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.

Prevalence of co-existent neoplasia in clinically diagnosed pterygia in a UK population.

INTRODUCTION: Ocular surface squamous neoplasia (OSSN) and pterygia share risk factors and co-exist in only a minority of cases. Reported rates of OSSN in specimens sent as pterygium for histopathological analysis vary between 0% and nearly 10%, with the highest rates reported in countries with high levels of ultraviolet light exposure. As there is a paucity of data in European populations, the aim of this study was to report the prevalence of co-existent OSSN or other neoplastic disease in clinically suspected pterygium specimens sent to a specialist ophthalmic pathology service in London, United Kingdom. METHODS: We performed a retrospective review of sequential histopathology records of patients with excised tissue submitted as suspected "pterygium" between 1997 and 2021. RESULTS: In total, 2061 specimens of pterygia were received during the 24-year period, with a prevalence of neoplasia in those specimens of 0.6% (n = 12). On detailed review of the medical records of these patients, half (n = 6) had the pre-operative clinical suspicion of possible OSSN. Of those cases without clinical suspicion pre-operatively, one was diagnosed with invasive squamous cell carcinoma of the conjunctiva. CONCLUSION: In this study, rates of unexpected diagnoses are reassuringly low. These results may challenge accepted dogma, and influence future guidance for the indications for submitting non-suspicious pterygia for histopathological analysis.

Phenotype and genotype of concurrent keratoconus and Fuchs endothelial corneal dystrophy.

PURPOSE: To characterise the phenotype and genotype of concurrent keratoconus and Fuchs endothelial corneal dystrophy (KC + FECD). METHODS: We recruited 20 patients with concurrent KC + FECD for a retrospective observational case series from the United Kingdom and the Czech Republic. We compared eight parameters of corneal shape (Pentacam, Oculus) with two groups of age-matched controls who had either isolated keratoconus (KC) or isolated FECD. We genotyped probands for an intronic triplet TCF4 repeat expansion (CTG18.1) and the ZEB1 variant c.1920G >T p.(Gln640His). RESULTS: The median age at diagnosis of patients with KC + FECD was 54 (interquartile range 46 to 66) years, with no evidence of KC progression (median follow-up 84 months, range 12 to 120 months). The mean (standard deviation (SD)) of the minimum corneal thickness, 493 (62.7) µm, was greater than eyes with KC, 458 (51.1) µm, but less than eyes with FECD, 590 (55.6) µm. Seven other parameters of corneal shape were more like KC than FECD. Seven (35%) probands with KC + FECD had a TCF4 repeat expansion of ≥50 compared to five controls with isolated FECD. The average of the largest TCF4 expansion in cases with KC + FECD (46 repeats, SD 36 repeats) was similar to the age-matched controls with isolated FECD (36 repeats, SD 28 repeats; p = 0.299). No patient with KC + FECD harboured the ZEB1 variant. CONCLUSIONS: The KC + FECD phenotype is consistent with KC but with superimposed stromal swelling from endothelial disease. The proportion of cases with a TCF4 expansion is similar in concurrent KC + FECD and age-matched controls with isolated FECD.

Persistent orbital inflammation following complete excision of deep dermoid cysts.

Piecemeal excision of dermoid cysts carries the risk of implanting epithelial fragments into orbital fat, which is well recognized to continue secreting oily debris, inciting chronic, often granulomatous inflammation. The authors present the clinical and histological details for two patients with persistent lipogranulomatous inflammation for years after piecemeal excision of deep orbital dermoid cysts, in the absence of any residual epithelium. The importance of copious saline lavage - to 'float-out" and reduce microscopic lipid droplets - is also emphasised.

Presenting features for developmental cysts of the orbit.

