Invasive conjunctival squamous cell carcinoma (CSCC) is an aggressive, ocular surface malignancy. The mean annual age-standardised incidence rate of 0.45 cases per million per year is increasing with an average annual percent rise of 4.5% and occurs mainly in over 65-year-olds in temperate climates but in a younger demographic in the tropics. Invasive CSCC can lead to vision loss either from the destructive effects of the tumour or side effects of therapy, facial disfigurement from radical surgery, and death from metastases. There is no standardised treatment and not all cases are referred to a specialist ocular oncology centre. Recent progress in cancer immunology and genetics has revolutionised the treatment of cutaneous and head and neck SCCs, which share some similarities to invasive CSCC. A better understanding of invasive CSCC and its preinvasive intraepithelial lesions is required to lead to the development of novel targeted and immunotherapies both for local tumour control, globe sparing alternatives and to prevent disseminated disease. This review aims to provide a comprehensive clinical overview of the current knowledge regarding CSSC, its epidemiology, pathogenesis, presentation, diagnosis, management, recent advances in targeted and immunotherapies for personalised treatment of this disease, and early diagnosis strategies to improve patient outcomes.

A woman in her late 30s presented with a 3 week history of rapidly worsening vision in her right eye. Examination revealed a large amelanotic choroidal mass with subretinal fluid and progressive growth on serial imaging, raising suspicion of malignancy. Systemic workup identified a 14 cm lung mass, which was resected and histologically confirmed as grade II chondrosarcoma. Meanwhile, the choroidal lesion enlarged rapidly to a collar-stud configuration involving the posterior pole, suggesting this to be a chondrosarcoma metastasis. External beam radiotherapy was declined due to lack of histological confirmation and minimal evidence of choroidal metastasis developing from chondrosarcoma in the literature. Given the poor visual prognosis, rapid tumour growth and diagnostic uncertainty, enucleation was performed, confirming metastatic chondrosarcoma. Subsequent imaging demonstrated multifocal skeletal metastases and the patient was placed on palliative care. This case highlights choroidal metastasis as the first manifestation of pulmonary chondrosarcoma and underscores the diagnostic and management challenges in such rare presentations.

A 62-year-old female with known chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), without paraproteinemia and on no active CLL/SLL specific treatment, presented with bilateral proptosis, bilateral caruncle enlargement, and restricted eye movement associated with bilateral periocular and trunk skin yellowish non-ulcerated plaques. A magnetic resonance image scan (MRI) showed bilateral infiltration of all the extraocular muscles and intra-orbital fat with neck lymphadenopathy, suggesting lymphoma infiltration. Clinically, high-grade transformation of the CLL/SLL was suspected. One of the periocular skin and orbit lesions were biopsied for histology. These showed atypical lymphocytes, the morpho-immunohistochemical features of which confirmed CLL/SLL. No features of high-grade transformation were identified. Between the CLL/SLL nodules was a palisaded granulomatous lesion formed of necrobiotic collagen cuffed by swathes of variably xanthomatised CD163 positive histiocytes, with numerous multinucleated giant cells resembling Touton type giant cells. The features were those of a very unusual collision lesion of CLL/SLL and necrobiotic xanthogranuloma (NBX) in the same biopsy-a highly unusual occurrence.

PURPOSE:To report a case of Ocular Whipple's Disease (WD) that presented as chronic bilateral uveitis and to highlight the essential role of molecular diagnostics in reaching a definitive diagnosis. METHODS:This report describes the case of a 67-year-old female with chronic, refractory uveitis. The patient underwent a diagnostic vitrectomy. The collected vitreous sample was analyzed using histopathology with Periodic Acid-Schiff (PAS) staining, transmission electron microscopy (EM), and polymerase chain reaction (PCR) for Tropheryma whipplei. RESULTS:Histopathology of the vitreous revealed bubbly histiocytes containing PAS-positive granules, and EM confirmed the presence of Tropheryma whipplei bacteria. PCR analysis of fresh vitreous fluid yielded a positive result for T. whipplei 16S rRNA. In contrast, systemic evaluation, including a duodenl biopsy, was negative for WD. Following treatment with appropriate antibiotics, the patient's ocular inflammation resolved, and visual acuity improved significantly. CONCLUSION:Ocular WD should be considered in the differential diagnosis for chronic, unexplained uveitis, even when systemic symptoms are absent. PCR analysis of vitreous fluid is an invaluable tool for confirming the diagnosis and is crucial for guiding appropriate, sight-saving therapy.

