James J. Augsburger

Sunlight exposure as risk factor for intraocular malignant melanoma

In a case-control study, we compared 444 patients with intraocular malignant melanoma with matched controls to evaluate the role of exposure to ultraviolet radiation and other risk factors in the pathogenesis of this tumor. Persons born in the southern United States had a relative risk of 2.7 (95 per cent confidence interval, 1.3 to 5.9) as compared with those born in the North. Subjects with brown eyes were protected as compared with those with blue eyes (relative risk, 0.6; 95 per cent confidence interval, 0.4 to 0.8), but complexion and hair color were not important risk factors. Patients with intraocular malignant melanoma were also more likely to have spent time outdoors in their gardens, to have sunbathed, and to have used sunlamps. Rarely wearing hats, visors, or sunglasses while in the sun was a risk factor for the disease (relative risk, 1.9; 95 per cent confidence interval, 1.6 to 2.2). These data suggest that sunlight exposure is an important risk factor for intraocular melanoma.

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.

Effectiveness of Treatments for Metastatic Uveal Melanoma

PURPOSE To evaluate and comment on published peer-reviewed literature for evidence of effectiveness of treatments for metastatic uveal melanoma. DESIGN Analytical nonexperimental study of published peer-reviewed data. METHODS Literature search and analysis of pertinent articles published between January 1, 1980 and June 30, 2008. RESULTS Of 80 identified publications, 12 (15.0%) were review articles without original information, 2 (2.5%) were review articles combined with case reports, 22 (27.5%) were case reports, 16 (20.0%) were retrospective descriptive case series reports, 3 (3.75%) were pilot studies of a novel intervention, 2 (2.5%) were prospective phase I clinical trials, 8 (10.0%) were prospective phase I/II clinical trials, and 15 (18.75%) were prospective phase II clinical trials. None of the articles reported a prospective, randomized phase III clinical trial. The largest reported unselected patient groups had a median survival of 3 to 4 months after detection of metastasis, whereas the largest selected patient groups showed substantially longer median survival times. CONCLUSIONS Although median survival time after diagnosis of metastatic uveal melanoma tends to be substantially longer in selected patient subgroups subjected to aggressive invasive interventions than it is in unselected groups, much if not most of this apparent difference in survival is likely to be attributable to selection bias, surveillance bias, and publication bias rather than treatment-induced alteration of expected outcome. Published peer-reviewed articles do not provide compelling scientific evidence of any survival benefit of any method of treatment for any subgroup of patients with metastatic uveal melanoma.

Cobalt Plaque Therapy of Posterior Uveal Melanomas

One hundred patients with choroidal melanomas who were treated by the authors with cobalt plaque radiotherapy were analyzed with regard to tumor regression, visual results, complications, and mortality rate. The follow-up period at the time of this writing ranged from one to five years. These preliminary observations indicate that cobalt plaque radiotherapy induces tumor regression in 96% of cases, preserves useful vision in many cases and has fewer complications during the one- to five-year follow-up period than previously believed.

Radiation Optic Neuropathy

The ophthalmoscopic findings in a series of 14 eyes with radiation-induced optic neuropathy are described. Typically, the entity manifests acutely as disc swelling with surrounding exudate, hemorrhages, and subretinal fluid. Optic atrophy may ensue in the later stages. Similar to radiation retinopathy, radiation optic neuropathy also seems to occur secondary to vascular damage. In contrast to visual loss secondary to radiation retinopathy, the visual acuity in certain eyes with decreased vision attributable to radiation optic neuropathy may improve over a period of several months.

