Incidence and survival of uveal melanoma in Northern Ireland: how incomplete data can skew results in rare cancers.

BACKGROUND: The majority of Northern Irish uveal melanoma (UM) patients are diagnosed in Sheffield. This study aims to present incidence and survival outcomes for UM patients from Northern Ireland (NI). METHODS: Collaborative retrospective study between Sheffield and Northern Ireland Cancer Registry (NICR). For UM cases not on both databases, outcomes and survival rates (via Kaplan-Meier analysis) were compared. Anonymised NICR data were used to calculate whole-population incidence of UM for NI. RESULTS: In total, 161 patients from NI were diagnosed in Sheffield, 90 of which were not registered with NICR at the start of this study. Data-omissions were not consistent across patient groups, leading to significant differences between those patients registered and those not. Registered patients had an all-cause 5-year survival rate of only 68.9% compared to 92.5% of those not registered (p < 0.01) and were >17x more likely to have systemic metastases than those not registered (p < 0·001). Following rectification of data-omissions, the European age-standardised incidence rate of UM for NI was 8·6 per million. CONCLUSIONS: This study illustrates the impact of incomplete population-wide data, serving as a real-world lesson in case-identification bias. Rare cancers are at higher risk of omission due to systemic failures as the small numbers involved are not detected by system-wide validation procedures. Following this study, data-transfer agreements between England and NI were actioned, preventing future data-omissions. We present survival and incidence data for UM in NI for the first time, showing the incidence is amongst the highest in Europe, with good survival rates.

To suture or not to suture? Does globe immobilisation technique affect clinical outcome in stereotactic radiosurgery for uveal melanoma?

INTRODUCTION: Stereotactic radiosurgery (SRS) is a valuable treatment option for uveal melanoma, offering excellent tumour control rates and eye preservation. Its efficacy relies upon accurate localisation of the tumour, which is challenging in the mobile eye. Various methods of globe immobilisation have been used, including non-invasive devices, such as eye movement tracking and suction cups, but common practice is to use local anaesthetic block with or without transconjunctival suturing of the extraocular muscles. Some studies have suggested that the addition of muscle suturing to local anaesthetic block provides better immobilisation of the globe, when compared to anaesthetic block alone. Controversy exists regarding the clinical relevance of this observation and ocular oncologists differ in their choice of immobilisation technique. METHODS: In order to establish if the addition of muscle suturing to local anaesthetic block improves clinical outcomes, we performed a retrospective review of all cases that underwent SRS for uveal melanoma over a 10-year period (May 2008 to May 2018). Based on surgeon preference, all patients received either local anaesthetic block plus muscle suturing (Group A) or local anaesthetic block alone (Group B) to induce globe akinesia. Outcomes assessed were primary treatment failure, tumour recurrence, secondary enucleation and death rate. RESULTS: In our cohort of 290 eyes; 118 patients were in group A and 172 patients were in group B. There were no cases of primary treatment failure in either group. With a minimum of 24 months follow-up, only 3 patients experienced tumour recurrence (1 in group A and 2 in group B). There was no significant difference in recurrence, enucleation and all-cause death rates between the two groups. CONCLUSION: Our retrospective review suggests that although extraocular muscle suturing may be considered by some units to provide superior globe immobilisation for SRS, it does not alter the clinical outcome.

Usefulness of PAX8 Immunohistochemistry in Adult Intraocular Tumor Diagnosis.