A 51-year-old male presented with a rapidly growing right caruncular nodular lesion. Excisional biopsy performed elsewhere showed an apocrine adenocarcinoma of the caruncle with positive margins. Clinically, there was no obvious residual disease, mapping biopsies were negative, and cryotherapy of the surgical base was performed.The tumor recurred both anteriorly in the lower fornix and deeper in the anterior orbit a year later. These were surgically excised with adjuvant radiotherapy (60 Gy in 30 fractions). Unfortunately, the tumor continued to recur posteriorly to progressively first involve optic canal and cavernous sinus, then planus sphenoidale (with loss of right eye vision), and then intracranially with each recurrence treated with stereotactic radiosurgery. Six years from last treatment, the latest MRI revealed the involvement of Meckel's cave and optic chiasm, which is now being treated with hormonal treatment. This is the first case of invasive apocrine adenocarcinoma of the caruncle with intracranial extension treated multimodally with surgery, radiotherapy, repeated stereotactic radiosurgery, and hormone therapy.

INTRODUCTION:Limbal stem cell deficiency (LSCD) is commonly caused by ocular surface burns. Corneal nerve damage, often due to infection, inflammation, trauma, leads to neurotrophic keratopathy (NK). This study investigates corneal sensation and nerve damage in patients with unilateral total LSCD before and after autologous cultivated limbal epithelial transplantation (Auto-CLET). METHODS:This prospective, single-centre case series included patients with unilateral total LSCD due to severe burns treated at Royal Victoria Infirmary, UK, between June 2012 and January 2018. Corneal sensation was assessed using Cochet-Bonnet aesthesiometry at baseline and 6 months post-Auto-CLET, and in vivo confocal microscopy (IVCM) was used to examine nerve regeneration. RESULTS:Twenty-three patients (19 males, 4 females) received Auto-CLET. Successful restoration of the ocular surface was achieved in all patients, confirmed by slit lamp examination, impression cytology, and IVCM at follow-ups up to 36 months. Baseline best corrected visual acuity was 1.67 logMAR in the affected eye compared to a mean of -0.08 in the healthy eye. Corneal aesthesiometry in LSCD eyes averaged 9.13 mm at baseline, increasing to 12.0 mm at 6 months post-Auto-CLET, though this change was not statistically significant (p = 0.26). IVCM revealed no regeneration of corneal nerves at any follow-up intervals, indicating persistent nerve damage. CONCLUSIONS:Despite successful ocular surface restoration, corneal nerve damage persisted, leaving patients at risk of persistent NK. To address this, we strongly suggest continuous topical treatment with blood derived products, such as serum eye drops, but also newly developed therapies such as IGF and rhNGF class of drugs.

BackgroundDifferentiating neoplastic and non-neoplastic uveal tumours can present a diagnostic challenge; intra-ocular biopsy may be necessary. The novel trans-scleral Essen Forceps biopsy (TSEB) technique can improve diagnostic yield compared to fine needle aspiration biopsy (FNAB). We present a case demonstrating the technique and its added value. We also review the success rate of TSEB performed at two tertiary eye centres.MethodsRetrospective case report and consecutive case series from August 2021 to March 2023. Inclusion criteria were patients who underwent TSEB of posterior uveal lesions from Moorfields Eye Hospital and Sheffield Teaching Hospitals in the United Kingdom. The outcomes were biopsy success rate and complication rateResultsEleven biopsies met the inclusion criteria. Eight (73%) were successful, which comprised six uveal melanomas, one melanocytoma and one extranodal marginal zone (ENMZ) lymphoma. One TSEB did not yield tissue for histological examination because of perioperative sample handling. Two (18%) biopsies were histologically inconclusive; both were treated as uveal melanoma on clinical grounds or repeat biopsy. The only complication was vitreous loss and retinal hole without retinal detachment in one eye with a very posterior, shallow choroidal lesion.ConclusionTSEB is an effective alternative to established biopsy techniques, yielding larger tissue samples than FNAB with intact tissue architecture. We recommend adding TSEB to the armamentarium of the ocular oncologist.

