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.

Impact of COVID-19 pandemic on eye cancer care in United Kingdom.

The COVID-19 pandemic has had an unprecedented impact on the National Health Service in United Kingdom. The UK Ocular Oncology Services evaluated the impact on the adult eye cancer care in the UK. All four adult Ocular Oncology centres participated in a multicentre retrospective review comparing uveal melanoma referral patterns and treatments in a 4-month period during the national lockdown and first wave of the COVID-19 pandemic in 2020 with corresponding periods in previous 2 years. During the national lockdown, referral numbers and confirmed uveal melanoma cases reduced considerably, equalling to ~120 fewer diagnosed uveal melanoma cases compared to previous 2 years. Contrary to the recent trend, increased caseloads of enucleation and stereotactic radiosurgery (p > 0.05), in comparison to fewer proton beam therapy (p < 0.05), were performed. In the 4-month period following lockdown, there was a surge in clinical activities with more advanced diseases (p < 0.05) presenting to the services. As the COVID-19 pandemic continues to mount pressure and reveal its hidden impact on the eye cancer care, it is imperative for the Ocular Oncology Services to plan recovery strategies and innovative ways of working.

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.

Primary photodynamic therapy for small amelanotic choroidal melanomas: consecutive case series of 69 patients with at least 24-month follow-up.

AIMS: To investigate the success and recurrence rates and visual outcomes in a large case series of amelanotic posterior choroidal melanomas treated by means of primary photodynamic therapy (PDT) with verteporfin. METHODS: Retrospective case series from a single specialist ocular oncology centre. All patients had a clinical diagnosis of choroidal melanoma and were selected for PDT based on tumour characteristics. Included patients had at least 24 months of follow-up from initiation of treatment and all but one had not received treatment prior to PDT. RESULTS: 69 patients were included. Mean tumour thickness was 1.9 mm (range 0.5-4.4), while the mean basal diameter was 6.9 mm (range 2.4-11.0). Included lesions were stage cT1a (n=66) or cT2a (n=3). The mean duration of follow-up from treatment initiation was 57 months (range 24-116 months). Seven lesions (10%) failed to respond to PDT. 10 patients (16%) experienced recurrence during follow-up. Overall success rate in this series was 75% (n=52). 83% of successfully treated patients (n=43) maintained or gained vision by final follow-up. Visual outcomes were significantly better in those patients who received PDT therapy alone in comparison to those who needed other treatments for their melanoma (Fisher's exact test, p=0.004). Unfortunately, one patient (1.4%) in the series developed systemic metastases and died. CONCLUSION: Selected amelanotic posterior uveal melanomas may be successfully treated with PDT with retention of good vision in the majority of cases, maintained with a mean of 57 months (minimum of 24 months) of follow-up.

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.

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.

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.

Conjunctival Blue Naevus in an Anophthalmic Socket.

PURPOSE OF THE STUDY: To describe an unusual brown pigmented lesion of the conjunctiva in an anophthalmic socket in a 16-year-old male. PROCEDURES: A 16-year-old male patient presented with socket irritation whilst wearing an artificial eye due to meibomian gland dysfunction. An area of flat, subepithelial, dark brown pigmentation with irregular and indistinct borders on the bulbar conjunctiva of the anophthalmic socket was seen. The patient believed it had been present for at least 2 years. His past ocular history was of childhood trauma to the right eye at the age of 9 years, and he underwent primary enucleation and hydroxyapatite orbital implant insertion at that time. Unfortunately, the implant extruded and was removed a year later. RESULTS: An incisional biopsy of the pigmented lesion showed a conjunctival, subepithelial bland spindle cell melanocytic lesion, with uniform-sized and -shaped melanosomes. Immunohistochemistry showed the cells to express Melan A and HMB45 and they were negative for CD68 and pan-cytokeratins. The features were of a common blue naevus. CONCLUSION: This is the first documentation of a post-enucleation conjunctival naevus in an anophthalmic socket. We propose a pathogenesis and suggest surveillance as there is a risk of transformation to melanoma.

Photodynamic Therapy for Eye Cancer.

Photodynamic therapy is well-established as a treatment for a number of conditions in ophthalmology, principally in the field of medical retina, but less so in ocular oncology. Cancer of the eye is rare, the commonest lesions to affect the globe being choroidal melanoma (as a primary malignancy) and choroidal metastases (a secondary malignancy). The mainstay of treatment of such lesions remains radiotherapy in various forms, however, photodynamic therapy does have a useful role to play in the management of such patients. In this article, I hope to review the current indications, treatment regimes, and the risks and benefits of photodynamic therapy (PDT) as a treatment for eye cancer.

