Analysis of Long-term Outcomes of Radiotherapy and Verteporfin Photodynamic Therapy for Circumscribed Choroidal Hemangioma.

PURPOSE: To determine the long-term therapeutic outcome for different treatments of circumscribed choroidal hemangioma (CCH). DESIGN: Retrospective observational study. SUBJECTS: Patients with newly diagnosed CCH. METHODS: Observation, verteporfin (Visudyne) photodynamic therapy (PDT), lens-sparing external beam radiotherapy (LS-EBRT), or plaque brachytherapy. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA) at baseline and throughout follow-up, tumor dimensions, and OCT central thickness (where available) at baseline and throughout follow-up were recorded. RESULTS: There were 60 treatment-naïve consecutive cases with CCH between January 2000 and June 2014; 42 (70%) received treatment. These were LS-EBRT (23/60 [38%]; mean follow-up, 45.5 months), PDT (16/60 [27%]; mean follow-up, 38 months), and plaque radiotherapy (3/60 [5%]; mean follow-up, 92 months). Macular location, mottled or orange pigment, and absence of drusen were significantly more frequent in the treatment group. In the LS-EBRT group, median thickness reduction on ultrasound B scan was 1.6 mm (mean ± standard deviation, 1.65±1.6; range, -6.5 to +0.7). The mean ± standard deviation BCVA gain was 0.22±0.34, with >3 Snellen lines in 48% of cases. Kaplan-Meier estimates were 80% for any gain and 40% for >3 Snellen lines gain at 5 years. In the PDT group, the median decrease in thickness was 0.95 mm (mean ± standard deviation, 1.0±0.8; range, -2.5 to +0.2). The mean ± standard deviation BCVA gain was at 0.3±0.51, with >3 Snellen lines in 30% of cases. Kaplan-Meier estimates were 93% for any gain and 68% for >3 Snellen lines at 5 years. Double versus single duration PDT had more favorable outcomes with a greater reduction in tumor thickness (P = 0.04), central retinal thickness (P = 0.02), and improvement in visual acuity (median, 0.33 vs -0.05). There was no difference in decrease in tumor thickness or BCVA gain between the LS-EBRT and PDT groups. With plaque brachytherapy, the mean decrease in thickness was 2.5 mm, but BCVA loss of >2 Snellen lines was noted in all 3 cases at the end of follow-up. Radiation complications developed in 10 of 23 cases (43.5%) from the LS-EBRT group and 2 of 3 cases (67%) from the plaque brachytherapy group. CONCLUSIONS: LS-EBRT is equivalent to PDT in CCH management for post-treatment BCVA and tumor thickness reduction. The risk of LS-EBRT and plaque brachytherapy was late radiation-related complications. Double duration PDT was more favorable than single duration.

MESECTODERMAL LEIOMYOMA OF THE CILIARY BODY PRESENTING AS ANTERIOR STAPHYOMA.

PURPOSE: To report two cases of mesectodermal leiomyoma of the ciliary body presenting as anterior staphyloma. METHODS: Two case reports with cytopathologic correlation. RESULTS: First patient (15-year-old boy) presented with a nodular lesion in the sclera. Second patient (31-year-old woman) was found to have a brown ciliary body mass. Growth of the lesion and extrascleral extension was noticed after several years of follow-up. Ultrasonography, light microscopy, and immunohistochemistry of both cases are described confirming mesectodermal leiomyoma of the ciliary body. CONCLUSION: Mesectodermal leiomyoma, despite its rarity, should be considered in the differential diagnosis of uveal tract tumors. Clinically, the diagnosis is difficult and histopathological and immunohistochemical assesment is necessary to avoid inappropriate diagnosis and erroneous treatment.

Anterior Segment Seeding in Eyes With Retinoblastoma Failing to Respond to Intraophthalmic Artery Chemotherapy.