A 47-year-old female developed a reddish swelling of the right medial canthus over 3 months. On examination, a red, firm mass, involving the right medial canthal and extending into the inferior fornix was present and the globe was displaced upwards and inwards. A staging MRI scan confirmed a lacrimal sac lesion with anterior orbit extension. After an equivocal biopsy, the patient underwent debulking surgery. Histology showed a lacrimal sac invasive adenosquamous carcinoma, comprising poorly differentiated squamous carcinoma and invasive adenocarcinoma areas arranged in a tubulo-glandular pattern. The adenocarcinoma harboured numerous cilia. p16 showed block positivity of both components and micro-dissected tissue from both areas showed the presence of HPV16 DNA by PCR. This is the first description of ciliated adenosquamous carcinoma of the lacrimal sac and this finding is placed into the context of what is known about ciliated head and neck adenosquamous carcinomas and the role of high-risk HPV.

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%).

Several nomenclature and grading systems have been proposed for conjunctival melanocytic intraepithelial lesions (C-MIL). The fourth "WHO Classification of Eye Tumors" (WHO-EYE04) proposed a C-MIL classification, capturing the progression of noninvasive neoplastic melanocytes from low- to high-grade lesions, onto melanoma in situ (MIS), and then to invasive melanoma. This proposal was revised to the WHO-EYE05 C-MIL system, which simplified the high-grade C-MIL, whereby MIS was subsumed into high-grade C-MIL. Our aim was to validate the WHO-EYE05 C-MIL system using digitized images of C-MIL, stained with hematoxylin and eosin and immunohistochemistry. However, C-MIL cases were retrieved from 3 supraregional ocular pathology centers. Adequate conjunctival biopsies were stained with hematoxylin and eosin, Melan-A, SOX10, and PReferentially expressed Antigen in Melanoma. Digitized slides were uploaded on the SmartZoom platform and independently scored by 4 ocular pathologists to obtain a consensus score, before circulating to 14 expert eye pathologists for independent scoring. In total, 105 cases from 97 patients were evaluated. The initial consensus diagnoses using the WHO-EYE04 C-MIL system were as follows: 28 benign conjunctival melanoses, 13 low-grade C-MIL, 37 high-grade C-MIL, and 27 conjunctival MIS. Using this system resulted in 93% of the pathologists showing only fair-to-moderate agreement (kappa statistic) with the consensus score. The WHO-EYE05 C-MIL system (with high-grade C-MIL and MIS combined) improved consistency between pathologists, with the greatest level of agreement being seen with benign melanosis (74.5%) and high-grade C-MIL (85.4%). Lowest agreements remained between pathologists for low-grade C-MIL (38.7%). Regarding WHO-EYE05 C-MIL scoring and clinical outcomes, local recurrences of noninvasive lesions developed in 8% and 34% of the low- and high-grade cases. Invasive melanoma only occurred in 47% of the cases that were assessed as high-grade C-MIL. This extensive international collaborative study is the first to undertake a comprehensive review of the WHO-EYE05 C-MIL scoring system, which showed good interobserver agreement and reproducibility.

Einleitung: Die Brachytherapie mit Ruthenium-106 (Ru-106) ist eine der am weitesten verbreiteten augenschonenden Behandlungsmethoden des Aderhautmelanoms. Diese Patienten benötigen eine langfristige Überwachung des behandelten Tumorrestes, um sicherzustellen, dass es nicht zu einem lokalen Rezidiv kommt. Neue oder fortschreitende pigmentierte Läsionen in behandelten Augen werden oft als verdächtig angesehen, insbesondere wenn eine extrasklerale Ausbreitung befürchtet wird. Fallvorstellungen: Wir stellen 2 Fälle von posteriorem Aderhautmelanom vor, die 5 bzw. 10 Jahre zuvor mit Ru-106 behandelt worden waren. In beiden Fällen entwickelten sich dunkle/schwarze subkonjunktivale Läsionen auf der vorderen Augenoberfläche im Quadranten der Bindehautperitomie während der Behandlung mit Ru-106. Beide wiesen ähnliche histopathologische Befunde auf: schwarzes, anorganisches, partikuläres Fremdmaterial unterschiedlicher Konfluenz, das sich auf Elastin- und Kollagenfasern ablagerte. Die energiedispersive Röntgenmikroanalyse bestätigte das Vorhandensein von Silber im Material.

