Patient understanding of genetic information influences reproductive decision making in retinoblastoma.

BACKGROUND: Retinoblastoma is the most common malignant tumour of the eye in childhood, with nearly all bilateral tumours and around 17% to 18% of unilateral tumours due to an oncogenic mutation in the RB1 gene in the germline. Genetic testing enables accurate risk assessment and optimal clinical management for the affected individual, siblings, and future offspring. MATERIAL AND METHODS: We carried out the first UK-wide audit of understanding of genetic testing in individuals with retinoblastoma. A total of 292 individuals aged 16 to 45 years were included. RESULTS: Patients with bilateral disease were significantly more likely to understand the implications of retinoblastoma for siblings and children. There was a significant association between not knowing the results of genetic testing or not understanding the implications and not having children, particularly in women. Surprisingly, this was also true for individuals treated for unilateral disease with a low risk of retinoblastoma for their offspring. CONCLUSION: We are concerned that individuals may be making life choices based on insufficient information regarding risks of retinoblastoma and reproductive options. We suggest that improvement in transition care is needed to enable individuals to make informed reproductive decisions and to ensure optimal care for children born at risk of retinoblastoma.

Choroidal metastasis from follicular cell thyroid carcinoma masquerading as circumscribed choroidal haemangioma.

Choroidal metastases from follicular thyroid carcinoma are uncommon and usually present as an amelanotic lesion against a background of known systemic disease. We present the case of a 56-year-old woman with a thyroid metastatic focus with unusual clinical presentation, systemic involvement, and early response to systemic treatment. A review of the literature accompanies this case presentation.

Circumscribed choroidal haemangioma mimicking chronic central serous chorioretinopathy.

We describe a rare case of bilateral circumscribed choroidal haemangioma in an otherwise healthy male, which mimicked chronic central serous chorioretinopathy (CSCR). A 52-year-old Asian man presented with a one-year history of visual decline in his left eye. The vision in the right eye had been reduced for 15 years. Visual acuity was 6/60 in the right eye and 6/18 in the left eye. Fundus examination of the right eye revealed an area of discoloration with overlying retinal pigment epithelial changes in the macula and evidence of prior surrounding argon laser photocoagulation. The left macula showed a raised choroidal lesion with overlying retinal pigment epithelial changes and associated subretinal fluid. This appearance illustrates how chronic retinal pigment epithelial alterations associated with longstanding subretinal fluid exudation from circumscribed choroidal haemangiomas may mimick the appearance of chronic central serous chorioretinopathy. B-scan ultrasonography, fluorescein angiography, indocyanine green angiography and optical coherence tomography helped to establish the diagnosis. The active lesion in the left eye was treated with verteporfin photodynamic therapy with improvement in vision.

Plaque radiotherapy treatment with ruthenium-106 for iris malignant melanoma.

PURPOSE: To report the results of ruthenium-106 plaque radiotherapy for iris malignant melanoma. METHODS: A retrospective study of 15 patients with pure iris melanoma treated with ruthenium-106 plaque radiotherapy from June 1998 to June 2006. The main outcome measures were tumour control and ocular complications. RESULTS: Of the 15 patients, 8 had biopsy-proven melanoma (6 incisional and 2 excisional biopsies). In the remaining seven patients enlargement of the lesion was documented. The median follow-up was 96 months (ranging from 14 months to 12 years). Common radiation-related complications included cataract in 9 (60%) patients, dry eyes in 3 (20%) patients and elevated intraocular pressure in 4 (27%) patients. Vision was preserved in 80% of patients. Local tumour control was obtained in all patients. CONCLUSIONS: Ruthenium-106 plaque radiotherapy is an effective treatment for primary malignant iris melanoma, resulting in excellent local control with preservation of vision. Main complications included cataract, dry eyes, and glaucoma.

Predicting local control of choroidal melanomas following ¹°6Ru plaque brachytherapy.

