Devron H. Char

PRIMARY INTRAOCULAR LYMPHOMA (OCULAR RETICULUM CELL SARCOMA) DIAGNOSIS AND MANAGEMENT

The authors retrospectively reviewed the diagnosis and management of 20 intraocular lymphoma patients who initially presented with either ocular or central nervous system (CNS) disease. As the ophthalmic community has become more aware of this entity, the interval between symptoms and diagnosis has significantly shortened. Diagnosis can usually be made on cytopathologic examination of vitreous cells. However, in three cases more than one vitreous biopsy was necessary. Results of cytologic examination appeared to be more accurate than those of conventional lymphocyte surface marker studies in the diagnosis of an intraocular lymphoma. Long-term survival occurred in some patients treated with a combination of intrathecal chemotherapy and ocular/CNS irradiation.

Helium ions versus iodine 125 brachytherapy in the management of uveal melanoma : a prospective, randomized, dynamically balanced trial

PURPOSE Optimal radiation therapy for uveal melanoma is uncertain, and the relative efficacies of radioactive plaques and charged particles are unclear. METHODS The authors prospectively studied helium-ion irradiation and iodine 125 (125I) brachytherapy in a randomized, dynamically balanced trial. Of the 184 patients who met the eligibility criteria, 86 were treated with helium ions and 98 with 125I brachytherapy. RESULTS No patients with uveal melanoma had a history of systemic malignancy. Tumors were less than 15 mm in maximum diameter and less than 10 mm in thickness. A minimum tumor dose of 70 GyE was delivered to the tumor apex. There was a significantly higher local recurrence rate after 125I brachytherapy than after helium-ion irradiation. Enucleations occurred more frequently after brachytherapy (relative risk = 1.99; 95% confidence interval, 0.78-5.78). More anterior segment complications occurred after helium-ion irradiation. To date, there has been no measurable impact on survival. CONCLUSIONS Most uveal melanomas can be managed with radiation with retention of the eye. There was better tumor control with helium-ion irradiation; however, there were more anterior segment complications.

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.

Intraepithelial and invasive squamous cell carcinoma of the conjunctiva: analysis of 60 cases

AIM To evaluate the clinical features, treatment results, and recurrence rates in patients with either intraepithelial or invasive squamous cell carcinoma of the conjunctiva. METHODS Retrospective analysis of 60 cases (22 conjunctival intraepithelial and 38 invasive squamous cell carcinomas) to determine patterns of clinical presentation, aetiological factors, and treatment results. The mean patient age was 64 years old. 70% of the patients were male. Patients were treated with a variety of therapies, depending on the degree of tumour involvement; most cases were treated with frozen section controlled excision and adjunctive cryotherapy. Modified eye wall resection or enucleation was done for intraocular invasion and exenteration was done for orbital involvement. RESULTS Red eye (68%) and ocular irritation (57%) were the most common presenting symptoms. 44% of the patients had other eye findings consistent with extensive solar exposure. 20% of the patients had a history of malignant skin tumours. Visceral malignancies developed in 8%. Scleral involvement was present in 14 (37%), intraocular involvement in five (13%), and orbital invasion in four (11%) cases with invasive squamous cell carcinoma. After a mean follow up of 56 months (18–226 months) the rate of new or recurrent tumours was 4.5% for intraepithelial squamous carcinoma and 5.3% for invasive squamous cell carcinoma. No patient developed metastases or tumour related deaths. CONCLUSION Excision with intraoperative control of the surgical margins and adjunctive cryotherapy results in good tumour control rates.

Orbital metastases: diagnosis and course

AIMS Three issues were investigated in adult outpatients with orbital metastases. One, how accurate are current diagnostic methods? Two, what is the survival associated with orbital metastases? Three, did any clinical factors correlate with prognosis in this patient cohort? METHODS Retrospective analysis of patients with orbital metastases managed in an ocular oncology unit. RESULTS 11 of 31 (35%) patients had no known primary malignancy at the time of orbital diagnosis. In eight of 31 (26%) computed tomography and/or magnetic resonance imaging data did not yield the diagnosis of metastases. In 15 of 17 (88%) cases a fine needle aspiration biopsy was diagnostic. Several types of therapy were used. The median survival was 1.3 years. CONCLUSION Orbital metastases, even with newer diagnostic techniques can be difficult to diagnose. Management was based on location and extent of both orbital and systemic disease as well as vision. In most cases, orbital symptoms were palliated; however, survival was dismal. No clinical factor correlated with prognosis.

Vogt-Koyanagi-Harada Syndrome

We studied 51 patients who developed Vogt-Koyanagi-Harada (V-K-H) syndrome after corticosteroid therapy. The final visual acuity was better than 6/15 (20/50) in 50%, and less than 6/60 (20/200) in 25% of the patients. The severity and extraocular manifestations of this disease also appeared to be less than observed in patients before the clinical use of corticosteroids. Corticosteroid therapy probably altered the clinical picture in this disease, although other possibilities, including a skewed patient population, may account for these differences.

The role of radiation therapy in the management of ocular reticulum cell sarcoma.

Nine patients with ocular lymphomas were seen in the Department of Ophthalmology and the Division of Radiation Oncology at UCSF and Ralph K. Davies Medical Center, San Francisco, from 1978 through 1974. Six of the 9 patients had visual symptoms as the first manifestation of their disease. Eight of the 9 patients developed intracranial lymphoma at some time during the course of the disease. Despite lymphoma work‐up including bone marrow biopsies and lymphangiogram, only 1 patient was found to have documented systemic involvement. The diagnosis of ocular lymphoma was based on pathologic material from the eye in 5 cases or from central nervous system biopsy in 4 patients in association with tumor cell infiltrates in the retina and vitreous clouding. Radiation therapy to the eyes improved vision in 10 of 13 eyes treated in 8 patients. The usual dose was in the range of 3500 to 4500 rads given over 4–5 weeks. In addition, 7 patients received central nervous system irradiation. Review of the literature reinforced the findings of this series showing the frequent association of ocular lymphoma with intracranial lymphoma and the rare systemic dissemination. This disease process has previously been referred to as ocular reticulum cell sarcoma. Cancer 45:688‐692, 1980.