PURPOSE: To evaluate the distribution of the PAX8 transcription factor protein in ocular tissues and to investigate if immunohistochemical stains for this biomarker are useful in the diagnosis of intraocular tumors. DESIGN: Observational case series. PARTICIPANTS: Excision and cytologic analysis specimens of 6 ciliary body epithelial neoplasms, 2 iris epithelial neoplasms, 3 retinal pigment epithelial neoplasms, 3 intraocular medulloepitheliomas, 15 uveal melanomas, and 5 uveal melanocytomas. METHODS: Hematoxylin-eosin and PAX8 immunohistochemical stains were performed on all specimens. In appropriate cases, bleached preparations and other immunohistochemical stains, including AE1/AE3 cytokeratin, Lin28A, and CD45, were performed. MAIN OUTCOME MEASURES: Distribution of PAX8 expression in normal and neoplastic tissue. RESULTS: Strong nuclear PAX8 expression was observed in the normal corneal epithelium, iris sphincter pupillae muscle, iris pigment epithelium and dilator muscle complex, nonpigmented and pigmented epithelia of the ciliary body, lens epithelium, and a subset of retinal neurons. The normal retinal pigment epithelium and uveal melanocytes did not stain for PAX8. The ciliary body epithelial and neuroepithelial tumors (adenoma, adenocarcinoma, and medulloepithelioma) showed uniform strong nuclear PAX8 immunoreactivity. All melanocytic tumors (iris melanoma, ciliary-choroidal melanoma, and melanocytoma) and retinal pigment epithelial neoplasms showed negative results for PAX8. A subset of tumor-associated lymphocytes, most prominent in uveal melanoma, showed positive results for PAX8. The uniformity of the PAX8 staining was superior to the variable cytokeratin staining in the ciliary epithelial neoplasms and the variable Lin28A staining in malignant medulloepithelioma. The veracity of PAX8 staining was equally as robust on cytologic analysis and open-flap biopsy specimens of ciliary epithelial and iris epithelial neoplasms, melanocytoma, and melanoma. CONCLUSIONS: PAX8 has proven to be a very useful diagnostic marker in a select group of adult intraocular tumors, and we highly recommend its inclusion in diagnostic antibody panels of morphologically challenging intraocular neoplasms.

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.

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.

Correction to: Human papillomavirus type 16 causes a defined subset of conjunctival in situ squamous cell carcinomas.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Human papillomavirus type 16 causes a defined subset of conjunctival in situ squamous cell carcinomas.

Squamous cell carcinoma of the conjunctiva is associated with a number of risk factors, including HIV infection, iatrogenic immunosuppression and atopy. In addition, several studies have suggested an involvement of HPV, based on the presence of viral DNA, but did not establish whether there was active infection or evidence of causal disease association. In this manuscript, 31 cases of conjunctival in situ squamous cell carcinoma were classified as HPV DNA-positive or -negative, before being analysed by immunohistochemistry to establish the distribution of viral and cellular biomarkers of HPV gene expression. Our panel included p16INK4a, TP53 and MCM, but also the virally encoded E4 gene product, which is abundantly expressed during productive infection. Subsequent in situ detection of HPV mRNA using an RNAscope approach confirmed that early HPV gene expression was occurring in the majority of cases of HPV DNA-positive conjunctival in situ squamous cell carcinoma, with all of these cases occurring in the atopic group. Viral gene expression correlated with TP53 loss, p16INK4a elevation, and extensive MCM expression, in line with our general understanding of E6 and E7's role during transforming infection at other epithelial sites. A characteristic E4 expression pattern was detected in only one case. HPV mRNA was not detected in lower grades of dysplasia, and was not observed in cases that were HPV DNA-negative. Our study demonstrates an active involvement of HPV in the development of a subset of conjunctival in situ squamous cell carcinoma. No high-risk HPV types were detected other than HPV16. It appears that the conjunctiva is a vulnerable epithelial site for HPV-associated transformation. These cancers are defined by their pattern of viral gene expression, and by the distribution of surrogate markers of HPV infection.

Increased Non-Homologous End Joining Makes DNA-PK a Promising Target for Therapeutic Intervention in Uveal Melanoma.

Uveal melanoma (UM) is the most common primary intraocular tumour in adults, with a mean survival of six months following metastasis. The survival rates have not improved in over 30 years. This study has shown that sister chromatid exchange (SCE) is low in UM which is likely due to a reduced expression of FANCD2. As FANCD2 can function to suppress non-homologous end joining (NHEJ), this study therefore investigated NHEJ in UM. The activation of the catalytic subunit of the NHEJ pathway protein DNA-dependent protein kinase (DNA-PK) was measured by analysing the foci formation and the ligation efficiency by NHEJ determined using a plasmid-based end-joining assay. Using small-interfering RNA (siRNA) knock-down, and chemical inhibitors of DNA-PK, the survival of primary UM cultures and two cell lines were determined. To assess the homologous recombination capacity in response to the inhibition of DNA-PK, a SCE analysis was performed. In addition, to support the findings, the messenger RNA (mRNA) expression of genes associated with NHEJ was analysed using the Cancer Genome Atlas (TCGA)-UM RNAseq data (n = 79). The NHEJ activity and DNA-PKcs activation was upregulated in UM and the inhibition of DNA-PK selectively induced apoptosis and sensitized to ionising radiation and inter-strand cross-linking agents. The inhibition of the NHEJ protein DNA-PK is lethal to UM, indicating a potentially effective therapeutic option, either alone or as a sensitizer for other treatments.