BACKGROUND: We evaluated the control rate of choroidal melanomas treated with ¹°6Ru plaque brachytherapy to identify the risk factors associated with local recurrence and lack of response. METHODS: A retrospective review of ¹°6Ru plaque brachytherapy for patients with choroidal melanoma treated at St Bartholomew's Hospital, London. Survival analysis was used to assess associations between evaluated age, sex, location, foveal proximity, tumour base and height, presence of lipofuscin and subretinal fluid, apex dose, radiation rate and type of plaque with time to local recurrence. Logistic regression analysis was used to assess to evaluate the association between the same set of variables and lack of tumour response. RESULTS: From January 2002 to December 2006 189 patients were treated. The follow-up ranged from 12 to 78 (median 33) months. None of the patients received adjuvant diode laser thermotherapy. The control rate was 85.7% (14 recurred while 13 did not respond). Of the patients who had local recurrence, univariate survival analysis demonstrated an association with younger patients, foveal proximity, preoperative subfoveal fluid and tumour base >11 mm. Age and foveal proximity remained significant in a Cox multiple variable model (p=0.03). Of the patients who did not respond, logistic regression analysis showed that lack of response was associated with a tumour height >5 mm, confirmed through multiple variable analysis (p=0.027). CONCLUSIONS: Tumours that are close to the fovea in young patients appear more likely to show local recurrence. Tumour height >5 mm was the only prognostic factor that determined lack of response. These results may be used to select which tumours require adjuvant therapy.

Salvage external beam radiotherapy after failed primary chemotherapy for bilateral retinoblastoma: rate of eye and vision preservation.

BACKGROUND: Radiation is implicated in the induction of second malignancies in children with bilateral retinoblastoma. There is a need to determine whether this risk can be justified by good visual outcome when external beam radiotherapy (EBRT) is used as a salvage treatment. AIM: To study the effectiveness of EBRT as a salvage treatment after failed primary chemotherapy and focal treatment in bilateral retinoblastoma. METHODS: This is a retrospective observational case series. The outcome measures after EBRT are: rate of eye preservation, rate of tumour control, visual potential, visual acuity and radiation-induced side-effects. RESULTS: Thirty-six eyes (22 patients) were included. The median follow-up after EBRT was 40 months (19-165 months). Thirty-two eyes received lens-sparing radiotherapy, and four received whole-eye radiation. The rate of eye preservation was 83.3% (30/36 eyes). Twenty-four eyes (66.7%) were controlled by EBRT and required no further treatment. Of the 30 preserved eyes, 20 eyes (66.7%) had extramacular tumours without retinal detachment and therefore potential for central vision. The final visual acuity was recorded for 19 eyes. Ten eyes (52.6%) read 6/9-6/5, three eyes (15.8%) read 6/18-6/36, and six eyes (31.6%) read 6/60 or worse. Significant radiation- induced side effects were limited to cataracts and dry eyes with whole-eye radiation. There were no second cancers or deaths. CONCLUSION: Salvage EBRT is highly effective in preserving eyes with useful vision in bilateral retinoblastoma after failed chemotherapy and focal treatments. These results will help the parents and ophthalmologists of such patients to reach an informed decision when weighing up the benefits of EBRT against its potential oncogenic effect.

Retinoblastoma in Great Britain 1963-2002.

AIM: This paper describes the epidemiology and family history status of 1601 children with retinoblastoma in Great Britain diagnosed 1963-2002 and summarises the practical consequences for diagnosis and counselling of developments in molecular genetics. METHODS: Incidence rates were analysed according to year of diagnosis and tumour laterality. Cases were classified as heritable or non-heritable on the basis of laterality and family history of the disease. RESULTS: There were 998 unilateral cases, 581 bilateral and 22 of unknown laterality. Bilateral cases tended to be diagnosed at a younger age than unilateral. All bilateral cases are regarded as heritable, and 35% had a family history of the disease. 7% of the unilateral cases had a family history and are therefore heritable. Thus, at least (41%) of our cases are heritable. This is an underestimate, since these data on family history are incomplete. For unilateral cases aged below 1 year, the reported incidence rate increased significantly (p<0.0001) by about 2.5% per year; for the age group 1-4 years, the average increase was about 0.5% per year (not significant).

Retinoblastoma: treatment and survival in Great Britain 1963 to 2002.

