Proton beam radiotherapy for choroidal and ciliary body melanoma in the UK-national audit of referral patterns of 1084 cases.

INTRODUCTION: Proton beam therapy has been utilised for the treatment of uveal melanoma in the UK for over 30 years, undertaken under a single centre. In the UK, all ocular tumours are treated at one of four centres. We aimed to understand the variation in referral patterns to the UK proton service, capturing all uveal melanoma patients treated with this modality. METHODS: Retrospective analysis of data regarding all patients treated at the Clatterbridge Proton service between January 2004 and December 2014. RESULTS: A total of 1084 patients with uveal melanoma were treated. The mean age was 57 years (range 9-90 years), basal diameter of 11.5 mm (range 2.0-23.4 mm) and tumour thickness of 3.9 mm (range 0.1-15.4 mm). The majority were TNM stage I (39%) or II (36%). The distance to the optic nerve varied from 0 to 24.5 mm with 148 (14%) of patients having ciliary body involvement. There were variations in the phenotypic characteristic of the tumours treated with protons from different centres, with London referring predominantly small tumours at the posterior pole, Glasgow referring large tumours often at the ciliary body and Liverpool sending a mix of these groups. DISCUSSION: In the UK, common indications for the use of proton treatment in uveal melanoma include small tumours in the posterior pole poorly accessible for plaque treatment (adjacent to the disc), tumours at the posterior pole affecting the fovea and large anterior tumours traditionally too large for brachytherapy. This is the first UK-wide audit enabling the capture of all patients treated at the single proton centre.

Photodynamic therapy as initial treatment for small choroidal melanomas.

PURPOSE: To evaluate Verteporfin photodynamic therapy (PDT) as primary treatment for small, posterior choroidal melanoma. DESIGN: Retrospective cohort review. SUBJECTS, PARTICIPANTS AND CONTROLS: Retrospective case note review of 20 patients with small juxtapapillary and juxtafoveal choroidal melanomas treated with PDT at the Liverpool Ocular Oncology Clinic. METHODS: Patient and tumour characteristics, PDT session details, visual acuity and B-scan ultrasonography measurements as well as colour fundus photographs at each examination were collated and analysed. MAIN OUTCOME MEASURES: Local tumour control and Best Corrected Visual Acuity (BCVA). RESULTS: The 20 patients (14 male, 6 female) had a mean age of 61.2 years (range, 40-85) and were treated between 2001 and 2012. Seven tumours were amelanotic, while 13 were pigmented. Of 20 melanomas, 11 (55%) showed complete regression on B-scan ultrasonography and colour photography; five (25%) showed partial regression; four (20%) remained unchanged and two (10%) showed further growth, for which alternative standard treatment was required. Baseline BCVA was 0.1 logMAR (mean; range 0.0-0.6) compared to a post-PDT BCVA of 0.4 logMAR (mean; range -0.2 to 1.7) over a follow-up of 60.0 months (mean; range 25-156 months). CONCLUSIONS: PDT can induce tumour regression in a significant proportion of small, posterior, choroidal melanomas but is less reliable than other forms of therapy. It may have a role in patients with special visual requirements if they accept the increased risk of treatment failure requiring radiotherapy.

Conjunctival squamous cell neoplasia: the Liverpool Ocular Oncology Centre experience.