A Case of a Cavitary Iris Melanoma with Aqueous Cytological Modulation.

Malignant melanoma is the most common primary malignant tumour of the iris, but represents a small proportion of all uveal melanomas. The authors describe a 34-year-old male with a pigmented lesion of the iris. The lesion remained stable for 7 years, but the patient re-presented after this time with sudden enlargement of the mass and hyphaema. Excisional biopsy confirmed cavitary melanoma of the iris. This is the first reported case of cavitation in a primary iris melanoma. The patient has not had any further adjuvant treatment and remains metastasis free at 5 years of follow-up.

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.

In vivo diagnosis of intraocular osseous metaplasia in neovascular age-related macular degeneration.

A 75-year-old man presented with deterioration of right eye vision for 6 months. He had no relevant medical history. Fundus examination revealed subretinal fluid, fibrosis, and subretinal hemorrhages. Ocular coherence tomography of the right macula illustrated an underlying subretinal lesion with internal lamellae, resembling trabecular bone elsewhere in the body. Bruch's membrane was clearly intact beneath the lesion, indicating an extrachoroidal location. The lesion appeared highly reflective on B-scan ultrasonography, consistent with ossification. Although initially misdiagnosed as choroidal osteoma, this lesion represents in-vivo intraocular osseous metaplasia at the site of neovascular age-related macular degeneration. The authors believe that similar lesions may have been misdiagnosed as "atypical" osteoma caused by failure to identify their extrachoroidal location.

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.

Primary Myoepithelial Carcinoma of the Conjunctiva.

A 38-year-old female, otherwise fit and well, presented with a mass on her left medial bulbar conjunctiva that had been enlarging for several months. Examinations showed a fixed pinkish tumour, 9 mm in maximum extent, spanning from the plica to the medial limbus. The tumour was removed in toto. Histology revealed it to be a biphasic tumour composed of lobules and infiltrative cords within a sclerotic matrix. The cells were spindle-shaped to epithelioid, with nuclear atypia and occasional mitotic figures. The tumour was positive for smooth muscle actin, beta-catenin, and vimentin. All other markers of myoepithelial differentiation and cytokeratins were negative. Genetic analysis showed no evidence of EWSR1 or PLAG1 rearrangements. The light microscopic features and immunohistochemistry strongly supported a tumour with myoepithelial differentiation. The cellular atypia, mitotic activity, and infiltrative edges all pointed to myoepithelial carcinoma. Body imaging/screening showed no evidence of tumour elsewhere, supporting that the tumour was a primary of the conjunctiva. This is the first report of a myoepithelial tumour of the conjunctiva. The patient remains recurrence-free after 3 years of follow-up.

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.

Phenotypic Plasticity in Uveal Melanoma Is Not Restricted to a Tumor Subpopulation and Is Unrelated to Cancer Stem Cell Characteristics.

Purpose: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and approximately half of those diagnosed will die of metastasis. This study investigates whether UM progression is driven by a subpopulation of stem-like cells, termed "cancer stem cells" (CSCs). Methods: Expression of postulated stem cell markers aldehyde dehydrogenase (ALDH), CD44, and CD133 was analyzed in UM cell lines and primary UM short-term cultures (STCs) established from tumor samples. Additionally, the notion of a "cellular hierarchy" within UM was investigated. Finally, the phenomenon of phenotypic plasticity in response to environmental factors was explored. Results: We demonstrate that expression of ALDH, CD44, and CD133 does not select for a subpopulation of stem-like cells in either UM cell lines or UM STCs. Furthermore, there is an absence of a cellular hierarchy in cell lines and all cells in culture are able to drive tumor progression. Last, we show that established UM cell lines and UM STCs are plastic in nature and switch their phenotype in response to environmental stimuli. Conclusions: We hypothesize that this capacity to undergo phenotypic plasticity may be a consequence of neural crest lineage and renders the exploration of the CSC hypothesis extremely challenging in UM.