IMPORTANCE: Anterior chamber seeding following intraophthalmic artery chemotherapy is rarely reported. OBJECTIVES: To describe clinicopathologic observations in eyes in which intraophthalmic artery chemotherapy for retinoblastoma failed and to report anterior chamber involvement. OBSERVATIONS: A retrospective case series of 12 enucleated eyes (11 patients) with retinoblastoma refractory to intraophthalmic artery chemotherapy between March 1, 2010, and October 31, 2013, at University College London Institute of Ophthalmology and the Retinoblastoma Service, Royal London Hospital. Data analysis was conducted from June 1, 2014, to March 1, 2015. The International Classification of Retinoblastoma groups were B in 1 eye (8%), C in 4 eyes (33%), and D in 7 eyes (58%). Systemic chemotherapy with vincristine sulfate, etoposide, and carboplatin had failed in 10 patients (91%) and 6 eyes (50%) received additional local treatments. In 6 eyes (50%) anterior chamber invasion was clinically detectable. On histopathologic examination, 4 eyes (33%) had no viable retinal tumor; the remainder had poorly differentiated tumor (6 eyes [50%]) or moderately differentiated tumor (2 eyes [17%]). Anterior segment involvement occurred in the ciliary body and/or ciliary muscle (7 eyes [58%]), iris (6 eyes [50%]), and cornea (4 eyes [33%]). CONCLUSIONS AND RELEVANCE: Intraophthalmic artery chemotherapy can fail in eyes with retinoblastoma. In contrast to previous reports on outcomes following intraophthalmic artery chemotherapy, our series shows involvement of the anterior segment of the eye, including the ciliary body, iris, and cornea. Careful case selection and follow-up are advised.

Spectrum of RB1 mutations identified in 403 retinoblastoma patients.

BACKGROUND: Retinoblastoma (RB) is a malignant, childhood tumour of the developing retina that occurs with an estimated frequency of 1 in 20 000. Identification of oncogenic mutations in the RB1 gene aids in the clinical management of families with a heritable predisposition to RB. Here we present the spectrum of genetic and epigenetic changes identified in 194 tumours and 209 blood samples, from 403 unrelated RB patients. METHODS: Mutation screening was carried out across all 27 RB1 exons and their associated splice sites. Small coding sequence changes were detected using fluorescent conformation analysis followed by sequencing. Large exonic deletions were detected by quantitative fluorescent PCR. Methylation specific PCR of the RB1 promoter was performed to detect epigenetic alterations. Polymorphism analysis was used to determine loss of heterozygosity in tumour samples. RESULTS: 95% of the expected mutations were identified in the tumour samples, with 16 samples exhibiting only one mutation, while two samples had no detectable RB1 mutation. 96% of bilateral/familial RB blood samples and 9.5% of unilateral sporadic blood samples, yielded mutations. 111 were novel mutations. CONCLUSIONS: The full range of screening techniques is required to achieve a high screening sensitivity in RB patients.

Prospective study of sentinel lymph node biopsy for conjunctival melanoma.

BACKGROUND: To report our experience with sentinel lymph node biopsy for staging patients with conjunctival melanoma. METHODS: A prospective review of patients with conjunctival melanoma who underwent sentinel lymph node biopsy at St Bartholomew's Hospital from May 2008 to May 2012. The selection criterion for sentinel node biopsy depended on the tumour thickness (≥2 mm) and location of the conjunctival melanoma. The main outcome measures were the incidence of sentinel lymph node positivity and the procedure-related complications. RESULTS: In 4 years, 26 out of 70 patients met the selection criteria for sentinel lymph node biopsy. 4 patients declined and 22 patients consented for the procedure. Technetium-99m failed to identify a sentinel lymph node in four of the 22 patients (18%). Of the remaining 18 patients, two were found to have subclinical micrometastasis in regional lymph nodes. Median follow-up was 20 months (range 6-36 months). No false-negative events were observed. Complications of the procedure included transient blue staining of the epibulbar surface in five patients and transient facial nerve palsy in one patient. CONCLUSIONS: Sentinel lymph node biopsy is a safe procedure with minimal complications. It should be considered for the staging of conjunctival melanomas, especially melanomas in non-limbal location or conjunctival melanomas ≥2 mm thick.

Autonomic cardio-respiratory reflex reactions and superselective ophthalmic arterial chemotherapy for retinoblastoma.

