Faculty Bibliography

PURPOSE: To investigate the value of whole-body positron emission tomography/computed tomography (PET/CT) as a screening tool for patients with uveal metastasis. DESIGN: Retrospective observational case series. METHODS: setting: Clinical practice. study population: Eighteen patients with uveal metastatic tumors were evaluated. Patients had no history of malignancy or a past medical history of malignancy without known active metastasis or known systemic cancer. intervention: Whole-body PET/CT was used as a screening tool to evaluate the intraocular tumor, to evaluate for multi-organ metastatic disease, and for cancer staging. main outcome measures: Detection and PET/CT uptake of primary tumors and metastatic disease. RESULTS: PET/CT imaging uncovered previously occult primary nonocular cancers (11/18, 61%), revealed progression of known primary systemic cancer (7/18, 39%), and confirmed multi-organ metastases in all cases (18/18, 100%). PET/CT findings were used to direct nonocular, confirmatory biopsy in 67% of cases (12/18). No uveal biopsies were required. PET/CT revealed lymph nodes and bone as the most common metastatic sites. The intraocular tumor was detectable in 28% of cases. Small, non-avid tumors and those within the hypermetabolic, PET-avid brain were falsely negative. CONCLUSION: This study suggests that whole-body PET/CT can be useful for clinical evaluation of patients with uveal metastases. It allowed for screening of the entire body and directed extraocular biopsy. Commonly used for tumor staging, PET/CT aided in the detection of the primary cancer in patients with metastatic uveal tumors.

Retinoinvasive uveal melanoma demonstrates prominent diffuse retinal and optic nerve invasion, with little or no involvement of the adjacent choroid. Prior studies have advanced hypotheses on the potential role of molecular and cellular interactions in the pathogenesis of retinoinvasiveness and neuroinvasiveness, but the precise molecular events are not known. Here, we investigate the role of neutrotrophic factors in the pathogenesis of retinoinvasive uveal melanoma. The records of three ophthalmic pathology departments (The New York Eye and Ear Infirmary, Wills Eye Institute, and University of California San Francisco) were searched to identify all cases of retinoinvasive uveal melanoma, yielding four eyes (all previously irradiated). Eight eyes with nonretinoinvasive melanomas (four irradiated and four nonirradiated) were randomly selected as controls. All enucleated eyes were examined histopathologically and immunohistochemically for the expression of neurotrophic factor receptors [Pan-Trk, p75 neurotrophin receptor (p75(NTR) and ciliary neurotrophic factor receptor-alpha]. Histopathologic features were similar in both retinoinvasive and control melanomas with regard to choroidal tumor location and size, neovascular glaucoma, and cell type. The eyes with retinoinvasive melanoma showed diffuse retinal invasion beyond the choroidal tumor (n=4) and prelaminar (n=1) and retrolaminar (n=2) optic nerve invasion. The control melanomas showed focal retinal invasion over the tumor apices (n=6) and prelaminar optic nerve invasion (n=1). Nonirradiated melanomas demonstrated no trace immunoreactivity for neurotrophic factor receptors, whereas irradiated melanomas showed more prominent (trace to moderate) immunoreactivity. When controlled for irradiation, no difference in immunoreactivity for neurotrophin receptors nor tumor duration was observed between retinoinvasive and nonretinoinvasive melanomas. This study failed to demonstrate a direct causation between the expression of neurotrophin receptors and a retinoinvasive uveal melanoma growth pattern.

