLUSION: This is the first report of localized conjunctival amyloid deposition, secondary to a retinal detachment radial explant. It is proposed that the localized amyloid deposit arose from the ocular surface irritative effects of the radial explant.

Multi-Modal Mass Spectrometric Imaging of Uveal Melanoma.

Matrix assisted laser desorption ionisation mass spectrometry imaging (MALDI-MSI), was used to obtain images of lipids and metabolite distribution in formalin fixed and embedded in paraffin (FFPE) whole eye sections containing primary uveal melanomas (UM). Using this technique, it was possible to obtain images of lysophosphatidylcholine (LPC) type lipid distribution that highlighted the tumour regions. Laser ablation inductively coupled plasma mass spectrometry images (LA-ICP-MS) performed on UM sections showed increases in copper within the tumour periphery and intratumoural zinc in tissue from patients with poor prognosis. These preliminary data indicate that multi-modal MSI has the potential to provide insights into the role of trace metals and cancer metastasis.

Oedipism: An unusual case of auto-enucleation including mechanism of avulsion.

INTRODUCTION: Self-inflicted enucleation, also known as auto-enucleation (AE) or Oedipism, is an uncommon and severe form of ocular injury which presents as an ophthalmic and psychiatric emergency. Usually known to occur with untreated psychosis, this case is a rare report which demonstrates AE as a result of a subsequently diagnosed drug induced psychosis. We report the clinical presentation, management and for the first time a detailed speculative account about the mechanism of AE, based on our clinicopathologic findings. CASE REPORT: A 53-year old Afro-Caribbean patient was arrested following an altercation and was incarcerated awaiting arraignment. The patient had no previous psychiatric history but tested positive for cannabis, opiates and cocaine as well as admitting to illicit drug use in the community. Whilst in custody, the patient self-enucleated his right eye. The patient declined consent to eye examination and was subsequently admitted under section 2 of the Mental Health Act. After full work-up including Goldmann visual fields and magnetic resonance imaging, he underwent right orbital exploration under anesthetic where AE was confirmed whilst the left eye showed evidence of attempted enucleation. The residual tenons and conjunctiva was subsequently repaired without placement of an orbital implant in the right orbit. The globe was sent for histology which revealed clues to the potential mechanism of auto-enucleation. CONCLUSION: This case is unique as it offers an alternative presentation to those most commonly reported in the current literature, highlights the sparsity of literature detailing the mechanism of AE and stimulates discussion around various potential systemic etiological differential diagnoses, management strategies and complications of AE.

Cutaneous Malignant Melanoma Metastasis to the Pseudophakic Lens Capsule with Associated Granulomatous Intraocular Inflammation.

Intraocular cutaneous melanoma metastasis (ICMM) is a rare event, accounting for only 5% of all metastases to the eye and orbit. The vast majority of such metastases primarily affect the choroid and vitreoretinal structures. Only three previous cases of predominant lens structure ICMM have been reported in the literature. Histological examination, in all three past cases, was performed on enucleation specimens of painful blind eyes. We present the first case of ICMM to the lens capsule in a comfortable, seeing, pseudophakic eye. This was histologically confirmed following diagnostic pars plana vitrectomy and capsulotomy, and was found to be associated with background granulomatous intraocular inflammation. The potential causes of the granulomatous inflammation are discussed.

Arthrographis kalrae Keratitis Complicated by Endophthalmitis: A Case Report With Literature Review.

OBJECTIVES: To report the first case of Arthrographis kalrae keratitis complicated by endophthalmitis in the UK and to review the current literature. METHODS: A case report with literature review. RESULTS: A 65-year-old male patient, with a background of treated B-cell lymphoma and herpes simplex virus-related neurotrophic keratopathy, presented with a large infiltrative corneal ulcer in the right eye. The patient was immediately commenced on empirical antifungal treatment in view of the clinical suspicion of fungal keratitis (FK). The initial corneal scrape identified the organism as nonspecific "mold," and the identity of A. kalrae was subsequently confirmed using matrix-assisted laser/desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS). During the clinical course, the patient received topical, intrastromal, intracameral, and systemic antifungal treatment, repeat therapeutic corneal cross-linking treatment, and three penetrating keratoplasties. Although a temporary improvement was achieved with therapeutic corneal cross-linking treatment, the FK progressed relentlessly and was ultimately complicated by an endophthalmitis despite maximum medical and surgical treatment, eventuating in an enucleation. CONCLUSIONS: A. kalrae keratitis is an exceptionally rare clinical entity that poses significant therapeutic challenges. MALDI-TOF-MS serves as a useful diagnostic technique in identifying this rare organism. Although the literature suggested that A. kalrae keratitis may sometimes be controlled with antifungal medical treatment alone, this approach was proven to be futile in our immunocompromised patient with pre-existing neurotrophic keratopathy, suggesting that early surgical intervention such as therapeutic keratoplasty may be required in these cases.