AIM: This paper describes the treatment and survival of 1576 children with retinoblastoma in Great Britain diagnosed 1963-2002. METHODS: Survival rates were analysed according to period of diagnosis and tumour laterality. RESULTS: Survival was calculated by calendar period of diagnosis, 1963-1982 and 1983-2002. For both unilateral and bilateral retinoblastoma, survival improved between the two periods. The survival curves for the two periods were significantly different: for unilateral retinoblastoma p<0.00001, for bilateral p<0.01. For unilateral cases, the estimated 5-year survival rates rose from 85% for those diagnosed in 1963-1967 to 97% for those diagnosed in 1998-2002. The equivalent rates for bilateral cases were 88% and 100%. CONCLUSION: Survival rates were already high at the start of the study period. They increased with changes in treatment regimens.

The success of primary chemotherapy for group D heritable retinoblastoma.

AIMS: To report the ocular survival and event-free survival following primary multiagent chemotherapy for group D, heritable bilateral retinoblastoma (RB). METHODS: The RB database was used to identify children with heritable, bilateral RB treated with primary chemotherapy (six cycles of vincristine, etoposide and carboplatin). Only Group D eyes with more than 12 months' follow-up were analysed. The timing, number and type of salvage treatments were recorded. Kaplan-Meier estimates for the ocular survival and event-free survival (percentage of eyes that avoided external beam radiotherapy and/or enucleation) were performed as a function of time. RESULTS: Of 18 group D eyes, two (11%) were treated successfully with chemotherapy alone, nine (50%) underwent successful salvage treatment, and seven (39%) were enucleated. The median time from completing chemotherapy to enucleation was 9 months (range 4 to 25 months). Ocular survival was 67% at 2 years. External beam radiotherapy proved successful salvage treatment in five of nine eyes, so the event-free survival was 34% at 2 years. CONCLUSION: Multiagent chemotherapy alone is rarely sufficient for the preservation of group D eyes. External beam radiotherapy and plaque radiotherapy remain important salvage treatments for advanced, heritable retinoblastoma.

Patterns of regional head and neck lymph node metastasis in primary conjunctival malignant melanoma.

OBJECTIVE: To correlate patterns of regional lymph node metastasis with the site of origin in primary conjunctival malignant melanoma. DESIGN: Retrospective analysis (1990-2003) of clinical data. SETTING: Two London tertiary referral centres. PARTICIPANTS: 12 patients presenting with regional metastases after failed local treatment for conjunctival malignant melanoma. RESULTS: 6 cases predominantly involving the temporal conjunctiva metastasised to the pre-auricular lymph nodes. Two cases predominantly involving the nasal conjunctiva metastasised to the submandibular nodes. Of the two cases with purely multifocal disease, one metastasised to the pre-auricular nodes and another to both submandibular and parotid nodes. One primary conjunctival malignant melanoma had its origin in temporal conjunctiva but metastasised to submandibular nodes, and another case originating from nasal conjunctiva metastasised to pre-auricular nodes. CONCLUSIONS: Temporal conjunctival melanotic lesions tend to metastasise clinically to pre-auricular lymph nodes and nasal conjunctival melanotic lesions metastasise to the submandibular lymph nodes. Patterns appear consistent with laboratory-based anatomically mapped lymphatic drainage basins of the conjunctiva.

Vitreous relapse following primary chemotherapy for retinoblastoma: is adjuvant diode laser a risk factor?