PURPOSE: To test the safety, tolerability, and efficacy of subconjunctival ranibizumab (Lucentis [Genentech, Inc.]) for squamous cell carcinoma of the conjunctiva and cornea. METHODS: Five patients with recurrent squamous cell carcinoma of the conjunctiva and cornea enrolled in this nonrandomized, single center, phase I pilot study as an alternative to radiation or exenteration. Subconjunctival ranibizumab (0.5 mg) was given on a monthly or twice monthly basis. Patients were examined for safety, tolerability, and efficacy using visual acuity, blood pressure, urinalysis, comparative slit lamp biomicroscopy with photography, and high frequency ultrasound imaging. RESULTS: Five male patients with biopsy-proven squamous conjunctival carcinoma were found to have recurrent disease. Each patient had been initially treated with combinations of primary excision (n = 1) or excision and cryotherapy (n = 4), and all (n = 5) had failed separate courses of both topical interferon a and mitomycin 0.02%. Tumors were multifocal and involved between 8 and 12 clock hours of the limbus. A median of 22 injections (range 12-27) was given over a mean 19 months (range 6-24). Three patients had a complete response (no clinically apparent disease) during the 2-year study, while 2 failed treatment despite demonstrating an initial partial response. Treatment was well-tolerated, as 4 patients demonstrated stable or improved visual acuity, and none had significant systemic or ocular side effects. CONCLUSIONS: This 2-year study demonstrated that subconjunctival ranibizumab induced regression of squamous cell carcinoma of the conjunctiva and cornea. Therefore, antivascular endothelial growth factor chemotherapy may offer a new strategy, complement excision and cryotherapy, or provide an alternative to radiation and/or exenteration. Further, larger investigations utilizing a larger group of patients are needed to determine the ideal dose, route of drug delivery, and case selection.

Purpose. To report on whole body positron emission tomography/computed tomography (PET/CT) screening for metastasis at diagnosis of primary uveal melanoma. Methods. Since August 2003, 333 consecutive patients were diagnosed with uveal melanoma and underwent whole body screening for metastatic disease with PET/CT along with liver function tests and physical examination. Abnormal findings prompted further biopsies, blood tests, imaging, or clinical evaluations for confirmation. The presence of metastatic disease and second cancers were evaluated. Results. Using the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) 7th edition criteria, 104 tumors were classified T1 (31%), 162 T2 (49%), 37 T3 (11%), and 30 T4 (9%). Seven of 333 (2.1%; 95% confidence interval [CI] 0.8-4.3) patients had metastatic melanoma. One tumor was a T3 and 6 were T4. Thus, 3% of T3 and 20% of T4 melanomas were found to have metastases at the time of initial diagnosis. Ten patients (3.3%; 95% CI 0.9-5.5) had synchronous second cancers and 28 (8.4%) concurrent benign lesions. The most common metastatic sites were liver (7/7) and bone (2/7). Discussion. This study suggests that PET/CT improves the yield of detecting both extrahepatic metastases, especially from tumors defined as AJCC-T4, and synchronous primary cancers, irrespective of the size of the uveal melanoma. With respect to liver metastases, PET/CT demonstrated high sensitivity and positive predictive values, indicating an overall better performance than conventional screening procedures

PURPOSE: To evaluate the intravitreal antivascular endothelial growth factor, bevacizumab, for treatment of radiation optic neuropathy (RON). METHODS AND MATERIALS: A prospective interventional clinical case series was performed of 14 patients with RON related to plaque radiotherapy for choroidal melanoma. The RON was characterized by optic disc edema, hemorrhages, microangiopathy, and neovascularization. The entry criteria included a subjective or objective loss of vision, coupled with findings of RON. The study subjects received a minimum of two initial injections of intravitreal bevacizumab (1.25 mg in 0.05 mL) every 6-8 weeks. The primary objectives included safety and tolerability. The secondary objectives included the efficacy as measured using the Early Treatment Diabetic Retinopathy Study chart for visual acuity, fundus photography, angiography, and optical coherence tomography/scanning laser ophthalmoscopy. RESULTS: Reductions in optic disc hemorrhage and edema were noted in all patients. The visual acuity was stable or improved in 9 (64%) of the 14 patients. Of the 5 patients who had lost vision, 2 had relatively large posterior tumors, 1 had had the vision decrease because of intraocular hemorrhage, and 1 had developed optic atrophy. The fifth patient who lost vision was noncompliant. No treatment-related ocular or systemic side effects were observed. CONCLUSIONS: Intravitreal antivascular endothelial growth factor bevacizumab was tolerated and generally associated with improved vision, reduced papillary hemorrhage, and resolution of optic disc edema. Persistent optic disc neovascularization and fluorescein angiographic leakage were invariably noted. The results of the present study support additional evaluation of antivascular endothelial growth factor medications as treatment of RON