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

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

Paraneoplastic Granulomatous Vitritis: Elaboration of 8 Cases.

PURPOSE: To describe the clinical features in a series of 8 patients with cytologically proven granulomatous vitritis in the context of systemic malignancy. DESIGN: Retrospective case review series from 2004 through 2018 to identify all cases of cytologically proven granulomatous vitritis and to analyze its disease associations and causes. PARTICIPANTS: Twenty-three patients with a cytologic diagnosis of granulomatous vitritis were identified, 8 of whom demonstrated systemic malignancy. MAIN OUTCOME MEASURES: To identify a clinical profile of the 8 cases of granulomatous vitritis occurring in the setting of systemic malignancy, focusing on the timing of the eye presentation compared with the timing of the systemic malignancy. METHODS: Patients with a cytologic diagnosis of granulomatous vitritis seeking treatment from 2004 through 2018 were included in this retrospective case series. Case notes were recalled and reviewed for demographic features, medical history, presenting symptoms, investigations, surgical procedures, and follow-up. RESULTS: Twenty-three patients were diagnosed cytologically with granulomatous vitritis. Ten of 23 patients (43%) showed autoimmune and infectious causes, 5 of 23 patients (22%) showed were idiopathic causes, and 8 of 23 patients' (35%) disease was associated with systemic malignancy. In the latter group, the median age at presentation was 70 years (range, 55-89 years). Six patients showed bilateral disease, and the remaining 3 showed unilateral disease. Three of 8 patients showed primary systemic malignancy diagnosed after eye symptoms and 5 of 8 showed malignancy before the eye symptoms. These latter 5 patients all demonstrated a major relapse, metastasis, or both at the time of eye symptoms. CONCLUSIONS: Paraneoplastic vitritis is primarily a disease of older age, with 67% of those affected older than 65 years. Ophthalmologists should maintain a high index of suspicion of paraneoplastic cause in bilateral posterior segment inflammation of uncertain origin, presenting for the first time, or heralding malignancy recurrence or metastasis in known cases of malignancy.

FULL DIAGNOSTIC VITRECTOMY WITH POSTERIOR VITREOUS DETACHMENT INDUCTION FOR THE DIAGNOSIS OF VITRITIS DUE TO UNCERTAIN ETIOLOGY.

PURPOSE: To report on the diagnostic outcomes and safety of full diagnostic vitrectomy (FDV) with surgical posterior vitreous detachment induction for diagnosing vitritis of uncertain etiology. METHODS: Forty-nine patients underwent primary FDV using the cassette washings for histopathological analysis. In addition, an undiluted core vitreous sample was obtained for microbial analysis in suspected infective cases. Cases were retrospectively given a diagnosis of inflammatory, infective, or neoplastic based on the results at final follow-up and the outcome of primary FDV categorized as diagnostic or nondiagnostic. The success of FDV was evaluated in relation to the final diagnosis. The need for additional intraocular biopsies and intraoperative or postoperative complications was also recorded. RESULTS: Full diagnostic vitrectomy was diagnostic in 26/49 cases (53%) and nondiagnostic in 23 (47%). The diagnostic success rate was greatest in neoplastic (16/20, 80%) and infective cases (9/13, 69%). Seven cases (14%) required additional biopsies to establish the diagnosis, and in 15/49 cases (31%), no cause of vitritis was identified. Intraoperative retinal breaks occurred in 3/49 cases (6%) and retinal detachment in 1/49 cases (2%). Three of 49 cases (6%) developed transiently elevated intraocular pressure postoperatively. CONCLUSION: Full diagnostic vitrectomy in combination with an undiluted core vitreous biopsy for suspected infections is safe and effective at securing a diagnosis in vitritis, particularly in cases of neoplasia.

Early and Late Histological and Ultrastructural Findings in Resected Infantile Capillary Hemangiomas Following Treatment with Topical Beta-Blocker Timolol Maleate 0.5.