AIMS: To evaluate rates of vitreous relapse among retinoblastoma patients treated with primary chemotherapy and assess diode laser as a potential risk factor for relapse. METHODS: Retrospective review of all patients treated with primary chemotherapy at a large ocular oncology centre. Eyes that developed vitreous relapse were coded with regard to Reese-Ellsworth Group, laterality, time to relapse, type of relapse (vitreous base or non-vitreous base relapse), treatments used (including adjuvant diode laser), and ocular preservation. Individual tumour foci treated with laser hyperthermia were also coded for laser parameters including power settings, number of treatments, and concomitant administration of systemic chemotherapy (chemothermotherapy). RESULTS: 15 of 106 eyes (14.15%) developed vitreous relapse over a 6 year period. Mean time to relapse was 7.2 months after chemotherapy was completed. Five cases (33%) were of the vitreous base variety. Ocular salvage was attempted in 11 cases using a variety of methods; one patient was lost to follow up. Six of the remaining 10 eyes (60%) were salvaged. Eight of 38 eyes (21%) treated with systemic chemotherapy and laser hyperthermia developed vitreous relapse compared with seven of 68 eyes (10%) treated with primary chemotherapy alone (p<0.005). Laser settings, number of hyperthermia treatments, and the concomitant use of systemic chemotherapy (chemothermotherapy) were not associated with higher rates of vitreous relapse. CONCLUSION: Nearly one in seven eyes with retinoblastoma treated with primary chemotherapy may develop vitreous relapse. The administration of diode laser hyperthermia appears to increase this risk. Despite additional therapy a number of these eyes succumb to enucleation.

Proton beam therapy and iris neovascularisation in uveal melanoma.

PURPOSE: Local treatment of uveal melanoma by radiotherapy involves the use of brachytherapy with radioactive plaques attached to the sclera, or proton irradiation. Both treatments induce growth arrest within the tumour and its slow involution over several years. Although ocular retention rates are excellent, regrowth of tumours due to resistance and neovascular glaucoma leads to enucleation of up to 10% of affected eyes. Proton irradiation involves part of the iris in most cases and we noticed that neovascularisation only occurred in the part of the iris that was not irradiated. We therefore conducted this study to determine the relationship between the development of iris neovascularisation and iris irradiation. METHODS: A total of 21 enucleation specimens from patients who had previously had proton irradiation were collected from the files of the Department of Pathology, Moorfields Eye Hospital during the 5-year period from 1994 to 1999. Sections of these eyes were assessed for VEGF-A, bFGF, and von Willebrand Factor (vWF) by immunohistochemistry. Ophthalmic notes and radiotherapy records were reviewed to assess the extent of iris irradiation. RESULTS: In all, 11 cases showed clinical evidence of iris neovascularisation and were selected for further study. Three of these eyes also showed clinical evidence of regrowth of the tumour. Histological evidence of iris neovascularization was noted in all 11 of the eyes examined, and was only present in the nonirradiated side of the iris in 8/11 eyes. NVI was present on both sides of the iris in three cases, but was less severe in the irradiated part. Expression of VEGF-A was at most weak within the tumour, but was present in the detached retina and in the epithelium of both ciliary body and iris. Some bFGF staining was noted around vessels in the iris stroma. CONCLUSIONS: Our results suggest that irradiation leads to iris atrophy, and that atrophic, irradiated iris is resistant to the development of neovascularisation.

Recruiting donors for autopsy based cancer research.

The use of human tissue for scientific research is a highly sensitive issue. A lack of confidence in patient recruitment is one reason for the failure of many studies to be funded and it is important therefore that recruitment procedures are as effective and sympathetic as possible. The authors recruited patients with uveal melanoma into a postmortem study investigating tumour latency in this cancer. Two approaches were used--firstly a direct approach when patients attended clinic and secondly an initial approach by mail followed by telephone contact. In the first year of study the authors had a take up rate of 88.5%, significantly higher than the average rate of 40% quoted by the National Institute for Clinical Excellence (NICE). Key features are a sympathetic personal approach by experienced oncology nurses, the provision of clear information, and the inclusion of the next of kin in the recruitment procedure.

Globe conserving treatment of the only eye in bilateral retinoblastoma.