Conjunctival Melanoma during Pregnancy.

PURPOSE: To describe the clinical and histopathological features of a conjunctival melanoma (CM) during early pregnancy. PROCEDURES: A 37-year-old, 20-week pregnant primigravida was referred to the Sheffield Ocular Oncology Service with a rapidly growing lesion arising from the right superior conjunctival fornix, noted from the first trimester of pregnancy. This was associated with pain and bloody discharge. Incisional biopsy confirmed the clinical suspicion of invasive CM. She was treated by primary surgical excision and cryotherapy under local anaesthesia. RESULTS: Histology of the excised specimen showed an invasive malignant melanoma with surrounding in situ conjunctival changes arising from a naevus. The melanoma was 10.5 mm thick, focally necrotic, and had a mitotic count of 11/mm2 focally. The patient responded well to surgical treatment. She gave birth to a healthy boy, and the placenta showed no evidence of metastatic melanoma. There has been no recurrence or distant metastasis during 5 years of follow-up. CONCLUSION: CM during pregnancy is extremely rare. Because of possible transformation to malignant melanoma, we recommend close monitoring of females known to have pigmented conjunctival lesions of the conjunctiva during pregnancy.

The Pediatric Choroidal and Ciliary Body Melanoma Study: A Survey by the European Ophthalmic Oncology Group.

PURPOSE: To collect comprehensive data on choroidal and ciliary body melanoma (CCBM) in children and to validate hypotheses regarding pediatric CCBM: children younger than 18 years, males, and those without ciliary body involvement (CBI) have more favorable survival prognosis than young adults 18 to 24 years of age, females, and those with CBI. DESIGN: Retrospective, multicenter observational study. PARTICIPANTS: Two hundred ninety-nine patients from 24 ocular oncology centers, of whom 114 were children (median age, 15.1 years; range, 2.7-17.9 years) and 185 were young adults. METHODS: Data were entered through a secure website and were reviewed centrally. Survival was analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. MAIN OUTCOME MEASURES: Proportion of females, tumor-node-metastasis (TNM) stage, cell type, and melanoma-related mortality. RESULTS: Cumulative frequency of having CCBM diagnosed increased steadily by 0.8% per year of age between 5 and 10 years of age and, after a 6-year transition period, by 8.8% per year from age 17 years onward. Of children and young adults, 57% and 63% were female, respectively, which exceeded the expected 51% among young adults. Cell type, known for 35% of tumors, and TNM stage (I in 22% and 21%, II in 49% and 52%, III in 30% and 28%, respectively) were comparable for children and young adults. Melanoma-related survival was 97% and 90% at 5 years and 92% and 80% at 10 years for children compared with young adults, respectively (P = 0.013). Males tended to have a more favorable survival than females among children (100% vs. 85% at 10 years; P = 0.058). Increasing TNM stage was associated with poorer survival (stages I, II, and III: 100% vs. 86% vs. 76%, respectively; P = 0.0011). By multivariate analysis, being a young adult (adjusted hazard rate [HR], 2.57), a higher TNM stage (HR, 2.88 and 8.38 for stages II and III, respectively), and female gender (HR, 2.38) independently predicted less favorable survival. Ciliary body involvement and cell type were not associated with survival. CONCLUSIONS: This study confirms that children with CCBM have a more favorable survival than young adults 18 to 25 years of age, adjusting for TNM stage and gender. The association between gender and survival varies between age groups.

High-Resolution Array CGH Analysis Identifies Regional Deletions and Amplifications of Chromosome 8 in Uveal Melanoma.