OBJECTIVE: To describe our experience with superselective ophthalmic artery chemotherapy (SOAC) in retinoblastoma and to report the serious adverse cardio-respiratory reactions we have observed. METHODS: SOAC was performed using a standardized protocol for general anesthesia, ophthalmic artery catheterization, and pulsed infusion of melphalan. Adverse reactions were defined as those in which the patient required active treatment to maintain cardio-respiratory stability. RESULTS: Between December 2008 and May 2012, 54 eyes in 52 patients were treated. 143 catheterization procedures were performed, with a technical success rate of 93% (n = 133). There were no deaths or major complications. Adverse cardio-respiratory reactions developed during 35 procedures (24%; 95% CI, 18-32%). All reactions occurred during second or subsequent catheterization procedures (39%; 95% CI, .29-49%) and were characterized by hypoxia, reduced lung compliance, systemic hypotension and bradycardia. Adverse events were successfully treated in all patients. One procedure was abandoned due to prolonged hemodynamic instability. CONCLUSION: Adverse cardio-respiratory reactions are commonly observed in SOAC for retinoblastoma. We believe that the adverse clinical signs represent an autonomic reflex response, akin to the trigemino-cardiac or oculo-respiratory reflexes, and all patients should be considered at-risk. Reactions occur only during second or subsequent procedures and can be life-threatening. The routine use of intravenous atropine does not seem to have altered the incidence or severity of these reactions. Anesthetists and interventional neuroradiologists involved in SOAC must be vigilant to ensure adverse reactions, when they develop, are treated quickly and effectively.

The use of strontium-90 Beta radiotherapy as adjuvant treatment for conjunctival melanoma.

Background/Aims. To report the safety and efficacy of strontium (Sr(90)) beta radiotherapy as adjuvant treatment for conjunctival melanoma. Methods. A retrospective cohort study was undertaken from 1999 to 2007 of all patients who underwent Sr(90) beta radiotherapy for incompletely excised conjunctival melanoma. Failure of treatment was defined as recurrence of a conjunctival melanoma at the same location following beta radiotherapy. Results. Twenty patients underwent Sr(90) beta radiotherapy for incompletely excised conjunctival melanoma. Median follow-up interval was 59 months (8-152). All patients had conjunctival melanoma involving the bulbar conjunctiva. Underlying diagnoses included PAM with atypia in 60% (12 of 20), PAM without atypia in 15% (3 of 20), and de novo conjunctival melanoma in 25% (5 of 20). Following Sr(90) beta radiotherapy, in 90% (18 out of 20) local control was achieved and visual acuity was not affected in any patient. Three patients (15%) had dry eye symptoms, episcleritis, and descemetcoele, respectively. No cataract or secondary glaucoma was reported. Conclusions. Sr(90) treatment is a very effective adjuvant treatment after excisional biopsy and cryotherapy for conjunctival melanoma with a local success rate of 90%. The treatment is not associated with significant side effects and visual acuity is not affected.

The biology of micrometastases from uveal melanoma.

BACKGROUND: The aim of this study was to investigate the possible causes of tumour latency in uveal melanoma primarily through the analysis of micrometastases in tissue obtained from donors postmortem. Various explanations have been proposed but there is no clear answer from animal studies and few human data. The main hypotheses may be divided into several areas--immunological control of metastatic cells, lack of angiogenesis within micrometastases and reduced cell turnover. METHODS: 196 patients were recruited to the study between 2003 and 2007. Patients were invited to take part and their relatives agreed to postmortem examination of their liver and lungs in the event of their death, including tissue sampling to assess the presence of micrometastases and their biology. Metastatic cells were detected by immunohistochemistry using a pan-melanoma antibody reagent, and by quantitative reverse transcriptase (qRT)-PCR for three melanoma-associated genes (tyrosinase Melan-A, and gp100) and a housekeeping gene (HMBS/PBGD) in samples stored in RNAlater or as formalin-fixed paraffin-embedded tissue. RESULTS: 22 deaths were investigated at autopsy as part of the study. Sixteen patients died with large deposits of metastatic melanoma, while six patients died of other causes. In addition, a liver resection for hepatic adenoma provided further tissue from a case without clinical evidence of metastasis. Metastatic melanoma cells were identified by immunohistochemistry of the liver samples in one case and by qRT-PCR in two further cases without macrometastases. There was no evidence of multicellular micrometastases sufficiently large to require angiogenesis and no associated inflammation was observed. CONCLUSION: The most likely explanation for latency in this setting is the inability of uveal melanoma cells in metastatic sites to grow.

