Mary E. Aronow

Tuberous sclerosis complex: genotype/phenotype correlation of retinal findings.

OBJECTIVE To evaluate genotype/phenotype correlations in individuals with astrocytic hamartoma (AH) and retinal achromic patch (AP) in the setting of tuberous sclerosis complex (TSC). DESIGN Retrospective consecutive case series. PARTICIPANTS A total of 132 patients enrolled in the Cleveland Clinic Foundation Tuberous Sclerosis Program (CCF-TSCP) and 907 patients from the Tuberous Sclerosis Alliance (TSC-A). METHODS Patient gender, age at TSC diagnosis, presence of TSC1 or TSC2 mutations, detailed ophthalmic examination findings, systemic manifestations, and whether or not the patient had a diagnosis of epilepsy or cognitive impairment were analyzed. MAIN OUTCOME MEASURES Genotype/phenotype correlation of retinal findings and systemic disease manifestations. RESULTS No significant difference was found in the prevalence of AH or AP in the CCF-TSCP (36.1%) and TSC-A (34.1%) groups (P = 0.743). Astrocytic hamartomas were bilateral in 43.3% and 18.1% (P=0.009) and multiple in 40.0% and 15.3% (P = 0.008) in the CCF-TSCP and TSC-A groups, respectively. In the CCF-TSCP group, the average number of AH was 4 (range, 2-7). Average tumor size was 1.0 disc diameter (range, 0.5-2.5 disc diameters). The most common location was along the arcades (41.5%), adjacent to the optic nerve (29.2%), and in the retinal periphery (27.7%). In the CCF-TSCP group, AP was observed in 12.0% of patients (40.0% bilateral, 50.0% multiple). The presence of retinal features was associated with giant cell astrocytoma (37.1% vs. 14.6%; P = 0.018), renal angiomyolipoma (60.0% vs. 27.1%; P = 0.003), cognitive impairment (77.1% vs. 43.8%; P = 0.002), and epilepsy (91.4% vs. 70.8% (P = 0.022) in those with and without retinal findings, respectively. In patients with retinal findings in both the CCF-TSCP and TSC-A groups, mutations in TSC2 were more frequent than in TSC1, 3.3 times and 5.8 times, respectively; in those without retinal findings, the relative rates were 0.67 times and 2.3 times, respectively. CONCLUSIONS Individuals with retinal findings are more likely to have concomitant subependymal giant cell astrocytomas, renal angiomyolipomas, cognitive impairment, and epilepsy. TSC2 mutations are more frequent in patients with retinal findings than in those without retinal findings.

Age-related Eye Disease Study 2: perspectives, recommendations, and unanswered questions.

Purpose of review This review provides a perspective on the Age-related Eye Disease Study 2 (AREDS2) including a summary of the goals and rationale of the study, major findings, subsequent management recommendations, and questions that remain to be answered. Recent findings The primary goal of the AREDS2 was to evaluate the efficacy and safety of lutein plus zeaxanthin and/or omega-3 long-chain polyunsaturated acid supplementation in reducing the risk of developing advanced age-related macular degeneration (AMD). AREDS2 also investigated the effects of omitting &bgr;-carotene and reducing the concentration of zinc from the original AREDS formulation. Although primary analysis from the AREDS2 did not reveal a benefit of daily supplementation with lutein/zeaxanthin on AMD progression, secondary exploratory analyses suggested that lutein/zeaxanthin were helpful in reducing this risk. Comparison of low-dose to higher-dose zinc showed no significant benefit. Summary The overall evidence on the beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than &bgr;-carotene in AREDS-type supplements. Questions remain regarding the AREDS2 study results such as: whether the findings are generalizable to the population as a whole, what is the long-term safety profile of lutein/zeaxanthin supplementation, should other carotenoids be included in AREDS-type supplements, and at what optimal doses?

Fine-needle aspiration biopsy of uveal melanoma: outcomes and complications

Purpose To report outcomes and complications of fine-needle aspiration biopsy (FNAB) of uveal melanoma performed for diagnostic and prognostic purposes. Methods Prospective interventional case series of 150 consecutive patients with a clinical diagnosis of uveal melanoma. The FNAB approach (transcorneal (TCO), transscleral (TSC) and transvitreal (TVT) was primarily determined by the location of the tumour. The FNAB was performed using a 25-gauge needle using a previously published technique. Prognostication was done using fluorescent in situ hybridisation detection of monosomy of chromosome 3. Results FNAB was obtained via TCO (8), TSC (71) and TVT (64) approach and impression smear in seven cases. Diagnostic yield was 92%. False-negative results were observed in 8%. Diagnostic yield was significantly correlated to biopsy approach (TCO 100%, TSC 96%, TSV 86%; p=0.029) and tumour size (basal diameter >5.0 mm; height >2.5 mm). Persistent haemorrhage (subretinal haemorrhage or vitreous) requiring surgical intervention (1%) and rhegmatogenous retinal detachment (1%) were rare. Endophthalmitis, hypotony, tumour recurrence, episcleral seeding were not observed over the average follow-up of 37 months. Prognostication could be performed in 85% of cases. Overall, only 47% of eligible patients enrolled into the adjuvant therapy trial. Conclusions FNAB for uveal melanoma with 25-gauge needle is a safe procedure that can yield diagnostic and prognostic information in vast majority of cases (92% and 85%, respectively). Even so, only about half of the eligible cases eventually enrolled into the adjuvant therapy trial. Possibility of negative FNAB yield should be considered when counselling patients with small tumours. Alternative means of diagnostic biopsy and methods of prognostication need to be assessed for small tumours.

