Hugh McGowan

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.

Ultrasound Biomicroscopy of Anterior Segment Tumors

BACKGROUND Ultrasound biomicroscopy is a new method of imaging the anterior segment of the eye at microscopic resolution using high frequency ultrasound. METHODS A prospective study was performed to evaluate the use of ultrasound biomicroscopy in imaging anterior segment tumors. Forty-five patients underwent clinical examination followed by slit-lamp photography, anterior segment B-scan ultrasonography, and ultrasound biomicroscopy according to an established protocol. RESULTS All lesions were clearly imaged by ultrasound biomicroscopy, while only 17 were detectable by conventional B-scan ultrasound. Ultrasound biomicroscopy allowed precise measurement and visualization of subsurface features in small tumors. Differentiation between solid and cystic lesions was easily achieved. The margins of ciliary body tumors could be more accurately defined. Histopathologic correlation was possible in four cases managed surgically. Ultrasound biomicroscopy images compared favorably with low-power microscopy. No complications were encountered. CONCLUSION Ultrasound biomicroscopy proved a valuable new noninvasive technique in the evaluation of anterior segment tumors.

Stereotactic Radiotherapy for Treatment of Juxtapapillary Choroidal Melanoma: 3-Year Follow-up.

Aims: To report the treatment outcomes and complication rates of stereotactic radiotherapy in the management of patients with juxtapapillary choroidal melanoma. Methods: A retrospective review of 64 consecutive patients with juxtapapillary choroidal melanoma, located within 2 mm of the optic disc, treated with stereotactic radiotherapy at Princess Margaret Hospital between October 1998 and January 2006. Results: The median age was 63 years. The median tumour height was 4.2 mm, and median largest basal diameter was 9.8 mm. The prescribed radiation dose was 70 Gy in five fractions over 10 days, and the median follow-up was 37 months. Post-treatment, the actuarial rates of local tumour control, metastases and survival at 37 months were 94%, 15% and 90%, respectively. Actuarial rates of radiation-induced complications at 37 months were neovascular glaucoma 42%, cataract 53%, retinopathy 81% and optic neuropathy 64%. Secondary enucleation was necessary for 10 patients (16%), in four patients for tumour recurrence and in six for painful neovascular glaucoma. Conclusions: Stereotactic radiotherapy offers a non-invasive alternative to enucleation and brachytherapy in the management of juxtapapillary choroidal melanoma with a high tumour control rate, however, at the expense of a significant rate of long-term ocular complications.

Ultrasound determination of the relationship of radioactive plaques to the base of choroidal melanomas

There is an assumption that radioactive plaques placed at surgery are, and will remain, in proper relationship to the base of the tumor. The plaque dose is calculated based on this assumption. In fact, factors such as loose sutures, improper diameter estimations, pressure from adjacent rectus muscles, and intervening tissue (oblique muscles) can compromise this relationship. Ultrasound provides a practical method of imaging the tumor and plaque simultaneously. The authors have used postoperative ultrasound to monitor the accuracy of iodine-125 plaque placement in nine cases. Detection of eccentrically placed and malpositioned plaques provides valuable insight which can be used to refine surgical technique. Detection of plaque tilting by oblique muscles can serve as a basis for recalculating dosage. The relationship of plaque margins to vital ocular structures such as the optic nerve can also be determined by ultrasound.

Neovascular Glaucoma After Stereotactic Radiotherapy for Juxtapapillary Choroidal Melanoma: Histopathologic and Dosimetric Findings