PURPOSE: To evaluate the clinical features of developmental cysts of the orbit. PATIENTS AND METHODS: Retrospective study of patients who had excision of cysts between 1992 and 2020. RESULTS: Three hundred and 58 patients (189 male; 53%) with orbital developmental cysts were identified, all being unilateral. Age at surgery varied from birth to 77 years (mean 17, median 18 years) and the average symptom duration was 5 years (median 18 months; range 1 day-50 years). The commonest presenting features were a peribulbar lump or upper lid swelling, followed by proptosis, pain, diplopia and reduced vision. Most patients (82%) had a palpable mass, with epidermoids, sebaceous dermoids and keratinised dermoids commonly affecting the superotemporal quadrant, and conjunctiva-containing cysts usually being biased to a medial location. Cysts were lined by keratinised epithelium with dermal structures (224/358; 63%), non-keratinised epithelium with dermal structures (69/358; 19%), epidermis without identifiable dermal structures (19/358 'epidermoids'; 5%), conjunctiva (12/358; 3%), respiratory epithelium (4/358; 1%), or mixed dermal and conjunctival epithelia (30/358 'dermo-conjunctival' cysts; 8%). Overall, two-thirds (242/358; 66%) had histological evidence of chronic intramural inflammation, and a half of cysts showed granuloma formation (178/358 cysts). Chronic inflammation was less common with conjunctival cysts (54%, 7/12 patients) and none showed granuloma formation. CONCLUSION: Developmental cysts of the orbit vary from the relatively common dermoid cysts to the extremely rare respiratory epithelial-lined cysts. Respiratory cysts, being deeper, may present late in life and cysts containing conjunctival epithelium tend to be less inflamed and typically favour the superonasal quadrant.

Fuchs endothelial corneal dystrophy: current perspectives on diagnostic pathology and genetics-Bowman Club Lecture.

Fuchs endothelial corneal dystrophy (FECD) was first described over a century ago. Since then, we have learnt much about its clinical manifestations, surgical and non-surgical treatment, microscopic appearance and pathogenesis. Over the past decade, significant advances have been made with respect to our understanding of FECD genetics. This progress now enables us to appreciate that FECD in fact describes multiple entities with distinct underlying genetic causes. For example, an early-onset and rare form of the disease has been attributed to missense mutations in the COL8A2 gene, whereas the vast majority of late-onset cases can be attributed to a non-coding repeat expansion within the TCF4 gene.FECD is one of the most common indications for corneal transplantation. In recent years, attention has turned to alternative treatment techniques that do not depend on donor tissue supply. The design and development of these non-surgical treatment approaches have benefited from increased knowledge of pathogenesis.This review will cover our current knowledge about the histology and genetics of FECD, and how combining these interdisciplinary approaches might may improve diagnostic accuracy and aid the development of therapeutics for this common and visually disabling disease.

Correlation between BAP1 Localization, Driver Mutations, and Patient Survival in Uveal Melanoma.

Uveal melanoma (UM) is an uncommon but highly aggressive ocular malignancy. Poor overall survival is associated with deleterious BAP1 alterations, which frequently occur with monosomy 3 (LOH3) and a characteristic gene expression profile. Tumor DNA from a cohort of 100 UM patients from Moorfields Biobank (UK) that had undergone enucleation were sequenced for known UM driver genes (BAP1, SF3B1, EIF1AX, GNAQ, and GNA11). Immunohistochemical staining of BAP1 and interphase FISH for chromosomes 3 and 8 was performed, and cellular localization of BAP1 was correlated with BAP1 mutations. Wildtype (WT) BAP1 staining was characterized by nBAP1 expression with <10% cytoplasmic BAP1 (cBAP1). Tumors exhibited heterogeneity with respect to BAP1 staining with different percentages of nBAP1 loss: ≥25% loss of nuclear BAP1 (nBAP1) was superior to chr8q and LOH3 as a prognostic indicator. Of the successfully sequenced UMs, 38% harbored oncogenic mutations in GNA11 and 48% harbored mutations in GNAQ at residues 209 or 183. Of the secondary drivers, 39% of mutations were in BAP1, 11% were in EIF1AX, and 20% were in the SF3B1 R625 hotspot. Most tumors with SF3B1 or EIF1AX mutations retained nuclear BAP1 (nBAP1). The majority of tumor samples with likely pathogenic BAP1 mutations, regardless of mutation class, displayed ≥25% loss of nBAP1. This included all tumors with truncating mutations and 80% of tumors with missense mutations. In addition, 60% of tumors with truncating mutations and 82% of tumors with missense mutations expressed >10% cBAP1.

Orbital involvement of Sitosterolemia.

Sitosterolemia is a rare inherited condition in which plant sterols are stored and deposited in the tissues. Described in 1974 by Battacharyya and Connor, it is characterized by tendon and tuberous xanthomas and a propensity to premature coronary atherosclerosis. We present the first reported case of the disease being manifest in the periorbital region. A 44-year-old man presented with a six-month history of swelling below the left eyebrow overlying the orbital rim, but without displacement of the globe. Magnetic resonance imaging identified a soft tissue mass within the orbit, with subsequent biopsy confirming a xanthogranulomatous process consistent with the diagnosis of sitosterolemia. Management of sitosterolemia aims to reduce plasma plant sterol concentrations which subsequently lowers serum cholesterol reducing the xanthomas and atherosclerotic cardiovascular diseases. This report highlights a rare, under-recognised condition (and indeed the first reporting periocular disease), and the potential dangers if misdiagnosed as hypercholesterolemia.