BACKGROUND: Infantile capillary hemangiomas (IHs) affect approximately 4-5% of infants. The systemic nonselective ß-adrenergic antagonist, propranolol, has become the standard first-line treatment for severe IHs. The topical ß-antagonist, timolol maleate, has also demonstrated efficacy and safety in treating superficial and some deep capillary hemangiomas. Despite their therapeutic success and prevalent use, the mechanism of action of ß-adrenergic antagonists in the treatment of IHs is not well understood. METHODS: Histopathological and electron microscopic evaluation of two periocular IHs excised at 1 week and 24 months following topical timolol treatment was performed. RESULTS: Distinct morphological differences were observed between spontaneously regressed and ß-antagonist-treated IHs. The former was characterized by diffuse collagen deposition and interstitial fibrosis, while the latter showed organized concentric collagen IV deposition within obliterated vessel lumen, suggestive of waves of endothelial cell apoptosis, leaving behind layers of basement membrane deposits as a stress response. CONCLUSIONS: Based on these observations, we hypothesize that, apart from their well-known cardiac and vasodilatory effects, ß-antagonists could induce endothelial cell apoptosis in IH leading to endovascular occlusion and we present supporting evidence to explain why this response might be specific to hypoxic tissue.

Outcomes of Penetrating Keratoplasty Following Autologous Cultivated Limbal Epithelial Stem Cell Transplantation.

The purpose of this study is to investigate the outcomes of penetrating keratoplasty (PKP) following autologous cultivated limbal epithelial stem cell transplantation (CLET). A prospective, single center, interventional cohort study investigating patients with unilateral total limbal stem cell deficiency (LSCD) treated with CLET who underwent PKP. Patients with confirmed corneal re-epithelialization > 6 months post-CLET, and with best-corrected visual acuity (BCVA) <0.3 logMAR were offered PKP. CLET survival assessed by slit lamp, corneal impression cytology (CIC), and in vivo confocal microscopy. Confirmation of corneal re-epithelialization by histological and immunocytochemical (ICC) examination of trephined corneal buttons. Mean change in best-corrected visual acuity (logMAR) following PKP and PKP survival at 12 months were calculated. Twenty patients underwent PKP. Mean time of PKP was 19 months (range 11-41 months, SD 7.26) post-CLET. Median follow-up time post-PKP was 15 months (range 1-32, SD 10.2). CIC and ICC of all corneas confirmed corneal re-epithelialization before PKP. Mean pre-PKP BCVA was 1.46 (range 0.3-2.7, SD 0.94) improving to a mean post-PKP BCVA of 0.74 (range 0-2.7, SD 0.87); mean improvement in BCVA post-PKP of 36 letters (95% CI 15.0-57.1, p = .002). Kaplan-Meier mean graft survival was 90.9% (95% CI 50.8-98.7) at 12 months. We recommend a two-stage approach with CLET followed by PKP >12 months later. Patients experienced a significant improvement in BCVA following PKP. PKP did not have a detrimental effect on CLET survival. PKP survival post-CLET is better than that reported for high risk PKP. Stem Cells 2018;36:925-931.

Genetic Background of Iris Melanomas and Iris Melanocytic Tumors of Uncertain Malignant Potential.

PURPOSE: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Iris melanoma comprises 4% to 10% of all UMs and has a lower mortality rate. The genetic changes in iris melanoma are not as well characterized as ciliary body or choroidal melanoma. The aim of this study was to gain more insight into the genetic background of iris melanoma and iris nevi. DESIGN: Multicenter, retrospective case series. PARTICIPANTS: Patients diagnosed with iris melanoma or iris nevi who underwent surgical intervention as primary or secondary treatment. METHODS: Next-generation sequencing of GNAQ, GNA11, EIF1AX, SF3B1, BAP1, NRAS, BRAF, PTEN, c-Kit, TP53, and TERT was performed on 30 iris melanomas and 7 iris nevi. Copy number status was detected using single nucleotide polymorphisms (SNPs) included in the next-generation sequencing (NGS) panel, SNP array, or fluorescent in situ hybridization. BAP1 immunohistochemistry was performed on all samples. MAIN OUTCOME MEASURES: Mutation and copy number status were analyzed. Results of BAP1 immunohistochemistry were used for survival analysis. RESULTS: In 26 of the 30 iris melanoma and all iris nevi, at least 1 mutation was identified. Multiple mutations were detected in 23 iris melanoma and 5 nevi, as well as mutations in GNAQ and GNA11. Furthermore, 13 of 30 BAP1, 5 of 30 EIF1AX, and 2 of 30 SF3B1 mutations were identified in iris melanoma. No correlation between BAP1 status and disease-free survival was found. The iris nevi showed 1 EIF1AX and 3 BAP1 mutations. Two of the nevi, with a BAP1 mutation, were histologically borderline malignant. Mutations in NRAS, BRAF, PTEN, c-KIT, and TP53 were detected in 6 iris melanomas and 4 iris nevi. CONCLUSIONS: Mutations that are often found in uveal and cutaneous melanoma were identified in this cohort of iris melanomas and iris nevi. Therefore, iris melanomas harbor a molecular profile comparable to both choroidal melanoma and cutaneous melanoma. These findings may offer adjuvant targeted therapies for iris melanoma. There was no prognostic significance of BAP1 expression as seen in choroidal melanoma. Consequently, iris melanoma is a distinct molecular subgroup of UM. Histologic borderline malignant iris nevi can harbor BAP1 mutations and may be designated iris melanocytic tumors of uncertain malignant potential.