OBJECTIVE: To evaluate clinical and histopathologic factors of squamous conjunctival neoplasia associated with recurrence. DESIGN: Retrospective, clinical case series. PARTICIPANTS: One hundred one eyes of 99 patients with squamous conjunctival dysplasia, carcinoma in situ, or squamous cell carcinoma. METHODS: Review of the medical records, pathology reports, and color photographs. MAIN OUTCOME MEASURES: Demographic information, laterality, tumor size, extension, pathologic diagnosis, seventh edition of the American Joint Committee on Cancer Classification (AJCC) staging system stage, treatment methods, recurrence, and duration of follow-up. RESULTS: Malignant squamous conjunctival neoplasia was seen most commonly in males at a median age of 71 years. Recurrences were seen in 12.9% (n = 13/101), with 92.3% occurring 6 to 12 months after primary treatment. Recurrence was not correlated significantly to age, gender, laterality, clinical appearance or focality of the tumor at presentation. However, tumors larger than 5 mm in diameter, tumors extending more than 2 mm onto the cornea, and tumors with local invasion (corneal, scleral, intraocular or orbital invasion) were associated with a higher risk of recurrence. Increasing AJCC T-stage was correlated strongly to the incidence of recurrence (P = 0.0006). Rates were 1.7% for Tis-staged tumors, 0% for T1- and T2-staged tumors, 34.3% for T3-staged tumors, and 50% for T4-staged tumors. Histopathologic diagnosis was correlated to recurrence (P = 0.037). None of the tumors defined histologically as dysplasia showed recurrence, whereas 12.8% of carcinoma in situ tumors and 22.2% of squamous cell carcinoma tumors recurred. Although the overall recurrence rate was 12.9%, the rate for tumors treated primarily at the authors' center was 4%, significantly less than the recurrence rate in previously operated tumors (P = 0.0003). Lymph nodes demonstrated positive results in 1%, and in no patient did distant metastasis develop. CONCLUSIONS: Advanced AJCC T-stage, locally invasive tumors, and more pathologically aggressive tumors were at higher risk for recurrence. Inadequate initial therapy also was an important risk factor for recurrence. Treatment strategies should be affected by tumor staging at presentation. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

OBJECTIVE: To evaluate slotted eye plaque radiation therapy for choroidal melanomas near the optic disc. DESIGN: A clinical case series. PARTICIPANTS: Twenty-four consecutive patients with uveal melanomas that were near, touching, or surrounding the optic disc. INTERVENTION: Slotted eye plaque radiation therapy. MAIN OUTCOME MEASURES: Recorded characteristics were related to patient, clinical, and ophthalmic imaging. Data included change in visual acuity, tumor size, recurrence, eye retention, and metastasis. RESULTS: From 2005 to 2010, 24 consecutive patients were treated with custom-sized plaques with 8-mm-wide, variable-depth slots. Radiation doses ranged from 69.3 to 163.8 Gy (mean, 85.0 Gy) based on delivering a minimum tumor dose of 85 Gy. All treatments were continuously delivered over 5 to 7 days. Mean patient age at presentation was 57 years. Tumors were within 1.5 mm of the optic nerve (n = 3, 13%), juxtapapillary (n = 6, 25%), touching >/=180 degrees (n = 7, 29%), or circumpapillary (n = 8, 33%). Ultrasound revealed dome-shaped tumors in 79% of patients, collar-button tumors in 17% of patients, irregular tumor in 1 patient (4%), and intraneural invasion in 2 patients. Mean initial largest basal dimension was 11.0 mm (standard deviation [SD] +/- 3.5 mm; median, 11.4 mm; range, 5.9-16.4 mm). Mean initial tumor thickness was 3.5 mm (SD +/- 1.7 mm; median, 3.0 mm; range, 1.4-6.9 mm). Initial visual acuities were a median 20/25 (range, 20/20 to hand motions) and decreased to a median 20/40 (range, 20/20 to no light perception). At a mean follow-up of 23 months, 12 patients required periodic intravitreal bevacizumab to suppress radiation optic neuropathy (RON) or maculopathy. To date, there has been a 100% local control rate. No patients have required secondary enucleation for recurrence or neovascular glaucoma. No patients have developed metastasis. CONCLUSIONS: Slotted plaque radiation therapy allows peripapillary, juxtapapilary, and circumpapillary choroidal melanomas (and a safety margin) to be included in the radiation targeted zone. Normalization of the plaque position beneath the tumor appears to increase RON and improve local control.