Metastatic Choroidal Melanoma

We studied the metastatic pattern of 41 patients initially referred with a primary choroidal melanoma who later developed widespread disease. In the order of frequency, the most common sites of metastatic involvement were the liver (56%), subcutaneous tissue (36.5%), and bone (7%). Whereas the median interval between enucleation and the onset of metastatic disease was approximately four years, in rare cases, metastases were diagnosed concurrently with a primary choroidal melanoma. Since patients with choroidal melanomas usually survive less than one year after the development of widespread disease, a metastatic examination should be done in all patients with pigmented choroidal tumors both before and after ocular therapy. From the data obtained in this and other studies on metastatic melanoma, a reasonable basic metastatic examination for choroidal melanoma patients should include a serum lactic dehydrogenase, a serum alkaline phosphatase, a routine chest X-ray, and a general physical examination.

Transcriptomic versus Chromosomal Prognostic Markers and Clinical Outcome in Uveal Melanoma

Purpose: To compare a gene expression–based classifier versus the standard genetic prognostic marker, monosomy 3, for predicting metastasis in uveal melanoma. Experimental Design: Gene expression profiling, fluorescence in situ hybridization (FISH), and array comparative genomic hybridization (aCGH) were done on 67 primary uveal melanomas. Clinical and pathologic prognostic factors were also assessed. Variables were analyzed by Cox proportional hazards, Kaplan-Meier analysis, sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios. Results: The gene expression–based molecular classifier assigned 27 tumors to class 1 (low risk) and 25 tumors to class 2 (high risk). By Cox univariate proportional hazards, class 2 signature (P = 0.0001), advanced patient age (P = 0.01), and scleral invasion (P = 0.007) were the only variables significantly associated with metastasis. Only the class 2 signature was needed to optimize predictive accuracy in a Cox multivariate model. A less significant association with metastasis was observed for monosomy 3 detected by aCGH (P = 0.076) and FISH (P = 0.127). The sensitivity and specificity for the molecular classifier (84.6% and 92.9%, respectively) were superior to monosomy 3 detected by aCGH (58.3% and 85.7%, respectively) and FISH (50.0% and 72.7%, respectively). Positive and negative predictive values (91.7% and 86.7%, respectively) and positive and negative likelihood ratios (11.9 and 0.2, respectively) for the molecular classifier were also superior to those for monosomy 3. Conclusions: Molecular classification based on gene expression profiling of the primary tumor was superior to monosomy 3 and clinicopathologic prognostic factors for predicting metastasis in uveal melanoma.

15 years experience with helium ion radiotherapy for uveal melanoma

PURPOSE To review the long-term experience of helium ion therapy as a therapeutic alternative to enucleation for uveal melanoma, particularly with respect to survival, local control, and morbidity. METHODS AND MATERIALS 347 patients with uveal melanoma were treated with helium ion RT from 1978-1992. A nonrandomized dose-searching study was undertaken, with doses progressively reduced from 80 GyE in five fractions to 48 GyE in four fractions, given in 3-15 days, mean of 7 days. RESULTS Local control was achieved in 96% of patients, with no difference in the rate of local control being seen at 80, 70, 60, or 50 GyE in five fractions. At the lowest dose level of 48 GyE in four fractions, the local control rate fell to 87%. Fifteen of 347 patients (4%) had local regrowth in the eye requiring enucleation (12 patients), laser (1 patient) or reirradiation (2 patients). The time of appearance of local regrowth ranged from 4 months to 5 years posttreatment, with 85% occurring within 3 years. Of the 347 patients, 208 are alive as of May 1, 1997. The median follow up of all patients is 8.5 years, range 1-17 years. Kaplan-Maier (K-M) survival is 80% at 5 years, 76% at 10 years, and 72% at 15 years posttreatment. Patients with tumors not involving the ciliary body have a 15-year K-M survival of 80%. The results for patients whose tumors involved the ciliary body are poor, with a 15-year K-M survival of 43%. Seventy-five percent of patients with tumors at least 3.0 mm from the fovea and optic nerve, and initial ultrasound height less than 6.0 mm, retained vision of 20/200 or better posttreatment. Patients with tumors larger than 6 mm in thickness, or with tumors lying close to the optic nerve or fovea, have a reduced chance of retaining useful vision. The enucleation rate is 19%, 3% for local failure and 16% because of complications of the helium RT, particularly neovascular glaucoma, which occurred in 35% of patients. CONCLUSIONS Local control and retention of the eye are excellent. Complications of therapy reduce vision and eye preservation. Twenty-four percent of patients manifested distant metastases 6 to 146 months posttreatment, mean of 43 months, median of 36 months. Late-appearing distant metastases do not appear to be caused by persistent tumor in the eye. The risk of metastases is high for patients with tumors greater than 7 mm in initial ultrasound height (37%), anterior tumors involving the ciliary body (47%), and in those with local failure (53%). Patients with tumors not involving the ciliary body and initial dimensions less than 10 mm had only an 8% chance of death from melanoma. A search for effective adjuvant therapy is needed for patients at high risk of metastases (large tumors, ciliary body involved, local regrowth in eye).