E. Rand Simpson

Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma.

PURPOSE This study evaluates the prognostic performance of a 15 gene expression profiling (GEP) assay that assigns primary posterior uveal melanomas to prognostic subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk). DESIGN Prospective, multicenter study. PARTICIPANTS A total of 459 patients with posterior uveal melanoma were enrolled from 12 independent centers. TESTING Tumors were classified by GEP as class 1 or class 2. The first 260 samples were also analyzed for chromosome 3 status using a single nucleotide polymorphism assay. Net reclassification improvement analysis was performed to compare the prognostic accuracy of GEP with the 7th edition clinical Tumor-Node-Metastasis (TNM) classification and chromosome 3 status. MAIN OUTCOME MEASURES Patients were managed for their primary tumor and monitored for metastasis. RESULTS The GEP assay successfully classified 446 of 459 cases (97.2%). The GEP was class 1 in 276 cases (61.9%) and class 2 in 170 cases (38.1%). Median follow-up was 17.4 months (mean, 18.0 months). Metastasis was detected in 3 class 1 cases (1.1%) and 44 class 2 cases (25.9%) (log-rank test, P<10(-14)). Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54 of 260 tumors (20.8%) were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log-rank test, P = 0.0001). By using multivariate Cox modeling, GEP class had a stronger independent association with metastasis than any other prognostic factor (P<0.0001). Chromosome 3 status did not contribute additional prognostic information that was independent of GEP (P = 0.2). At 3 years follow-up, the net reclassification improvement of GEP over TNM classification was 0.43 (P = 0.001) and 0.38 (P = 0.004) over chromosome 3 status. CONCLUSIONS The GEP assay had a high technical success rate and was the most accurate prognostic marker among all of the factors analyzed. The GEP provided a highly significant improvement in prognostic accuracy over clinical TNM classification and chromosome 3 status. Chromosome 3 status did not provide prognostic information that was independent of GEP.

Anterior Segment Optical Coherence Tomography and Ultrasound Biomicroscopy in the Imaging of Anterior Segment Tumors

PURPOSE To evaluate the utility of anterior segment optical coherence tomography (OCT) in the imaging of anterior segment tumors and compare the images to ultrasound biomicroscopy (UBM). DESIGN Prospective observational case series. METHODS Eighteen eyes of 18 patients with anterior segment tumors were evaluated at Princess Margaret Hospital. The evaluation included clinical examination, clinical photography, anterior segment OCT, and UBM. Comparison of images obtained by both methods was done. RESULTS Anterior segment OCT imaged small hypopigmented tumors with complete penetration. Cysts were incompletely imaged behind the iris pigment epithelium. Highly pigmented tumors, large tumors, and ciliary body tumors were incompletely penetrated. Even without complete penetration it was possible to differentiate cystic lesions from solid lesions. UBM penetrated all tumors completely. CONCLUSIONS Anterior segment OCT can penetrate small hypopigmented tumors and supply some information on internal characteristics of other tumors. UBM is preferable for clinical anterior tumor assessment and follow-up because of its superior ability to penetrate large tumors, highly pigmented tumors, and ciliary body tumors.

Current treatments for radiation retinopathy

Abstract Background. To review the currently available therapeutic modalities for radiation retinopathy (RR), including newer investigational interventions directed towards specific aspects of the pathophysiology of this refractory complication. Methods. A review of the literature encompassing the pathogenesis of RR and the current therapeutic modalities available was performed. Results. RR is a chronic and progressive condition that results from exposure to any source of radiation. It might be secondary to radiation treatment of intraocular tumors such as choroidal melanomas, retinoblastomas, and choroidal metastasis, or from unavoidable exposure to excessive radiation from the treatment of extraocular tumors like cephalic, nasopharyngeal, orbital, and paranasal malignancies. After the results of the Collaborative Ocular Melanoma Study, most of the choroidal melanomas are being treated with plaque brachytherapy increasing by that the incidence of this radiation complication. RR has been reported to occur in as many as 60% of eyes treated with plaque radiation, with higher rates associated with larger tumors. Initially, the condition manifests as a radiation vasculopathy clinically seen as microaneurysms and telangiectases, with posterior development of retinal hard exudates and hemorrhages, macular edema, neovascularization and tractional retinal detachment. Regrettably, the management of these eyes remains limited. Photodynamic therapy, laser photocoagulation, oral pentoxyphylline and hyperbaric oxygen have been attempted as treatment modalities with inconclusive results. Intravitreal injections of anti-vascular endothelial growth factor such as bevacizumab, ranibizumab and pegaptanib sodium have been recently used, also with variable results. Discussion. RR is a common vision threatening complication following radiation therapy. The available therapeutic options are limited and show unsatisfactory results. Further large investigative studies are required for developing better therapeutic as well as preventive treatment strategies.