PURPOSE: To report the outcome of patients with conjunctival squamous cell neoplasia (CSCN)--including conjunctival squamous cell carcinoma (SCC), conjunctival squamous intraepithelial neoplasia (C-SIN) and carcinoma in situ (CIS)-treated at the Liverpool Ocular Oncology Centre (LOOC). METHODS: Patients treated between January 1993 and September 2011 were identified and categorised as having 'primary' or 'salvage' treatment, according to whether they had undergone a surgical procedure before referral to our centre. Invasive SCC was treated by excision with adjunctive ruthenium plaque radiotherapy. C-SIN or CIS was treated with topical 5-fluorouracil (5-FU), and in a few cases, cryotherapy. RESULTS: Primary treatment was administered to 20 patients (16 males, four females). Mean age was 62 years (range, 33-85). Histological examination revealed C-SIN/CIS in ten patients and invasive SCC in nine. Median follow-up was 69 months (range, 34-168). Three patients required further topical chemotherapy for persistent/recurrent C-SIN. Salvage therapy was administered to 21 patients (15 males, six females). Mean age was 63 years (range, 26-82). Histology showed C-SIN/CIS in 11 patients and invasive SCC in ten. Median follow-up was 54.5 months (range, 36-120). At the close of this audit, there was no recurrence of invasive or metastatic disease in either the primary or salvage groups. CONCLUSIONS: Our established protocol for treatment of CSCN has proven successful in local tumour control, and avoids ocular complications. We advocate adjunctive radiotherapy in patients with invasive SCC and chemotherapy in C-SIN/CIS. For improved patient outcome, prompt referral to a specialist centre is encouraged.

Lack of BAP1 protein expression in uveal melanoma is associated with increased metastatic risk and has utility in routine prognostic testing.

BACKGROUND: The absence of BRCA1-associated protein 1 (BAP1) expression in uveal melanoma (UM) is associated with metastatic progression and reduced survival. In this study, we examine nuclear BAP1 (nBAP1) protein expression in primary UMs (PUMs) that show both 'typical' and 'atypical' clinical courses according to their chromosome 3 status, and secondary hepatic metastatic UM (MUM), correlating the results with histological, clinical and survival data. METHODS: Nuclear BAP1 expression was immunohistochemically assessed in tissue microarrays (TMAs) of: (a) 68 PUM patients, who had been treated surgically; and (b) 13 MUM patients, with 5 cases being paired with primary tumour tissue. All cases were fully annotated. The percentage of tumour cell nuclei staining positively for BAP1 was scored by independent observers. RESULTS: Nuclear BAP1 protein expression was absent in 35 out of 68 (51%) PUM patients, correlating strongly with poor prognostic clinicopathological and genetic parameters and reduced survival (Log rank, P<0.001). Lack of nBAP1 expression importantly identified a subset of 'atypical' PUM patients with disomy of chromosome 3 but with unexpected metastatic relapse. Nuclear BAP1 expression was absent in 10 out of 13 (77%) MUM and expression was concordant in all paired PUM and MUM patients. CONCLUSIONS: Absent nBAP1 protein expression is an independent survival predictor for UM patients, easily examined using immunohistochemistry.

Molecular pathology of uveal melanoma.

Like other cancers, uveal melanomas (UM) are characterised by an uncontrolled, clonal, cellular proliferation, occurring as a result of numerous genetic, and epigenetic aberrations. Signalling pathways known to be disrupted in UM include: (1) the retinoblastoma pathway, probably as a result of cyclin D1 overexpression; p53 signalling, possibly as a consequence of MDM2 overexpression; and the P13K/AKT and mitogen-activated protein kinase/extracellular signal-related kinase pathway pathways that are disturbed as a result of PTEN and GNAQ/11 mutations, respectively. Characteristic chromosomal abnormalities are common and include 6p gain, associated with a good prognosis, as well as 1p loss, 3 loss, and 8q gain, which correlate with high mortality. These are identified by techniques such as fluorescence in situ hybridisation, comparative genomic hybridisation, microsatellite analysis, multiplex ligation-dependent probe amplification, and single-nucleotide polymorphisms. UM can also be categorised by their gene expression profiles as class 1 or class 2, the latter correlating with poor survival, as do BRCA1-associated protein-1 (BAP1) inactivating mutations. Genetic testing of UM has enhanced prognostication, especially when results are integrated with histological and clinical data. The identification of abnormal signalling pathways, genes and proteins in UM opens the way for target-based therapies, improving prospects for conserving vision and prolonging life.

Conjunctival melanoma and melanocytic intra-epithelial neoplasia.