Ocular Adnexal Lymphoma: Assessment of a Tumor-Node-Metastasis Staging System

PURPOSE To assess distribution, correlations, and prognostic effect of tumor (T), node (N), and metastasis (M) staging on relapse and survival. DESIGN Retrospective clinical review. PARTICIPANTS Sixty-three patients diagnosed with primary ocular adnexal lymphoma (OAL) between January 1986 and November 2011. METHODS Complete ocular examination and systemic evaluation were performed. Patients were staged according to the American Joint Committee on Cancer (AJCC) seventh edition tumor-node-metastasis (TNM) clinical staging system for OAL and followed every 6 to 12 months (median follow-up, 27.9 months). MAIN OUTCOME MEASURES Relapse defined as lymphoma recurrence in the initial site of presentation, the contralateral ocular adnexal structures, or other systemic site and overall survival. RESULTS There were 40 men (63.5%). The median age was 65 years (range, 24-85 years). The affected site was the conjunctiva in 27 patients (42.9%), orbit in 38 patients (60.3%), and eyelid in 3 patients (4.8%). The histologic subtype was extranodal marginal zone lymphoma (EMZL) in 51 patients (81.0%). A total of 14 patients (23.3%) had T1, 42 patients (70.0%) had T2, 1 patient (1.7%) had T3, and 3 patients (5.0%) had T4 disease. A total of 48 patients (82.8%) had N0 disease, and 10 patients (17.2%) had N1-4 disease. M stage was M0 in 47 patients (81.0%) and M1 in 11 patients (19.0%). With advanced T stage, there was an increase in both N1-4 (P = 0.045) and M1 disease (P = 0.041). M1 disease was greater among patients with N1-4 disease compared with N0 stage (50.0% vs. 12.5%, P = 0.003). Overall, 18 patients (28.6%) relapsed and 6 patients (9.5%) died. In Cox analysis, relapse was not associated with T stage (hazard ratio [HR], 1.14 per 1 level increase, P = 0.71), N stage (HR, 1.47; P = 0.51 N1-4 vs. N0), or M stage (HR, 1.22; P = 0.76 M1 vs. M0). T stage was not associated with survival (HR, 0.86; P = 0.81), whereas N1-4 had marginally worse survival than N0 (HR, 5.35; P = 0.07), and M1 had worse survival than M0 (HR, 9.27; P = 0.008). CONCLUSIONS The TNM staging system for primary OAL is useful for precise characterization of extent of local disease. Although T stage does not predict relapse or survival, N1-4 and M1 stages indicated less favorable survival. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Chromosome 3 status in uveal melanoma: a comparison of fluorescence in situ hybridization and single-nucleotide polymorphism array.

PURPOSE To compare fluorescence in situ hybridization (FISH) using a centromeric probe for chromosome 3 (CEP3) and 3p26 locus-specific probe with single-nucleotide polymorphism array (SNP-A) analysis in the detection of high-risk uveal melanoma. METHODS Fifty cases of uveal melanoma (28 males, 22 females) treated by enucleation between 2004 and 2010 were analyzed. Fresh tissue was used for FISH and SNP-A analysis. FISH was performed using a CEP3 and a 3p26 locus-specific probe. Tumor size, location, and clinical outcome were recorded during the 7-year study period (median follow-up: 35.5 months; mean: 38.5 months). The sensitivity, specificity, positive predictive value, and negative predictive value were calculated. RESULTS Monosomy 3 was detected by FISH-CEP3 in 27 tumors (54%), FISH-3p26 deletion was found in 30 (60%), and SNP-A analysis identified 31 (62%) of the tumors with monosomy 3. Due to technical failures, FISH and SNP-A were noninterpretable in one case (2%) and two cases (4%), respectively. In both cases of SNP-A failure, tumors were positive for FISH 3p26 deletion and in a single case of FISH failure, monosomy 3 was found using SNP-A. No statistically significant differences were observed in any of the sensitivity or specificity measures. CONCLUSIONS For prediction of survival at 36 months, FISH CEP3, FISH 3p26, and SNP-A were comparable. A combination of prognostication techniques should be used in an unlikely event of technical failure (2%-4%).