Intracameral bevacizumab in the treatment of neovascular glaucoma and exudative retinal detachment after brachytherapy in choroidal melanoma.

Choroidal melanoma is the most common primary intraocular tumor in adults. Plaque brachytherapy is a common treatment option for medium-sized tumors. Radiation retinopathy and its sequellae, including neovascularization of the iris (NVI), neovascular glaucoma (NVG), and exudative retinal detachment (ERD), are among the known side effects of radiation treatment. NVI can develop as soon as 9 months after radiation (mean time of 27 months) and secondary NVG develops in up to 23% of eyes at 5 years. ERD occurs following plaque radiotherapy in up to 16% of patients. Treatment options for managing NVG secondary to brachytherapy include medical therapy, panretinal photocoagulation, cyclodestructive procedures, anti–vascular endothelial growth factor (VEGF) therapy, and, in some cases, enucleation. Typically, there are no specific treatments directed to ERDs in treated choroidal melanoma patients. Multiple reports have shown that intravitreal bevacizumab (Avastin, Genentech Inc, San Francisco, Calif.) an antiVEGF agent, reduces neovascular activity and vascular permeability in ocular tissues. Bevacizumab can be administered intravitreally or intracamerally to reduce NVI secondary to diabetes and other retinal vascular diseases. We report the use of intracameral bevacizumab in a patient with NVG and ERD following brachytherapy for a medium-sized choroidal melanoma. A 45-year-old woman was treated with iodine-125 (I-125) brachytherapy for a medium-sized choroidal melanoma (thickness of 6.8 mm, 10 mm at its largest diameter). There was no retinal detachment (RD) at the time of diagnosis. Fourteen months post treatment, a total ERD was noted despite local tumor control (4.26 mm thickness). Three months later, she developed a painful left eye and decreased visual acuity to no light perception (NLP).The intraocular pressure (IOP) was 50 mm Hg. Corneal edema was present, with 360° of NVI; the angle was open and neovascularization of the angle was noted. The tumor height was 4.35 mm by ultrasound. Maximum medical therapy was initiated to treat the elevated IOP. Panretinal photocoagulation could not be performed because of the extent of the RD. Bevacizumab (1.25 mg) was injected intracamerally since the intravitreal approach was deemed unsafe in the presence of an RD. One week post injection, the IOP was 36 mm Hg. On examination, there was regression of the iris and angle neovascularization, which was evident on iris angiography (Fig. 1). One month post injection, visual acuity remained NLP, IOP was 20 mm Hg, and some iris vessels were visible. Intracameral bevacizumab injections were repeated

Ciliary body melanoma: a special challenge

Although there is little doubt that the delayed recognition of ciliary body melanoma has a bearing on patient management and ultimate survival, the most compelling issues that face the clinician treating this neoplasm relate to the metastatic patterns and mechanisms of the disease. Several aspects of diagnosis and management of this tumour provide a unique challenge to the clinician. Ciliary body melanoma can remain clinically inapparent to the patient as well as to the clinician during its formative period. In management, tumour characteristics, including anterior and posterior margins, are more readily visualized with ultrasound biomicroscopy (UBM) than with other imaging techniques. UBM can provide valuable information when considering intervention, including biopsy, resection or plaque radiotherapy. Management depends on tumour size, intraocular involvement, patient preference and the presence or absence of systemic manifestations.

Stereotactic radiotherapy in the treatment of juxtapapillary choroidal melanoma: 2-year follow-up

OBJECTIVE To evaluate the efficacy and complications of stereotactic radiotherapy in the management of patients with juxtapapillary choroidal melanoma. DESIGN Retrospective review. PARTICIPANTS 64 patients with juxtapapillary choroidal melanoma. METHODS Consecutive patients with juxtapapillary choroidal melanomas located within 2 mm of the optic nerve, treated with stereotactic radiotherapy at Princess Margaret Hospital from October 1998 to January 2006, were reviewed for treatment effect and complication rates. RESULTS Median age was 63 years. Median tumor height was 4.2 mm, and median maximum tumor diameter was 9.8 mm. The prescribed radiation dose was 70 Gy in 5 fractions over 10 days, and the median follow-up was 26 months. After treatment, there was local tumor recurrence in 3 patients, and in 8 patients there was systemic progression. Actuarial rates of local tumor control, metastases, and survival at 26 months were 94%, 12%, and 94%, respectively. Rates of radiation-induced neovascular glaucoma, cataract, retinopathy, and optic neuropathy at 26 months were 28%, 45%, 80%, and 52%, respectively. Enucleation was necessary for 7 patients. CONCLUSIONS Stereotactic radiotherapy offers a noninvasive alternative with acceptable ocular toxicity rates to enucleation and brachytherapy in the management of juxtapapillary choroidal melanoma.

