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.

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.

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.

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.

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.

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.

Excision and delayed reconstruction with paraffin section histopathological analysis for periocular sebaceous carcinoma.

PURPOSE: To evaluate the use of excision and delayed reconstruction with rapid paraffin section analysis in patients with sebaceous carcinoma (SC) of the periocular region. METHODS: A retrospective study of patients with SC. Patients were identified from a contemporaneously maintained database and medical notes reviewed. Data were collected on known risk factors. Standard management started with conjunctival mapping biopsies. The tumor was excised with a 3-mm clinical margin and sent in formalin for histopathological analysis. The patient went home with dressings and returned 3 days later. Further excision or reconstruction was performed as indicated. Follow-up data were collected. RESULTS: Seventeen patients had excision and delayed reconstruction with paraffin section control. Ten had clear margins after 1 excision, and 7 were clear after 2 excisions. Reconstructive technique varied according to the defect. Three patients developed further tumor. One of these had a local recurrence treated with further excision and reconstruction. One developed a multicentric tumor with regional metastasis, and the third patient developed distant metastasis. Two patients died from SC. Average follow up was 5 years (2-9 years). CONCLUSIONS: Excision and delayed reconstruction using paraffin section histopathological analysis are in widespread use for the management of basal cell carcinomas in the periocular region. While some authors advocate the use of Mohs' micrographic surgery in patients with SC, this technique has been questioned due to the possible misinterpretation of subtle intraepithelial pagetoid spread with frozen section analysis. To preserve the function of the eyelid and ease of reconstruction, it is important to try and preserve as much healthy tissue as possible while effecting a successful excision. Excision and delayed reconstruction offer an excellent option for the management of this rare and highly malignant tumor.

Adult alveolar rhabdomyosarcoma of the lacrimal sac.

Lacrimal sac tumours are rare, but must be considered in the diagnosis of patients presenting with masses in the medial canthal region. We report a single case of lacrimal sac rhabdomyosarcoma in a 31-year-old man. The patient self-presented to the eye department with a 4-week history of discomfort, epiphora and a medial canthal mass. After no response to 1 week of oral antibiotics for a presumed diagnosis of dacryocystitis and the presence of firm mass extending above the medial canthal tendon, surgical exploration was carried out which revealed a lacrimal sac mass. Histologically this showed an alveolar rhabdomyosarcoma, which was confirmed on immunohistochemistry. After 4 rounds of chemotherapy and 50.4Gy of radical radiotherapy, the patient is well with no signs of further local or distant disease at 11-months follow-up and 20 months following initial diagnosis. To our knowledge, there are no previously reported adult cases of lacrimal sac alveolar rhabdomyosarcoma in the peer-reviewed literature. We want to highlight the unique diagnosis in this case as well as drawing attention to the possibility of malignancy in patients responding poorly to management when an initial diagnosis of dacryocystitis is made in the presence of a medial canthal mass.

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%).

PAX6 mutation in association with ptosis, cataract, iris hypoplasia, corneal opacification and diabetes: a new variant of familial aniridia?

BACKGROUND: We report a family with ptosis, cataract, iris hypoplasia and gradual corneal opacification occurring in association with a PAX6 mutation. DESIGN: Case-series. PARTICIPANTS: Fourteen family members - 8 affected, 6 unaffected controls. METHODS: All participants underwent ophthalmological assessment, including best-corrected visual acuity, slit-lamp-examination, pachymetry, endothelial cell-count, tonometry and dilated fundoscopy. All subjects underwent anthropometry and assessment of glycaemic status. Genetic analysis of the PAX6 gene was performed. MAIN OUTCOME MEASURES: Presence of ptosis, corneal, iris and lenticular changes, gycaemic and PAX6 status. RESULTS: All eight affected subjects had ptosis with reduced levator function, anterior polar cataracts, and corneal changes of variable severity - two patients had undergone penetrating keratoplasties, with graft histology revealing conjunctival cells on the cornea and severe fibroinflammatory change. Five patients had iris hypoplasia. One patient had aphakic glaucoma and another had hypoplastic optic discs. Four of the six controls had no ocular features of this syndrome, and two had isolated mild ptosis. There was no difference in height or body mass index between cases and family controls (p > 0.05), but Haemoglobin A1c was greater in the cases (median [interquartile range] 5.6(0.8) vs 5.1(0.3), p = 0.028). Genetic analysis confirmed a pathogenic PAX6 mutation in exon 12 (c1439delC) in all eight patients, but none of the controls. CONCLUSION: This is the first report of this particular constellation of ocular signs occurring in association with a PAX6 mutation. There was no association with anthropometric features, but affected subjects had worse glycaemia than controls, which may be related to the known role of PAX6 in development of the pancreas.

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.

Xanthogranulomatous variant of immunoglobulin G4 sclerosing disease presenting as ptosis, proptosis and eyelid skin plaques.

A 70-year-old male was referred to the oculoplastic clinic with left-sided ptosis and floppy eyelids. During follow-up, bilateral upper lid xanthelasma developed with worsening ptosis and proptosis, which was worse on the left side. A left orbital biopsy showed xanthogranulomatous inflammation of the orbit. The patient was treated with a variety of immune modulator regimes but due to a variety of side-effects, treatment was discontinued. The left orbit was surgically debulked twice and histology revealed xanthogranulomatous inflammation, with the additional features of sclerosis, lymphoid aggregates and a prominent population of plasma cells. Around 80% of the plasma cells expressed immunoglobulin G4 (IgG4). This case report reveals an association between xanthogranulomatous inflammation of the orbit and a prominent population of IgG4-positive plasma cells. We propose that the overall disease is a novel variant of IgG4 sclerosing disease of the orbit and suggest that cases of histologically proven xanthogranulomatous inflammation should be stained for IgG4 if there is an accompanying plasma cell population.

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.