AIMS: To quantify the rates of eye preservation and patient survival, local tumour relapse and recurrence, and development of new tumours in the remaining eye of children with bilateral retinoblastoma with one eye already enucleated. Also, in the same children, to describe the types of primary and secondary treatment procedures, and to define the anatomical outcome. METHODS: This is a retrospective observational case series report. The study participants consisted of 107 patients with bilateral retinoblastoma with one eye enucleated within 1 month of baseline examination and had their remaining eye treated conservatively. The main outcome measure were: primary treatment failures, new tumours, enucleation of the only eye, death, remission, and anatomical outcomes (retinal detachment, vitreous haemorrhage, and cataract). RESULTS: The median age at diagnosis was 8.4 (range 0.2-44, SD 10.1) months with a median ophthalmic follow up of 44.3 (8.1-114, SD 10.1) months. In 22 of the 107 patients (21%) the treated eye was in Reese Ellsworth groups I or II and in the remaining 85 (79%) in groups III-V at diagnosis. The primary treatment was cryotherapy in 14% (15/107) of eyes, radioactive plaque brachytherapy in 3.7% (4/107), and chemotherapy in 10% (11/107). It was lens sparing radiotherapy in 37% (40/107), whole eye radiotherapy in 29% (31/107), combined radiotherapy and chemotherapy in 2.8% (3/107), chemothermotherapy in 0.9% (1/107), and combined focal therapy in 1.8% (2/107). The primary treatment failed to achieve local tumour control during the follow up period in 37% (40/107) of eyes. In 17 eyes failure was due to inadequate control of the presenting tumour, in 16 to development of a new tumour, and in eight eyes to a combination of both. 35 (88%) of the 40 failures were managed by secondary conservative treatment and the remaining five were treated by enucleation of the only eye. There were eight (7.4%) deaths and the 3 year survival rate was 93% (100/108). Anatomical results included vitreous haemorrhage in four cases, tractional retinal detachment also in four cases, and 24 children required cataract surgery. CONCLUSIONS: Aggressive conservative treatment achieved a good rate of globe salvage without impairing survival.

Absence of BRAF gene mutations in uveal melanomas in contrast to cutaneous melanomas.

The recent discovery of activating mutations in the BRAF gene in many cutaneous melanomas led us to screen the genomic sequence of BRAF exons 11 and 15 in a series of 48 intraocular (uveal) melanomas, together with control samples from three cutaneous melanomas and the SK-Mel-28 cell line, which has a BRAF mutation. The same mutation was detected in two-thirds of our cutaneous melanoma samples, but was not present in any uveal melanomas. This finding further underlines the distinction between uveal and cutaneous melanomas, and suggests that BRAF inhibitors are unlikely to benefit patients with uveal melanoma.

Primary orbital melanoma masquerading as vascular anomalies.

PURPOSE: To review two cases of primary orbital melanoma presenting like orbital vascular anomalies. METHODS: Retrospective review of clinical presentation, treatment, radiology and pathology for two patients under the care of the Orbital Clinic at Moorfields Eye Hospital. RESULTS: Both lesions presented with the appearance and behaviour of vascular anomalies. In one case, a spindle cell melanoma appeared to be a low flow vascular anomaly with a loculated secondary haemorrhage and, in the other case, a melanoma of soft parts was considered to be an arteriovenous malformation and responded partially to embolisation. CONCLUSION: Primary malignant melanoma may present as a secondary vascular lesion of the orbit and this very rare tumour should be considered in the differential diagnosis of any vascular anomaly.

Uveal melanomas express vascular endothelial growth factor and basic fibroblast growth factor and support endothelial cell growth.

BACKGROUND: Tumour microvascularity is a significant determinant of prognosis for a large number of different tumours, including uveal melanoma. The development of blood vessels within these and other tumours is partly controlled by soluble pro-angiogenic cytokines, of which basic fibroblast growth factor (bFGF) and vascular endothelial growth factor-A (VEGF) are the best described. METHODS: Because VEGF has been inconsistently found within uveal melanomas and bFGF is described as an autocrine growth factor in cutaneous melanoma, the authors looked at the expression of these cytokines in uveal melanomas using immunohistochemistry and reverse transcriptase polymerase chain reaction (RT-PCR). The cross talk between uveal melanoma cells and endothelial cells was then assessed in an in vitro co-culture model. RESULTS: While most tumour cells expressed bFGF at the protein level by immunohistochemistry (89%), relatively few (22%) expressed VEGF, and this was of limited extent. All 20 tumours tested by RT-PCR contained mRNA for both bFGF and VEGF. Co-culture experiments using an ATP based bioassay showed that uveal melanomas could support the growth of a rat brain endothelial cell line (GPNT) and human umbilical vein endothelial cells (HUVEC), and that this could be modulated by cytokines and anti-cytokine antibodies. CONCLUSION: These results suggest that angiogenesis within uveal melanoma may be the result of a complex interplay between endothelial and tumour cells, and that bFGF and VEGF could play a part.