Conjunctival Angioimmunoblastic T-Cell Lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) represents an uncommon variant of T-cell lymphomas and most often presents insidiously with systemic symptoms. This report constitutes the first documented case of conjunctival AITL, masquerading as nodular episcleritis, and describes both the clinical and pathological findings. Furthermore, conjunctival T-cell lymphoma in general remains a rare occurrence, and a survey of previously reported cases reveals a wide variation in clinical presentation. A high index of suspicion, thorough examination and conjunctival biopsy are essential to reaching the diagnosis of conjunctival lymphoma.

Treatment of posterior uveal melanoma with multi-dose photodynamic therapy.

AIMS: To report on the use of multi-dose photodynamic therapy (PDT) in the treatment of posterior uveal melanoma. METHODS: Prospective case series. 18 patients with posterior uveal melanoma were treated with a minimum of three sessions of PDT. Mean tumour thickness was 1.92 mm (median 1.75, range 0.5-4.4 mm) while the mean basal diameter was 7.1 mm (median 6.3, range 5.2-11 mm). Patients were assessed for visual acuity, complications, tumour status and systemic metastases. RESULTS: In 16 cases, the tumour regressed with stable or improved vision in 15 patients (83%) over a mean follow-up period of 28 months (median 26.5, range 12-44 months). One patient developed an edge recurrence on two occasions ultimately requiring proton beam therapy while one patient showed no response to PDT before being successfully treated with proton beam therapy. Two patients developed scleritis requiring a short course of systemic steroids. No patient developed metastatic disease in the study period. CONCLUSIONS: Posterior uveal melanomas may be successfully treated with high dose PDT with retention of good vision in the majority of cases, at least in the short-term. Longer follow-up is required to see if these encouraging results are maintained.

Ocular surface squamous neoplasia: analysis of 78 cases from a UK ocular oncology centre.

BACKGROUND/AIMS: Ocular surface squamous neoplasia (OSSN) is a spectrum of disease, on which few large series have been published, none in particular, from the UK. The purpose of this study is to describe experience of this condition from a UK national ocular oncology centre, including statistical analysis to elucidate factors significant in recurrence. METHODS: Retrospective review of case notes, clinical photographs and histopathology reports. RESULTS: 78 cases were included, of which 10 (12.8%) recurred during the follow-up time (mean 37 months). The 1-year recurrence rate was 10.9%, and 5-year recurrence rate was 18.5% using Kaplan-Meier analysis, with a mean time to recurrence of 9.5 months. Significant factors in recurrence were tumour size and first treatment given. Grade of OSSN, including presence of invasive disease and positive biopsy margins were not found to be statistically significant in recurrence. CONCLUSIONS: OSSN in an uncommon disease in the UK population. However, when managed appropriately in a specialist centre, it is associated with good outcomes, even in recurrence situations.

Survival and complications following γ knife radiosurgery or enucleation for ocular melanoma: a 20-year experience.

BACKGROUND: We present our experience in treating ocular melanoma at the National Centre for Stereotactic Radiosurgery in Sheffield, UK over the last 20 years. METHOD: We analysed 170 patients treated with Gamma Knife radiosurgery, recorded the evolution of visual acuity and complication rates, and compared their survival with 620 patients treated with eye enucleation. Different peripheral doses (using the 50% therapeutic isodose) were employed: 50-70 Gy for 24 patients, 45 Gy for 71 patients, 35 Gy for 62 patients. FINDINGS: There was no significant difference in survival between the 35-Gy, 45-Gy and 50- to 70-Gy groups when compared between themselves (p = 0.168) and with the enucleation group (p = 0.454). The 5-year survival rates were: 64% for 35 Gy, 62.71% for 45 Gy, 63.6% for 50-70 Gy and 65.2% for enucleated patients. Clinical variables influencing survival for radiosurgery patients were tumour volume (p = 0.014) and location (median 66.4 vs 37.36 months for juxtapapillary vs peripheral tumours, respectively; p = 0.001), while age and gender did not prove significant. Regarding complications, using 35 Gy led to more than a 50% decrease, when compared with the 45-Gy dose, in the incidence of cataract, glaucoma and retinal detachment. Retinopathy, optic neuropathy and vitreous haemorrhage were not significantly influenced. Blindness decreased dramatically from 83.7% for 45 Gy to 31.4% for 35 Gy (p = 0.006), as well as post-radiosurgery enucleation: 23.9% for 45 Gy vs 6.45% for 35 Gy (p = 0.018). Visual acuity, recorded up to 5 years post-radiosurgery, was significantly better preserved for 35 Gy than for 45 Gy (p = 0.0003). CONCLUSIONS: Using 35 Gy led to a dramatic decrease in complications, vision loss and salvage enucleation, while not compromising patient survival.