This study examined PRAME (preferentially expressed antigen in melanoma) expression by immunohistochemistry and reverse transcription quantitative PCR (RT-qPCR) in 202 histologically unequivocal conjunctival melanocytic lesions: 76 nevi, 29 benign melanoses, 25 low-grade conjunctival intraepithelial melanocytic lesions (LGCMIL), 26 high-grade conjunctival melanocytic intraepithelial lesions/in-situ melanoma (HGCMIL), and 46 invasive melanomas. PRAME score 0 was seen in 96% of nevi (73/76), 96% of benign melanoses (28/29), and 88% of LGCMIL (22/25). PRAME score 4 was seen in 50% HGCMIL (13/26) and 76% invasive melanomas (35/46). PRAME score 4 had a sensitivity of 50% and specificity of 100% in differentiating between HGCMIL and benign melanosis/LGCMIL. PRAME score 4 had a sensitivity of 76% and specificity of 100% in differentiating between melanoma and nevi. Relative quantification of PRAME mRNA expression by RT-qPCR was performed on 49 cases (24%): 17 nevi, 3 benign melanoses, 5 LGCMIL, 9 HGCMIL, and 15 invasive melanomas. The analysis generated two distinct groupings with 'high' relative PRAME expression for the HGCMIL and invasive melanoma and 'low/zero' expression for nevi, benign melanosis, and LGCMIL. Thirty-three challenging conjunctival melanocytic lesions that had previous fluorescence in situ hybridization (FISH) analysis were studied: 18 nevi, 12 melanomas in a nevus, 2 nevoid melanomas, and 1 insitu melanoma. All nevi (100%) showed concordance between negative FISH and PRAME (scores 0 -3). Four of 13 melanomas (31%; in-situ, invasive, isolated, and in association with nevus) showed concordance between positive FISH and PRAME score 4. In conclusion, PRAME score 4 has 100% specificity for the diagnosis of HGCMIL and melanoma. PRAME is limited in its sensitivity in the

Indeterminate melanocytic proliferations of the conjunctiva have both benign and malignant features that previously made these lesions nearly impossible to categorize in existing classification schemes. With the evolution of immunohistochemistry and molecular genetics, however, subclassifications have emerged that allow for a more tailored diagnosis and management. These conjunctival melanocytic proliferations include deep penetrating nevus, granular cell nevus, and nevoid melanoma. There remains a small subset of conjunctival melanocytic proliferations that defy precise characterization as nevi, primary acquired melanosis, or melanomas despite currently available ancillary diagnostic modalities and remain indeterminate. We highlight these unusual types of nevi and melanomas, with an update on their morphologic, immunohistochemical, and molecular genetic characteristics.

The 5th edition of the World Health Organization (WHO) Classification of Tumours of the Eye and Orbit is the latest step in standardizing the diagnostic practice worldwide. Building upon the 4th edition, published in 2018, the 5th edition introduces new chapters on the eyelid and orbital tumors, and consolidates sections on hematolymphoid tumors, soft tissue and bone tumors, metastases and genetic tumor predisposition syndromes into dedicated chapters. Written in the format of the other 5th edition volumes, a systematic approach is taken to describe the defining characteristics of each tumor type and its staging, with the addition of macroscopic appearance, cytology, diagnostic molecular pathology, and essential and desirable diagnostic criteria. This volume highlights recent advances in the etiology, pathogenesis, and diagnosis of tumors of the eye and ocular adnexa. Radiologic and ophthalmic features are also emphasized. Moreover, the 5th edition includes updates on the classification scheme for certain tumors, such as vascular anomalies, and introduces tumors that have been recently identified in the eye and ocular adnexa. This editorial summarizes the major general changes in the 5th edition of the WHO classification of Tumours of the Eye and Orbit, and the specific updates in each taxonomic category, with an emphasis on advances in understanding tumor pathogenesis, diagnostic and prognostic criteria, and novel immunohistochemical and molecular markers.

Purpose To report the histopathological results of lacrimal gland biopsies over a 21-year period in a tertiary referral centre in the United Kingdom. To the best of our knowledge, this represents the largest series to be published in the United Kingdom. Methods A retrospective observational review was carried out for patients who underwent lacrimal gland biopsies in a tertiary referral centre at the University Hospitals of Leicester, United Kingdom between the years of 2000 and 2021. Results Lacrimal gland biopsies were performed on 248 patients during the specified 21-year period. They comprised 157 (63.3%) females and 91 (36.7%) males. The mean age at presentation was 50.8 years (range 15–94 years). The majority of patients were Caucasian (69.4%, n = 172) followed by Asians (25.0%, n = 62), African/Afro-Caribbean (4.8%, n = 12) and other ethnicities (0.8%, n = 2). The most common histopathological diagnosis was chronic inflammation dacryoadenitis (69.0%, n = 171) followed by lymphomas (15.3%, n = 38). Conclusion Our study shows that chronic inflammation accounts for the majority of histopathological diagnosis followed by lymphoproliferative disorders.