Transpositional Autokeratoplasty in a Patient with Unilateral Choroidal Melanoma and Contralateral Exposure Keratopathy.

Penetrating keratoplasty was required to improve corneal clarity in the left eye, which had suffered chronic exposure keratopathy following a cerebellopontine angle tumor with facial nerve involvement. The right eye had a large choroidal melanoma, which had failed brachytherapy, but the cornea was transparent and healthy. The right eye corneal button was sutured to the left eye host and a donor corneal button was sutured to the right eye rim. The right eye was subsequently enucleated. Two years later, the patient had 6/12 visual acuity with a clear graft and no tumor seeding in the host eye. Although limited opportunities arise to employ transpositional autokeratoplasty, where appropriate, it offers an alternative to conventional allokeratoplasty with a lower risk of immune rejection.

Histopathologically proven mucinous cystadenocarcinoma metastatic to the choroid.

PURPOSE: To report the first case of conventional transcleral choroidal biopsy in the diagnosis of ovarian carcinoma metastatic to the choroid and to summarize the published cases of ovarian carcinoma metastatic to the choroid. METHODS: Case report and Medline literature review. RESULTS: This is the tenth case reported in the literature and the only case that underwent conventional transcleral choroidal biopsy. Transcleral choroidal biopsy allowed the diagnosis of metastatic mucinous cystadenocarcinoma of the ovary. Choroidal metastases are not associated with central nervous system involvement; however, investigations may reveal distal boney or pulmonary metastases. CONCLUSION: Ovarian carcinoma rarely metastases to the choroid and unlike breast carcinoma, concurrent central nervous system disease has not been reported. When systemic investigations fail to reveal active intraperitoneal disease or distal metastases, the clinician should consider referral to an ocular oncology center for a choroidal biopsy.

Choroidal neovascularization induced by transcleral microdiathermy for localization of a juxtapapillary choroidal melanoma.

Transcleral transillumination is a useful tool for the localization of juxtapapillary uveal tract tumors that do not cast a shadow with conventional transpupil-lary transillumination. The main choice of treatment for juxtapapillary uveal tract melanoma consists of either episcleral plaque brachytherapy or proton beam radiotherapy. In both instances, an external surgical approach is required that involves localization of the tumor and marking of the overlying sclera. Transcleral microdiathermy often creates corresponding areas of chorioretinal atrophy. This article describes the technique of transcleral transillumination coupled with microdiathermy to mark the sclera in a patient in whom a choroidal neovascular membrane developed adjacent to a microdiathermy-induced area ofchorioretinal atrophy after the described surgical technique. To avoid the postoperative development of a choroidal neovascular membrane, transcleral transillumination can be used without the application of microdiathermy.

Gastric metastases from conjunctival melanoma.

The aim of the study is to discuss the pattern and risk factors for metastatic disease in conjunctival melanoma. We draw comparisons with cutaneous metastatic melanoma. We describe the clinical course of a patient with recurrent conjunctival melanoma in the context of primary acquired melanosis with atypia. The local disease was eventually treated with a lid splitting exenteration. The patient suffered from an isolated distant metastasis to the gastric wall that was managed by partial gastrectomy. Conjunctival melanoma has many similarities with its cutaneous counterpart. In both conditions the regional lymph nodes are the most common site for metastases, however, isolated distant metastases can occur. Gastric metastases are frequently seen in cutaneous melanoma. This is the first report of an isolated gastric metastasis from a conjunctival melanoma.

Presence and phenotype of dendritic cells in uveal melanoma.