Background/aims To assess spectral domain-optical coherence tomography (SD-OCT) contribution to choroidal osteoma characterisation. Methods A retrospective chart review of a series of patients diagnosed with choroidal osteoma, which included patient, clinical, ultrasonographic, photographic and SD-OCT imaging. Results 11 patients were included in this series. Their mean age was 42.5 years (median=43.0; range, 14-73). Using statistical analysis, the mean basal diameters of tumours as derived from fundus photographs (5.2 mm) and ultrasound images (6.4 mm) were significantly different (paired t-test, p=0.03). Tumours were SD-OCT hyporeflective in two cases, isoreflective in seven cases and hyper-reflective in two cases. Intrinsic reflectivity of the tumour was inhomogeneous in four cases. The overlying choroid was compressed by the tumour in eight cases and the retina exhibited degenerative changes in five cases. Conclusion This study revealed that SD-OCT provided deeper and higher resolution images of choroidal osteoma when compared with previous studies using time domain-OCT. These findings offer new insights into the pathophysiology and diagnosis of choroidal osteoma

A 46-year-old woman with a T4N0M0 choroidal melanoma was staged for metastatic disease with whole-body positron emission tomography/CT imaging. She underwent enucleation of the right eye and placement of a 20-mm MEDPOR spherical implant. Four months after surgery, follow-up positron emission tomography/CT imaging revealed physiologic metabolic activity in the MEDPOR implant with no evidence of orbital melanoma or chronic inflammation

OBJECTIVE: To collaborate with multiple centers to identify representative epidemiological, clinical, and pathologic characteristics of melanoma of the iris. This international, multicenter, Internet-assisted study in ophthalmic oncology demonstrates the collaboration among eye cancer specialists to stage and describe the clinical and pathologic characteristics of biopsy-proven melanoma of the iris. METHODS: A computer program was created to allow for Internet-assisted multicenter, privacy-protected, online data entry. Eight eye cancer centers in 6 countries performed retrospective chart reviews. Statistical analysis included patient and tumor characteristics, ocular and angle abnormalities, management, histopathology, and outcomes. RESULTS: A total of 131 patients with iris melanoma (mean age, 64 years [range, 20-100 years]) were found to have blue-gray (62.2%), green-hazel (29.1%), or brown (8.7%) irides. Iris melanoma color was brown (65.6%), amelanotic (9.9%), and multicolored (6.9%). A mean of 2.5 clock hours of iris was visibly involved with melanoma, typically centered at the 6-o'clock meridian. Presentations included iritis, glaucoma, hyphema, and sector cataract. High-frequency ultrasonography revealed a largest mean tumor diameter of 4.9 mm, a mean maximum tumor thickness of 1.9 mm, angle blunting (52%), iris root disinsertion (9%), and posterior iris pigment epithelium displacement (9%). Using the American Joint Commission on Cancer-International Union Against Cancer classification, we identified 56% of tumors as T1, 34% of tumors as T2, 2% of tumors as T3, and 1% of tumors as T4. Histopathologic grades were G1-spindle (54%), G2-mixed (28%), G3-epithelioid (5%), and undetermined (13%) cell types. Primary treatment involved radiation (26%) and surgery (64%). Kaplan-Meier analysis found a 10.7% risk of metastatic melanoma at 5 years. CONCLUSIONS: Iris melanomas were most likely to be brown and found in the inferior quadrants of patients with light irides. Typically small and unifocal, melanomas are commonly associated with angle blunting and spindle cell histopathology. This multicenter, Internet-based, international study successfully pooled data and extracted information on biopsy-proven melanoma of the iris