Monosomy 3 by FISH in Uveal Melanoma: Variability in Techniques and Results

Tumor monosomy 3 confers a poor prognosis in patients with uveal melanoma. We critically review the techniques used for fluorescence in situ hybridization (FISH) detection of monosomy 3 in order to assess variability in practice patterns and to explain differences in results. Significant variability that has likely affected reported results was found in tissue sampling methods, selection of FISH probes, number of cells counted, and the cut-off point used to determine monosomy 3 status. Clinical parameters and specific techniques employed to report FISH results should be specified so as to allow meta-analysis of published studies. FISH-based detection of monosomy 3 in uveal melanoma has not been performed in a standardized manner, which limits conclusions regarding its clinical utility. FISH is a widely available, versatile technology, and when performed optimally has the potential to be a valuable tool for determining the prognosis of uveal melanoma.

Paraneoplastic vitelliform retinopathy: clinicopathologic correlation and review of the literature.

Traditionally, the paraneoplastic retinopathies have been classified into two groups: melanoma-associated retinopathy (MAR) and cancer-associated retinopathy. MAR occurs in individuals with metastatic cutaneous or uveal melanoma and is characterized by nyctalopia, photopsias, and variable vision loss. In most cases, the fundus is essentially normal in appearance. More recently, there have been multiple reports of a MAR-like retinopathy with associated detachments of the retinal pigment epithelium and neurosensory retina. Such a clinical presentation has been termed paraneoplastic vitelliform retinopathy. We describe an 80-year-old man with metastatic cutaneous melanoma who developed paraneoplastic vitelliform retinopathy. For the first time, histopathology from enucleation specimens provides a clinicopathologic disease correlation with focal abnormalities in the inner nuclear and outer plexiform layers.

Ocular Adnexal Lymphoma: Staging and Treatment

A definitive diagnosis of ocular adnexal lymphoma (OAL) is based upon biopsy as benign conditions including reactive lymphoid hyperplasia cannot be differentiated based on clinical grounds alone. Once the diagnosis has been established, OAL is classified and staging is performed. OAL can coexist with lymphoma in other systemic sites in 15–25 % of cases. For this reason, a multidisciplinary approach is necessary and includes a thorough systemic evaluation and referral to an experienced medical oncologist.

Management of radiation maculopathy.

Radiation maculopathy is a delayed onset complication of radiation exposure. Various host and radiation parameters determine the risk of developing radiation maculopathy, which may be progressive. Total radiation dose delivered to the macula is the most important modifiable factor. Radiation maculopathy is not a singular entity as clinical manifestations reflect combined effects of all damaged tissues. Current treatment using anti-vascular endothelial growth factor agents offers only a short-term, temporary, and modest visual improvement. Avoidance or prevention of radiation maculopathy may be the best option. Use of periocular steroid during plaque brachytherapy may prevent radiation maculopathy over the short term. Newer designs and techniques of delivering radiation to the eye need to be explored.

Autoantibody against transient receptor potential M1 cation channels of retinal ON bipolar cells in paraneoplastic vitelliform retinopathy.

BackgroundParaneoplastic retinopathy is caused by the cross-reaction of neoplasm-directed autoantibodies against retinal antigens and results in retinal damage. Paraneoplastic vitelliform retinopathy, a presumed paraneoplastic retinopathy with features of atypical melanoma-associated retinopathy, has recently been reported in patients with metastatic melanoma. Ocular ultrastructure and its autoantibody localization of paraneoplastic vitelliform retinopathy are still indefinable. This is the first report of anti-transient receptor potential M1 antibody directly against human retinal bipolar dendritic tips in a melanoma patient with paraneoplastic vitelliform retinopathy.Case presentationWe present a pair of postmortem eyes of an 80-year-old male with metastatic cutaneous melanoma, who developed paraneoplastic vitelliform retinopathy. The autopsied eyes were examined with light microscopy, immunohistochemistry, and transmission electron microscopy. Microscopically, the inner nuclear layer and outer plexiform layer were the most affected retinal structures, with local thinning. The lesions extended to the outer nuclear layer, resulting in focal retinal degeneration, edema, and atrophy. No active inflammation or melanoma cells were observed. Immunohistochemistry showed tightly compact bipolar cell nuclei (protein kinase C alpha/calbindin positive) with blur/loss of ON bipolar cell dendritic tips (transient receptor potential M1 positive) in diffusely condensed outer plexiform layer. The metastatic melanoma cells in his lung also showed immunoreactivity against transient receptor potential M1 antibody. Transmission electron microscopy illustrated degenerated inner nuclear layer with disintegration of cells and loss of cytoplasmic organelles. These cells contained many lysosomal and autophagous bodies and damaged mitochondria. Their nuclei appeared pyknotic and fragmentary. The synapses in the outer plexiform layer were extensively degenerated and replaced with empty vacuoles and disintegrated organelles.ConclusionThis case provides a convincing histological evidence of melanoma-associated autoantibodies directly against transient receptor potential M1 channels that target the ON bipolar cell structures in the inner nuclear and outer plexiform layers in paraneoplastic vitelliform retinopathy.