PURPOSE: Monosomy 3 (M3) and abnormalities of chromosome 8 associate with poor prognosis in uveal melanomas (UM). Although M3 has been the subject of more in-depth studies, none have intensively focused on chromosome 8. To elucidate the potential role of chromosome 8 abnormalities, array comparative genomic hybridization (aCGH) was performed on primary UM. METHODS: A specifically-designed custom high-resolution array was developed focusing on changes most implicated in UM. Probes for chromosome 8 had a mean spacing of 2.3 kb while chromosomes infrequently affected had a mean spacing of 36.6 kb. A series of 75 UM, including one formalin-fixed paraffin sample were analyzed, and where possible control DNA extracted from the patient's own peripheral blood was used. RESULTS: The most common copy number abnormalities were chromosome 8 (75%) and M3 (51%), with M3 and gain of the long arm of chromosome 8 (8q+) associated in 41% of cases. Also identified were partial deletions of chromosome 3 (3%) and regional 8q+ (23%), and the intensive coverage of chromosome 8 revealed small focal deletions and amplifications affecting both arms. The most significant predictor of prognosis was M3/8q+ having a hazard ratio of 10.1 (P < 0.0001). CONCLUSIONS: Neither 8p deletion nor focal changes affecting chromosome 8 were linked to outcome. The most significant indicator was M3/8q, and multiple 8q+ associated with shorter survival. Studying UM with this technology provides a powerful robust tool for predicting prognosis while considering other genetic changes, allowing the future incorporation of such data as it becomes clinically significant.

Unilateral Conjunctival in situ Squamous Carcinoma with Bilateral Conjunctival Chlorpromazine-Induced Secondary Melanosis Masquerading as in situ and Invasive Melanoma.

PURPOSE: To describe the clinical and histopathological features of a 61-year-old male with a history of eczema, asthma and schizophrenia on long-term chlorpromazine medication, who developed a unilateral limbal tumour in association with bilateral melanosis. PROCEDURES: The patient was referred for a routine cataract assessment, and an incidental pink gelatinous limbal lesion was detected on the left side, associated with bilateral speckled brown conjunctival pigmentation. The limbal lesion and brown pigmentation were biopsied. The tissue was fixed in standard buffered formalin and processed to paraffin wax, and sections were stained with haematoxylin and eosin. Tissue from the pigmented area was also processed for transmission electron microscopy. RESULTS: The biopsy from the limbal lesion showed an in situ squamous carcinoma associated with prominent numbers of intra-epithelial eosinophils. The biopsy of the pigmented area showed bilateral melanosis without atypia. The latter was attributable to an increase in melanin production rather than to melanocyte hyperplasia. Melanophages were also present in the adjacent substantia propria. These pigment changes were entirely compatible with chlorpromazine-induced secondary melanosis. CONCLUSIONS: This paper highlights the first documented occurrence of in situ squamous carcinoma with bilateral chlorpromazine-induced conjunctival secondary melanosis. This clinically masqueraded as in situ melanoma/primary acquired melanosis and invasive melanoma. Bilateral melanosis is rare, has many causes and, in this case, was drug induced. This highlights the importance of thorough history taking and illustrates that not all pigmented and amelanotic lesions are in situ melanomas, primary acquired melanosis or invasive melanomas. Lastly, atopy was a risk factor for the development of this in situ squamous carcinoma.

Hypertensive iridocyclitis associated with delayed onset biopsy proven Cytomegalovirus retinitis.

We describe a case of primary hypertensive iridocyclitis with biopsy-proven Cytomegaloviral retinitis. It is an observational case report of a 69-year-old diabetic gentleman on azathioprine for Crohn's disease who presented with recurrent episodes of hypertensive iridocyclitis. On the 4 th attendance in 5 months, a granular white lesion was noted in the temporal periphery of the mid-peripheral fundus and a chorioretinal and vitreous biopsy performed. Vitreous PCR was positive for Cytomegalovirus (CMV). Hematoxylin and eosin staining revealed cytomegalic-like inclusions within necrotic neural retina. Transmission electron microscopy revealed herpes family virus particles and immunohistochemistry demonstrated CMV protein. This case provides further evidence implicating CMV infection in the etiology of hypertensive iridocyclitis. With hindsight, the cumulative effect of diabetes and azathioprine on the immune surveillance system proved sufficient to render the patient susceptible to CMV retinitis.