Prevalence and Mechanisms of Secondary Intraocular Pressure Elevation in Eyes with Intraocular Tumors

A survey of 2704 eyes with intraocular tumors in patients who were evaluated on the Oncology Service at Wills Eye Hospital showed that 126 of the tumor-containing eyes (5%) had tumor-induced elevated intraocular pressure (IOP) at the time of diagnosis of the tumor. Of the 2111 eyes with uveal melanomas, secondary IOP elevation was present in 55 (3%). Secondary IOP elevation was present in 7% of eyes with iris melanoma, 17% with ciliary body melanoma, and 2% with choroidal melanoma. The most common mechanism of elevated IOP was tumor invasion of the angle in the case of iris melanomas, pigment dispersion and tumor invasion of the angle in the case of ciliary body melanomas, and iris neovascularization in the case of choroidal melanomas. Of the 256 eyes with uveal metastases, secondary IOP elevation was found in 12 eyes (5%). Secondary IOP elevation was present in 64% of eyes with iris metastases, 67% with ciliary body metastases, and 1% with choroidal metastases. The most common mechanism of elevated IOP was tumor invasion of the angle in the case of iris and ciliary body metastases, and angle closure in the case of choroidal metastases. There were 303 eyes with retinoblastoma, 17% of which had elevated IOP which was secondary to iris neovascularization in 70% of cases and to an angle closure without neovascularization in 27%. Several other intraocular tumors including lymphoma, leukemia, medulloepithelioma, melanocytoma, and adenoma of the iris pigment epithelium were occasionally associated with secondary elevated IOP.

Space-occupying orbital masses in children. A review of 250 consecutive biopsies.

A review was done of 250 consecutive biopsies for orbital space-occupying lesions in children. Benign cystic lesions were by far the most common, accounting for 52% of the lesions. Inflammatory lesions, usually biopsied to exclude the diagnosis of rhabdomyosarcoma, accounted for 16%. Among the 250 biopsies there were 14 primary malignant tumors (6%), ten of which were rhabdomyosarcoma. Although rhabdomyosarcoma is not the most common space-occupying orbital lesion in children, clinicians should be familiar with its clinical features and proceed with immediate biopsy followed by appropriate irradiation and chemotherapy if the diagnosis is established. However, biopsy should only be undertaken if there is reasonable suspicion that the lesion could be rhabdomyosarcoma or other childhood orbital malignancy.

Visual prognosis following treatment of acute central retinal artery obstruction.

The authors report the visual outcome in 34 consecutive cases of treated acute central retinal artery obstruction. Visual acuity equal to or better than 6/30 was recovered in 35% of the cases. The presenting visual acuity and duration of visual impairment appear to correlate with visual prognosis.

Fine Needle Aspiration Biopsy in the Diagnosis of Intraocular Cancer: Cytologic-Histologic Correlations

Fine needle aspiration biopsy was used as an investigational procedure in the evaluation of 71 eyes harboring a suspected intraocular malignancy between January 8, 1981, and January 21, 1983. Twenty-seven of these 71 biopsies were performed prior to any treatment as a diagnostic procedure and the others were performed following enucleation or tumor excision to provide specimens for cytologic-histologic correlation. The histologic findings confirmed the cytologic diagnosis of malignancy or benignancy in 94.3% of the 53 cases in which a corresponding tissue specimen was available for histologic evaluation. None of the eight eyes with a cytologically confirmed diagnosis of malignancy that were managed conservatively following the biopsy has experienced visual loss attributable to the biopsy. There have been no instances of documented needle tract seeding by tumor cells or orbital tumor recurrence to date in the 27 cases in which diagnostic fine needle aspiration biopsy had been performed prior to treatment.

The differential diagnosis of posterior uveal melanoma.

Two large studies from the Armed Forces Institute of Pathology (AFIP) have listed the various lesions which may clinically resemble malignant melanomas of the posterior uvea (pseudomelanomas). The studies from the AFIP were based upon histologic examination of eyes which were enucleated. The present study reports on 400 consecutive patients who were referred but who proved, by clinical evaluation, rather than by enucleation, to have a pseudomelanoma. Although about 40 different conditions were found to simulate melanoma, the more commonly encountered ones included suspicious choroidal nevus (26.5%), disciform degeneration (12.5%), peripheral disciform degeneration (11%), congenital hypertrophy of the retinal pigment epithelium (9.5%), and choroidal hemangioma (8%). The authors believe that this series provides the clinician with a differential diagnosis for posterior uveal melanomas which accurately reflects the clinical problem confronting ophthalmologists today.