The rarity of conjunctival melanoma has impeded progress in the management of patients with this cancer; however, much progress has occurred in recent years. Primary acquired melanosis is now differentiated histologically into hypermelanosis and conjunctival melanocytic intra-epithelial neoplasia, for which an objective reproducible scoring system has been developed. Mapping and clinical staging of conjunctival disease has improved. Adjunctive radiotherapy and topical chemotherapy have made tumour control more successful, with reduced morbidity. Genetic analyses have identified BRAF and other mutations, which may predict responsiveness to new chemotherapeutic agents, for example Vemurafenib, should metastatic disease develop. Multicentre studies are under way to enhance survival prediction by integrating clinical stage of disease with histological grade of malignancy and genetic abnormalities. Such improved prognostication would not only be more relevant to individual patients, but would also provide greater opportunities for basic science research.

Differences in uveal melanomas between men and women from the British Isles.

PURPOSE: The purpose of this study is to compare uveal melanomas (UMs) in men and women. METHODS: The Liverpool Ocular Oncology Centre (LOOC) database was reviewed. Patients treated for UM at the LOOC between 1993 and 2010 were selected. Differences between sexes were identified using the χ (2)-test for categorical variables and the Mann-Whitney test for continuous variables. RESULTS: The 3380 patients comprised 1685 women and 1695 men. The tumours were considered clinically to have arisen in choroid in 89.5%, ciliary body in 5.3%, and iris in 5.2%. Tumours in women were less likely to originate in choroid (87.2 vs 91.7%; P<0.001) and showed more circumferential spread in ciliary body (P<0.001) and iris (P=0.003). Tumours in men were more likely to extend to within 3 mm of optic disc or fovea (46.3 vs 39.0%, P<0.001), showing more extensive optic-disc involvement (P<0.001). The median largest basal tumour diameter was 12.2 mm in men and 11.9 mm in women (P=0.001). The tumour thickness had a median of 4.4 mm and 3.8 mm in men and women, respectively (P=0.015). The 180 ciliary body tumours occurred in 112 women and 68 men. In these, the prevalence of extraocular spread was higher in women (19.6 vs 8.8%; P=0.052). The 175 iris melanomas were more common in women than men (103 vs 72, respectively). CONCLUSIONS: In men, UMs tend to be larger and more posterior than in women.

Accuracy of choroidal melanoma diagnosis by general ophthalmologists: a prospective study.

PURPOSE: To estimate the proportion of 'false positives' in patients referred with a diagnosis of suspected choroidal melanoma by general ophthalmologists to an ocular oncology centre. METHODS: A prospective study of patients referred by general ophthalmologists to an ocular oncology centre was undertaken over a 14-week period. The diagnosis was made clinically in patients receiving radiotherapy or phototherapy and was confirmed by histopathology in patients requiring fine needle aspiration biopsy (FNAB) or enucleation. RESULTS: A total of 132 new patients were seen in 10 consecutive ocular oncology clinics between 29 March 2004 and 5 July 2004. The mean age was 62 years (range 28-88 years) and 60 (55%) were female. Among the 83 suspected malignant posterior segment lesions, the suspected diagnosis included choroidal melanoma (73), choroidal metastasis (6), 'choroidal tumour' (3), and 'Solid retinal detachment' (1). Only 50 of the 73 suspected melanomas were confirmed (68.5%; 95% CI, 57-78%), the oncologist's diagnosis in the remaining 23 being choroidal naevus (10), choroidal metastasis (1), circumscribed choroidal haemangioma (2) and others (10). Only one of six patients with suspected metastases had this condition, the remainder having melanoma (1), lymphoma (1), circumscribed choroidal haemangioma (1), and others (2). The 'choroidal tumours' and 'solid detachments' were found to be chorio-retinal disciform scar (1), varix of vortex vein (1), eccentric CNV (1), and subretinal haemorrhage (1) CONCLUSION: Approximately 30% of patients referred to an ocular oncology service with the diagnosis of choroidal melanoma have an incorrect diagnosis.

Delayed treatment of choroidal melanoma due to pregnancy.