PURPOSE Enucleation after stereotactic radiotherapy (SRT) for juxtapapillary choroidal melanoma may be required because of tumor progression (TP) or the development of intractable radiation-induced neovascular glaucoma (NVG). We compare pathologic changes and dosimetric findings in those eyes enucleated secondary to NVG as opposed to TP to better understand potential mechanisms. METHODS AND MATERIALS Patients with juxtapapillary choroidal melanoma treated with SRT (70 Gy in 5 fractions, alternate days over a total of 10 days) at the Princess Margaret Hospital, Toronto, Ontario, Canada, who underwent enucleation between 1998 and 2006 were selected. We correlated dosimetric data based on the patients original SRT treatment plan with histopathologic findings in the retina, optic nerve head, and anterior chamber. A dedicated ocular pathologist reviewed each case in a blinded fashion. RESULTS Ten eyes in ten patients were enucleated after SRT. Six were enucleated secondary to NVG and four secondary to because of TP. Aggressive tumor features such as invasion of the sclera and epithelioid cell type were observed predominantly in the TP group. Retinal damage was more predominant in the NVG group, as were findings of radiation-related retinal vascular changes of fibrinoid necrosis and hyalinization. No conclusive radiation-related effects were found in the anterior chamber. The maximum point dose and dose to 0.1 cc were lower for the anterior chamber as compared with the dose to the tumor, retina, and optic nerve head. The mean 0.1-cc doses to the retina were 69.4 Gy and 73.5 Gy and to the anterior chamber were 4.9 Gy and 17.3 Gy for the NVG group and tumor progression group, respectively. CONCLUSIONS Our findings suggest that NVG is due to radiation damage to the posterior chamber of the eye rather than primary radiation damage to the anterior segment.

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.

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.

Extrascleral extension in association with ciliochoroidal melanoma: ultrasound biomicroscopy with histopathological correlation

CASE REPORT We present the case of a 71-year-old man with a melanoma arising from the ciliary body and extending into the choroid. Ultrasound biomicroscopy (UBM) revealed connection via an emissary canal to a subconjunctival nodule. Although evaluation for metastasis was negative at the time of diagnosis, multiple hepatic metastatic deposits were found 2 years post-enucleation. COMMENTS It is crucial to identify the presence of scleral invasion and extrascleral extension for proper management planning in patients with choroidal melanomas. This case demonstrates that UBM is an accurate and useful tool for characterizing the morphologic pattern of scleral invasion of intraocular tumours.

Clinical and ultrasound biomicroscopy features associated with growth in iris melanocytic lesions.

PURPOSE To determine the clinical and ultrasound biomicroscopy (UBM) features associated with growth in iris melanocytic lesions. STUDY DESIGN Retrospective case series analysis. METHODS We included all iris melanocytic lesions that were monitored between January 2005 and November 2009. At the end of the analysis, 44 eyes of 44 patients were included in the final analysis. The clinical features analyzed were: iris color, largest base diameter, radial location of the lesion epicenter, circumferential location of the lesion epicenter, lesion configuration, lesion pigmentation, intrinsic vascularity within the lesion, presence of associated pigmentation, the impact on the pupil, presence of iris atrophy, and lesion-induced localized cataracts. The UBM features included lesion thickness, presence of corneal touch, presence of surface plaque, internal structure, and internal reflectivity. Regression analysis was performed to define the features associated with growth. RESULTS Twenty-three percent of the lesions showed documented growth. Mean follow-up was 21.4 months (range: 10-48). Clinical features associated with growth were a large basal diameter at baseline (P = .004) and inferior location (P = .004). UBM features associated with growth were: a greater baseline thickness (P = .01), presence of corneal touch (P = .007), an irregular internal structure (P = .0001), and the presence of dots and linear streaks (P < .0001). Clinical features that were not associated with growth were the radial location of the lesion in the iris (P > .999), lesion configuration (P > .999), lesion pigmentation (P > .999), the presence of pigment dispersion (P = .70), iris freckles (P = .15), corectopia (P > .999), ectropion (P > .999), and intrinsic vascularity (P = .70). UBM features not associated with growth were the presence of a surface plaque (P = .07) and the internal reflectivity (P = .77). CONCLUSION Substantial growth in iris melanocytic lesions is associated with original larger basal diameter and inferior lesion location. On UBM growth is associated with greater original thickness, presence of corneal touch, and an irregular internal structure. Presence of these features could modify the frequency of observation of those lesions.