Corneal Neurotization for Neurotrophic Keratopathy: Clinical Outcomes and In Vivo Confocal Microscopic and Histopathological Findings.

PURPOSE: To describe the long-term outcomes and in vivo confocal microscopic (IVCM) and histopathological findings after corneal neurotization surgery. METHODS: We included 2 patients who underwent corneal neurotization surgery for severe unilateral neurotrophic keratopathy secondary to cerebellopontine angle meningioma. Corneal sensation was measured using the Cochet-Bonnet esthesiometer (CBE) (0-60 mm). IVCM was performed using the Heidelberg HRT3 Rostock Corneal Module. Histopathological examination was performed on the excised corneoscleral disc of patient 2. RESULTS: In patient 1, corneal sensation improved from 0 mm preoperatively to 60 mm in all 4 quadrants by 2 years postoperatively and was maintained at 5 years postoperatively with identifiable subbasal and stromal corneal nerves on IVCM. In patient 2, corneal sensation improved from 0 mm preoperatively to 10 mm in 3 quadrants (9 months postoperatively) but returned to 0 mm in all quadrants by 2 years postoperatively. IVCM failed to identify any subbasal and stromal corneal nerves. At 5 years postoperatively, evisceration was performed to ameliorate uncontrolled and persistent ocular pain and poor cosmesis. Histopathological examination of the excised corneoscleral disc confirmed the presence of normal-sized, central corneal stromal nerve fascicles but without direct continuity with the transplanted perilimbal nerve bundles. CONCLUSIONS: Our study elucidates the mechanism of corneal neurotization surgery at a cellular level. Although only 1 patient achieved long-term improvement in corneal sensation postoperatively, the findings on IVCM and histopathological examination suggest that partial regeneration/maintenance of corneal nerves after corneal neurotization surgery is likely attributed to the paracrine neurotrophic support, instead of direct sprouting, from the perilimbal transplanted nerve fascicles.

Late Solitary Extraocular Recurrence From Previously Resected Iris Melanoma.

PURPOSE: To report on cases of late extraocular relapse of previously resected iris melanoma, without concurrent intraocular recurrence. DESIGN: Retrospective case series. METHODS: A retrospective chart review of 4 patients diagnosed with late subconjunctival relapse of previously resected iris melanoma. RESULTS: Three female patients and 1 male patient underwent iris tumor resection and presented to our service with suspicious conjunctival lesions at a median of 22 years later (mean: 21 years). None showed intraocular relapse. Treatment of the conjunctival tumors included excisional biopsy (n = 4), followed by cryotherapy (n = 3) and/or brachytherapy (n = 3). In all cases, histopathology confirmed malignant melanoma, with no intraepithelial component or associated melanosis. Genetic sequencing (n = 3) showed wild-type BRAF and NRAS in all. GNA11 mutation was found in 1 case. On array-based comparative genomic hybridization (n = 3), gain of 6p was found in 2 cases and gain of 8 in 2. Overall, findings were strongly suggestive of a diagnosis of late extraocular relapse from previously resected iris melanoma. In a median of 2.5 years (mean: 7.7 years) from the subconjunctival relapse, no further episodes of intraocular/extraocular recurrence were recorded, and all patients were free from distant metastasis. CONCLUSIONS: Patients undergoing iris melanoma resection are at risk of developing late solitary extraocular relapse even more than 30 years after surgery. In the absence of an intraocular component, diagnosis may be challenging, as tumors mimic a primary conjunctival lesion. Management by excisional biopsy followed by adjuvant therapy was successful, and histopathology and genetic analysis supported a diagnosis of extraocular uveal tumor spread rather than a primary conjunctival tumor.

Spindle Cell Lipoma of the Conjunctiva.

A 67-year-old woman presented with progressive enlargement of a long-standing mass on the surface of her OS associated with ocular surface irritation. The mass was excised en bloc. Histopathological examination showed a well-defined encapsulated tumor composed of wiry collagen containing bland spindle cells that were strongly positive for CD34 with scattered mature adipocytes. These features confirmed a diagnosis of spindle cell lipoma.