PURPOSE: The authors report a 27-year-old woman who presented with a large, choroidal melanoma when she was 28 weeks pregnant. Following detailed discussion with the patient, the decision was made to postpone any surgical treatment until after the birth of her child. METHODS: Case report. RESULTS: The patient had successful transscleral local resection of the tumor with 6/12 vision 6 months later. Cytogenetic studies showed a low risk of subsequent metastases. CONCLUSIONS: This case illustrates that deferring the treatment of a choroidal melanoma presenting during pregnancy can be a reasonable treatment plan, if the patient is highly motivated to keep the eye.

The patient's role in the decision-making process--a perspective from the Liverpool Ocular Oncology Centre.

PURPOSE: To examine the patient's role in the decision-making process in a tertiary adult ocular oncology service. METHODS: A prospective study was carried out of patients attending for follow-up at the Liverpool ocular oncology centre (LOOC), a tertiary adult ocular oncology service. Participants were patients who attended the clinic between September and October 2003. Through supervised completion of questionnaires, the main factors observed were: patients' preferred level of participation, patients' perceived level of participation, sources of information used by patients, and which sources they found most useful. RESULTS: In all, 39 patients were included in the study. The majority of patients (69.2%) would have preferred to make a shared decision with the doctor (10.3% preferring an active role, 20.5% preferring a passive role), while 48.7% perceived having had a shared role (25.6% felt they had had an active role, 25.6% a passive one). Outside the LOOC, general ophthalmologists were the most frequently cited source of information from health professionals, and were also scored as the most useful. Family and friends were the most common source of informal information, followed by use of the Internet. Tape recordings of the consultations were reported as the most popular resource provided by the LOOC. CONCLUSIONS: Patients attending the LOOC have a strong desire for involvement in the decision-making process. Patients receive little formal or informal information outside this tertiary centre. Further work is required to assess the effectiveness of physicians' communication skills and the influence of their recommendations on patient choice.

Double-blind comparison of survival analysis models using a bespoke web system.

The aim of this study was to carry out a comparison of different linear and non-linear models from different centres on a common dataset in a double-blind manner to eliminate bias. The dataset was shared over the Internet using a secure bespoke environment called geoconda. Models evaluated included: (1) Cox model, (2) Log Normal model, (3) Partial Logistic Spline, (4) Partial Logistic Artificial Neural Network and (5) Radial Basis Function Networks. Graphical analysis of the various models with the Kaplan-Meier values were carried out in 3 survival groups in the test set classified according to the TNM staging system. The discrimination value for each model was determined using the area under the ROC curve. Results showed that the Cox model tended towards optimism whereas the partial logistic Neural Networks showed slight pessimism.

Microarray comparative genomic hybridisation analysis of intraocular uveal melanomas identifies distinctive imbalances associated with loss of chromosome 3.

Defining regions of genomic imbalance can identify genes involved in tumour development. Conventional cytogenetics has identified several nonrandom copy number alterations (CNA) in uveal melanomas (UVM), which include monosomy 3, chromosome 6 abnormalities and gain of 8q. To gain further insight into the CNAs and define the regions involved more precisely we analysed 18 primary UVMs using 1 Mb BAC microarray comparative genomic hybridisation (CGH). Our analysis showed that the most common genomic imbalances were 8q gain (78%), 6p gain (67%) and monosomy 3 (56%). Two distinct CGH profiles could be delineated on the basis of the chromosome 3 status. The most common genetic changes in monosomy 3 tumours, in our study, were gain of 8q11.21-q24.3, 6p25.1-p21.2, 21q21.2-q21.3 and 21q22.13-q22.3 and loss of 1p36.33-p34.3, 1p31.1-p21.2, 6q16.2-q25.3 and 8p23.3-p11.23. In contrast, disomy 3 tumours showed recurrent gains of only 6p25.3-p22.3 and 8q23.2-q24.3. Our approach allowed definition of the smallest overlapping regions of imbalance, which may be important in the development of UVM.

Patient attitudes to receiving copies of outpatient clinic letters from the ocular oncologist to the referring ophthalmologist and GP.