Developmental Cysts of the Orbit With Mixed Conjunctival and Cutaneous Epithelial Phenotypes.

AIM: To describe the characteristics of patients presenting with congenital orbital cysts containing epithelia of both cutaneous phenotype-that is, epidermis with or without keratin, and at least one dermal structure (sweat gland or pilosebaceous unit)-and conjunctival phenotype (with goblet cells); these cysts with mixed lining are termed "dermo-conjunctival" cysts. PATIENTS AND METHODS: Review of clinical records for patients having dermo-conjunctival cysts that were treated between 1997 and 2017; patients with cysts of solely conjunctival or solely cutaneous origin were omitted. Data recorded included gender, age at presentation, laterality, orbital location, ophthalmic features, surgical and radiological data, and light microscopic findings. RESULTS: Of 241 patients with congenital orbital cysts, 22 (9%) contained both cutaneous and conjunctival epithelium; unlike the relatively common congenital cysts lined with solely cutaneous epithelia, these dermo-conjunctival cysts typically occupied the superonasal or nasal quadrants of the orbit (p < 0.000001). Fifteen (68%) of the 22 patients were male, and the group presented at a median age of 22 years (range 8-51 years), with symptoms for a median duration of 5 years (range 1 month-33 years). Fourteen (64%) had noted an orbital mass, 3 (14%) had inflammatory pain, and 1/22 (4%) had reduced acuity. Globe displacement was axial in 7 patients (32%) and nonaxial in 13 (59%), and ocular motility was restricted in 4/22 (18%). Of 17 patients with imaging, 9 (53%) had bone expansion, and the cyst was intimately related to the trochlea in 10 (59%). By definition, all cysts contained conjunctival epithelium with goblet cells: hair shafts were present in 13/22 (59%) specimens, sebaceous units in 18 (82%), sweat glands in 6 (27%), and keratinized epithelium was present in 8 (36%). Fourteen (63%) of cysts had mild chronic inflammation within the cyst wall, and granulomas were present in 8 (36%). CONCLUSION: Congenital dermo-conjunctival orbital cysts are rare and favor a medial location-this suggesting an origin from sequestered caruncular tissues, the only postseptal source of both dermal and conjunctival structures. Unlike pure cutaneous cysts that typically present as superficial masses in childhood, dermo-conjunctival cysts are often postseptal and present in adults.

Congenital Conjunctival Cysts of the Orbit.

PURPOSE: To evaluate the clinical presentation, anatomical location, and histological features of congenital conjunctival cysts of the orbit. The location and the histological features of inflammation in these patients were compared with those for 293 orbital dermoid cysts. PATIENTS AND METHODS: Retrospective review of the clinical details, imaging, and histopathology for patients who had excision of conjunctival cysts from their orbit between 1992 and 2020; patients with a history of trauma or surgery were omitted. RESULTS: Twelve patients (7 male; 58%) with congenital conjunctival cysts were identified, the patients presenting at an average age of 16 years (median 26; range 1-61) with a symptoms for a mean duration of 20 months (median 24; range 6-36). The commonest symptoms were peribulbar lump (6/12 patients; 50%), and eyelid swelling and blepharoptosis (6/12 patients; 50%). An orbitaxl mass was palpable in 10 patients (83%), 3 patients (25%) had mild proptosis (1-3 mm), and the cysts were most commonly located superiorly (6/12 patients; 50%) or superonasally (3/12; 25%) in the anterior half of the orbit. Imaging was performed in 7 cases, this showing an intimate relation to the common sheath of the superior rectus/levator complex in 3 patients (25%) and to the trochlea in 1 (8%). All cysts were excised completely, and no patient had postoperative complications or recurrence. Chronic mild and nonspecific inflammation was evident within the cyst wall in 7 cases (54%), but-unlike 55% of the 293 dermoid cysts-none showed granuloma formation. CONCLUSION: Congenital conjunctival cysts are rare and usually present with a palpable mass in the upper eyelid sulcus. A significant proportion of these cysts have an intimate relationship with the trochlea, or the superior rectus, levator palpebrae or superior oblique muscles and, to minimize the risk of postoperative diplopia or ptosis, particular care must be exercised during surgery.