Vascular endothelial growth factor is elevated in ocular fluids of eyes harbouring uveal melanoma: identification of a potential therapeutic window.

BACKGROUND: Improved local treatment of uveal melanoma makes it possible for many patients to retain the affected eye, but a proportion will develop secondary complications such as neovascularisation of the iris (NVI) and require enucleation. Although vascular endothelial growth factor A (VEGF-A) is known to correlate with NVI and can cause NVI in experimental models, this pro-angiogenic cytokine is consistently reported to be absent in uveal melanoma. Novel anti-VEGF therapies are now in clinical trial, and the authors therefore wished to determine whether VEGF-A was indeed elevated in melanoma bearing eyes. METHODS: VEGF-A concentrations were measured in aqueous and vitreous from 19 and 30 enucleated eyes respectively. RESULTS: Elevated VEGF-A concentrations (up to 21.6 ng/ml) were found in melanoma bearing eyes compared with samples from patients undergoing routine cataract extraction (all had values below 0.96 ng/ml). Immunohistochemistry showed VEGF-A protein in the iris and/or ciliary body of 54% and basic fibroblast growth factor (bFGF) in 82% of the eyes examined. VEGF was found to a limited extent and at very low levels in only 9% of these tumours. Aqueous or vitreous VEGF levels showed no apparent correlation with retinal detachment, tumour size, vascularity, or immunohistochemistry. Though limited in number, the highest VEGF levels correlated with previous radiation therapy, and with the presence neovascularisation of the iris or optic nerve head. bFGF was not significantly elevated in ocular fluids: it is known to be a pro-angiogenic agent and was detected in the majority of primary uveal melanomas. CONCLUSION: Based on this study, though the source of VEGF within eyes harbouring uveal melanoma is not clear, these data suggest that anti-VEGF therapy might prove useful in the management of some patients with NVI secondary to uveal melanoma.

Comparison of the ex vivo chemosensitivity of uveal and cutaneous melanoma.

Cutaneous and uveal melanoma both have a poor prognosis and chemotherapy is usually unsuccessful. We have previously reported the activity of a number of cytotoxic agents against metastatic cutaneous and primary choroidal uveal melanoma using an ex vivo adenosine triphosphate (ATP)-based chemosensitivity assay (ATP-TCA). In this study we compare the results obtained with the two types of melanoma. Cutaneous melanoma deposits in skin and lymph nodes (n = 58) and choroidal melanomas (n = 77) were tested using the ATP-TCA. Analysis of the data based on an arbitrary threshold for sensitivity shows that both types of melanoma exhibit heterogeneity of sensitivity to all the agents and combinations tested. With all the single agents except gemcitabine, cutaneous melanomas showed greater sensitivity in the assay, though this did not achieve statistical significance. This was also true with the drug combinations, with the exception of treosulfan + gemcitabine, which had similar activity in each type of melanoma. Of all the single agents tested, doxorubicin (47% of specimens classed as sensitive), vinorelbine (43%), treosulfan (41%) and paclitaxel (33%) showed the greatest activity with cutaneous melanoma. In the uveal melanoma samples, mitoxantrone (33%), gemcitabine (22%) and treosulfan (21%) showed the greatest activity. In contrast to the cutaneous melanomas, 13% of the uveal melanomas were sensitive to paclitaxel, 4% were sensitive to doxorubicin and 11% were found to be sensitive to vinorelbine. Both tumour types showed greater sensitivity to combinations of cytotoxic agents. The combination of treosulfan + gemcitabine was universally effective, with 72% of cutaneous melanomas and 80% of uveal melanomas exhibiting activity at the level selected to indicate sensitivity in the assay, though this will not necessarily indicate a similar level of clinical sensitivity.