AIM: To investigate patients' views and understanding on receiving a copy of the outpatient clinic letter from the ocular oncologist to the referring ophthalmologist and GP. METHODS: Face-to-face interviews were conducted with 52 patients attending outpatient ocular oncology follow-up clinics, in a semistructured format using a qualitative open-ended questionnaire. The clinics are held at Liverpool Ocular Oncology Centre, a tertiary specialist referral centre at St. Paul's Eye Unit in Royal Liverpool University Hospital. RESULTS: Patients' views on receiving a copy of the outpatient letter, their understanding of the letter, and improvements suggested. A total of 58% of patients had received a letter and 97% of them said they were glad they had it. Of this group 77% had shown it to family/friend. Consistent comments included: 'help with accepting the news;' 'good to be informed and to know what to expect;' 'confirmed what was said in the consultation.' Of the patients who had not received a copy of the letter, 64% replied that they would have liked a copy. A total of 80% of patients reported that they fully understood the letter. In all, 17% wanted medical terms to be explained, when asked to suggest improvements. CONCLUSIONS: Sending patients copies of the consultant outpatient letter seemed to be highly appreciated and a useful method of information giving regarding diagnosis and management.

The role and efficacy of non-linear models in decision making and prognostication.

In few types of cancer, genomic abnormalities have been linked to the phenotype and carcinogenesis with a degree of precision. For most cancers, however, this is not the case and the literature provides no clear indication of any logical process. The main difficulties are the great redundancy within the genome and proteome, the vast number of interconnections and the vast number of feedback loops. Such complicated systems can be modelled, but will require highly sophisticated analysis using computational mathematics techniques. Neural networks have been in common use in medical research for the past 20 years. They have been used for classification and for prediction of hazard or failure but are still not widely used for explanation. The binary output can be modified by, for example, adding a Bayesian function to the output stage so that survival probabilities can be given. We looked at the application of probabilistic neural networks in providing prognosis in two types of cancer; laryngeal carcinoma which has a relatively short hazard time and a medium survival rate and ocular melanoma with longer hazard time and higher survival rate. We compared their performance with the more traditional methods and studied their limitations and boundaries.

Role of MC1R variants in uveal melanoma.

Variants of the melanocortin-1 receptor (MC1R) gene have been linked to sun-sensitive skin types and hair colour, and may independently play a role in susceptibility to cutaneous melanoma. To assess the role of MC1R variants in uveal melanoma, we have analysed a cohort of 350 patients for the changes within the major region of the gene displaying sequence variation. Eight variants were detected - V60L, D84E, V92M, R151C, I155T, R160W, R163Q and D294H - 63% of these patients being hetero- or homozygous for at least one variant. Standard melanoma risk factor data were available on 119 of the patients. MC1R variants were significantly associated with hair colour (P=0.03) but not skin or eye colour. The frequency of the variants detected in the 350 patients was comparable with those in the general population, and comparison of the cumulative tumour distribution by age at diagnosis in carriers and noncarriers provided no evidence that MC1R variants confer an increased risk of uveal melanoma. We interpret the data as indicating that MC1R variants do not appear to be major determinants of susceptibility to uveal melanoma.

Bilateral uveal melanoma: a series of four cases.

AIM: To describe the occurrence of bilateral primary choroidal melanoma in four patients. METHODS: All patients attending the Liverpool Ocular Oncology Centre with uveal melanoma between January 1993 and February 2002 were identified, and those with bilateral primary choroidal melanoma were reviewed. Their presentation and management are described. RESULTS: Four patients, all female, were identified. Patient 1 presented with a right juxtapapillary melanoma at the age of 64, which was treated with krypton laser and endoresection, and then when aged 73 required proton beam radiotherapy for a melanoma in her left eye. Patient 2 presented at the age of 82 with bilateral choroidal melanomas and underwent simultaneous bilateral plaque radiotherapy. Patient 3 presented with bilateral choroidal melanomas at the age of 75 and was treated initially with bilateral proton beam radiotherapy. Patient 4 was treated at the age of 54 with right plaque radiotherapy for a choroidal melanoma, and 3 years later needed plaque radiotherapy for a melanoma in her other eye. CONCLUSION: Bilateral choroidal melanoma is possible and should be a consideration in the continuing management of patients with choroidal melanoma.