Ultrasound Biomicroscopic Imaging of Iris Melanoma: A Clinicopathologic Study

PURPOSE To demonstrate the correlation of ultrasound biomicroscopy (UBM) features of iris melanoma with histopathology. DESIGN Retrospective analysis of medical records. METHODS The medical records of patients that underwent surgery for iris melanoma at the Princess Margaret Hospital, University of Toronto, from June 1990 to October 1998 were reviewed. The clinical features, as well as the UBM findings prior to surgical intervention, were evaluated. The anatomic features noted on UBM were correlated with histopathologic features seen in the surgical specimens. RESULTS Fourteen cases met the inclusion criteria and were included in the final analysis. The ultrasound acoustic characteristics showed a broad spectrum of findings among iris melanomas. Tumor acoustic parameters correlated well with histologic features, including tumor vascularity, surface plaque, extrascleral extension, ciliary body involvement, and integrity of iris pigment epithelium. CONCLUSIONS UBM is a useful imaging technique for the in vivo assessment of primary iris melanoma and can provide detailed imaging of the tumors interface with the angle structures. The preoperative assessment of these tumors by UBM may aid the surgeon in choosing the most appropriate technique to ensure total removal.

A comparison between 125Iodine brachytherapy and stereotactic radiotherapy in the management of juxtapapillary choroidal melanoma

Aims To compare the treatment efficacy and radiation complications between 125Iodine brachytherapy and stereotactic radiotherapy in the management of juxtapapillary choroidal melanoma. Methods Consecutive juxtapapillary melanoma patients treated with radiotherapy were included. Patients were divided into two cohorts: patients treated with 125Iodine brachytherapy and patients with stereotactic radiotherapy. Comparison included the rates postradiotherapy local recurrence, secondary enucleation, metastasis and radiotherapy complications. Kaplan–Meier estimates were used to determine the actuarial rates, and logrank test to compare between the estimates. Results We included 94 patients with juxtapapillary melanoma treated with radiotherapy. The brachytherapy cohort included 30 patients and stereotactic radiotherapy was 64. The median follow-up was 46 months in both cohorts. No statistically significant differences existed between the two cohorts on comparing pretreatment clinical data and tumour characteristics. On comparing treatment efficacy, the actuarial rates at 50 months for tumour recurrence were 11% and 7% (p=0.61), secondary enucleation was 11% and 21% (p=0.30) and for metastasis were 4% and 16% (p=0.11), respectively. On comparing treatment complications, the actuarial rates at 50 months for cataracts were 62% and 75% (p=0.1), for neovascular glaucoma 8% and 47% (p=0.002), for radiation retinopathy 59% and 89% (p=0.0001), and for radiation papillopathy 39% and 74% (p=0.003), respectively. Conclusions Both 125Iodine brachytherapy and stereotactic radiotherapy demonstrate comparable efficacy in the management of juxtapapillary choroidal melanoma. However, stereotactic radiotherapy shows statistically significant higher radiation-induced ocular morbidities at 4 years postradiotherapy.

Intraocular extension of conjunctival invasive squamous cell carcinoma after pterygium surgery and cataract extraction.

Objectives Conjunctival squamous dysplasia can often be confused with pterygium and pinguecula. Incomplete excision of dysplastic tissue can lead to recurrence and rarely intraocular invasion. This study describes two cases in which invasive squamous cell carcinoma (SCC) of the conjunctiva was originally partially resected as pterygium and eventually required enucleation for intraocular invasion. Methods In this clinicopathologic small case series, two cases of intraocular SCC managed at a single tertiary ocular oncology institution are described. Clinical features, pathologic characteristics, and relevant imaging are described. Results In both cases, incomplete excision of conjunctival SCC was followed by rapid regrowth of the conjunctival lesion and signs of intraocular inflammation. An intraocular mass within the substance of the ciliary body was identified using ultrasound biomicroscopy in both the cases. Enucleation was performed. Pathologic features were typical to SCC. Conclusions Intraocular spread on conjunctival SCC occurs only rarely but tends to follow recurrence of the conjunctival lesion after attempted excision. Modes of invasion may include direct invasion through sclera, along the tract of the anterior ciliary vessels, or inoculation through intraocular surgery incision.

Cancer-associated nummular loss of RPE: expanding the clinical spectrum of bilateral diffuse uveal melanocytic proliferation.

This report describes a case of cancer-associated nummular retinal pigment epithelium loss associated with uterine cancer. The patient had progressive visual loss despite treatment with plasmapheresis, intravenous immunoglobulin, and local injection of corticosteroids. Clinical deterioration was corroborated by extension of the areas of retinal pigment epithelium loss, progression of cataracts, and growth of pigmented choroidal and iris lesions. Previously published cases of cancer-associated nummular retinal pigment epithelium loss did not describe the presence of cataracts or uveal melanocytic lesions. This case expands the clinical spectrum of bilateral diffuse uveal melanocytic proliferation.