BACKGROUND: Uveal melanoma arises in an immune-privileged site and can itself add to the immunosuppressive environment. Previous studies on cutaneous melanoma have shown the presence of tolerogenic dendritic cells (DCs), which could play an important role in the progression of the tumour. AIM: To examine the presence and functional status of DCs in a small series of uveal melanomas. METHODS: 10 cases of uveal melanoma were examined for the expression of FXIIIa, CD68, human leucocyte antigen (HLA)-DR, CD40, CD83, transforming growth factor betaR1 and indolamine 2,3 dioxygenase by immunohistochemical analysis on sections embedded in paraffin wax. RESULTS: CD68-positive macrophages were present in all of the tumours and were evenly distributed throughout. DCs expressing FXIIIa-positive were seen in 7 cases, and were often found concentrated in foci within the tumour mass. These cells were dendritic and expressed high levels of HLA-DR. The DCs did not express the maturation markers CD83 or CD40. In one case, concentration of DCs around the area of tumour necrosis was observed, and some of these cells expressed CD83. CONCLUSION: Numerous tolerising antigen-presenting cells may play a role in melanoma-related immunosuppression in the eye, although activation of DCs may be associated with tumour necrosis.

Post-menopausal bleeding: a rare presentation of metastatic uveal melanoma.

Uveal melanoma differs from cutaneous melanoma in many ways, including its pattern of metastasis, and exhibits latency with clinical evidence of metastasis sometimes appearing many years after primary diagnosis. Most patients develop metastasis within the liver, but some may present with metastasis to other sites. We report a case of uveal melanoma that presented with post-menopausal bleeding due to metastasis. Further investigation revealed widespread metastatic disease and the patient was not fit for chemotherapy. She died two months after presentation: autopsy revealed metastases in many sites, including the uterus, right ovarian fibroma, kidney, mesentery, liver, lung, thyroid, bone marrow and skin. The immediate cause of death was cardiac tamponade due to a malignant effusion secondary to cardiac metastasis. This case illustrates the widespread metastatic potential of uveal melanoma and highlights the potential for unusual presentation of metastatic disease from this eye tumor.

The effect of imatinib mesylate (Glivec) on human tumor-derived cells.

Imatinib mesylate is a specific inhibitor of the Bcr-Abl protein tyrosine kinase that competes with ATP for its specific binding site in the kinase domain. It has activity against platelet-derived growth factor receptor alpha and beta (PDGFR-alpha and -beta), and c-kit, the receptor for stem cell factor. We have used a standardized ATP-tumor chemosensitivity assay and immunohistochemistry to determine the cytotoxicity of imatinib mesylate in tumor-derived cells from cutaneous and uveal melanoma, and ovarian carcinoma. Imatinib mesylate was tested at concentrations ranging from 2.0 to 0.0625 micromol/l alone and in combination with a cytotoxic drug (cisplatin, doxorubicin, paclitaxel or treosulfan). Imatinib mesylate showed low inhibition (IndexSUM>300) across the range of concentrations tested in this study, with few tumors exhibiting increasing inhibition with increased drug concentration. The median IC90 values for cutaneous and uveal melanoma and ovarian carcinoma were 13.2 micromol/l (4.0-294.3 micromol/l), 12.0 micromol/l (2.0-285.4 micromol/l) and 7.71 micromol/l (6.51-11.02 micromol/l), respectively. Imatinib mesylate potentiated the effect of different cytotoxics in 9% (5/54) of cases and had a negative effect in 13% (7/54) of cases, with no effect in the remainder. No correlation of effect was noted with c-kit, platelet-derived growth factor receptor-alpha or platelet-derived growth factor receptor-beta expression, assessed by immunohistochemistry. The signaling pathways mediated by activation of c-kit or platelet-derived growth factor receptor may act as antiapoptotic survival signals in some cancers and inhibition of these pathways may potentiate the activity of some cytotoxic drugs by inhibiting the survival signal. Growth inhibition, however, may reduce the efficacy of cytotoxic drugs, which tend to target proliferating cells preferentially, and clinical effects are therefore difficult to predict.

Current trends in the treatment of ocular melanoma by radiotherapy.

The Collaborative Ocular Melanoma Study (COMS) has recently confirmed once and for all that it is safe to attempt to preserve an eye with a posterior uveal melanoma by demonstrating no survival advantage of enucleation over plaque radiotherapy. While COMS has been under way, we have set out in London to define the selection criteria for conservative therapy versus enucleation for the various categories of melanoma in terms of size, location within the eye, and presence or absence of retinal detachment. The evolution of this approach has culminated in an overall ocular survival rate of 94% in 597 patients following radiation therapy combined with a mean loss of visual acuity of only 2.4 Snellen lines in the eyes preserved.