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Background: In uveal melanomas, immune infiltration is a marker of poor prognosis. This work intended to decipher the biological characteristics of intra-tumor immune population, compare it to other established biomarkers and to patients' outcome., Methods: Primary, untreated, and mainly large uveal melanomas with retinal detachment were analyzed using: transcriptomic profiling (n = 15), RT-qPCR (n = 36), immunohistochemistry (n = 89), Multiplex Ligation-dependent Probe Amplification (MLPA) for copy number alterations (CNA) analysis (n = 89), array-CGH (n = 17), and survival statistics (n = 86)., Results: Gene expression analysis divided uveal melanomas into two groups, according to the IFNγ/STAT1-IRF1 pathway activation. Tumors with IFNγ-signature had poorer prognosis and showed increased infiltration of CD8 + T lymphocytes and macrophages. Cox multivariate analyses of immune cell infiltration with MLPA data delineated better prognostic value for three prognostic groups (three-tier stratification) than two (two-tier stratification). CNA-based model comprising monosomy 3, 8q amplification, and LZTS1and NBL1 deletions emerged as the best predictor for disease-free survival. It outperformed immune cell infiltration in receiver operating characteristic curves. The model that combined CNA and immune infiltration defined risk-groups according to the number of DNA alterations. Immune cell infiltration was increased in the high-risk group (73.7%), where it did not correlate with patient survival, while it was associated with poorer outcome in the intermediate risk-group., Conclusions: High degree of immune cell infiltration occurs in a subset of uveal melanomas, is interferon-gamma-related, and associated with poor survival. It allows for two-tier stratification, which is prognostically less efficient than a three-tier one. The best prognostic stratification is by CNA model with three risk-groups where immune cell infiltration impacts only some subgroups., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: To report a case of primary orbital melanoma successfully managed by custom-designed iodine-125 plaque., Design: Case report., Methods: A 59-year-old man with no systemic or secondary melanocytic tumor was diagnosed with primary orbital melanoma after transconjunctival incisional biopsy. He was treated with unshielded iodine-125 plaque (90 Gy) that was sutured to the sclera. The radiation plan was calculated to safely target the initial tumor volume and any residual intrascleral or loose orbital melanoma cells that could have been disseminated to the surrounding orbital tissues during incisional biopsy., Results: After 66 months' follow-up, the patient was still alive with partial remission of his liver metastases. Routine orbital magnetic resonance imaging studies confirmed the lack of orbital recurrence., Conclusions: Plaque radiotherapy appears to be a reasonable alternative to exenteration or external irradiation for orbital melanoma after biopsy confirmation.

Objective: To determine the effect of indocyanine green (ICG) injection on the regression pattern of choroidal melanomas treated with transpupillary thermotherapy (TTT)., Design: Prospective, randomized, controlled study., Participants: Of the 60 patients with posterior pole choroidal melanoma, 30 were managed with TTT alone (control group), and 30 received adjuvant ICG before TTT., Methods: Subjects with selected choroidal melanoma were treated with TTT by using infrared radiation delivered from the diode laser. For those patients randomized to ICG administration, the start of TTT was based on the onset of fluorescence documented on ICG angiography., Main Outcome Measures: Final tumor thickness (1.5 mm) and temporal tumor thickness regression., Results: The mean initial tumor basal diameter was 7.7 mm, and tumor thickness was 2.9 mm in the TTT treatment group. Tumor dimensions were initially 7.8 mm in the base and 3.1 mm in thickness in the TTT + ICG treatment group. During a median follow-up of 30 months (range, 6-49 months), the mean tumor thickness gradually decreased to 2.3 mm at month 3 and to 1.9 mm at month 6 after the initial session in the TTT treatment group and to 2.5 mm at month 3 and 2.2 mm at month 6 in the TTT + ICG treatment group. In the TTT treatment group, the reduction of tumor thickness was 19% at month 3 and 30% at month 6. In the TTT + ICG treatment group, the reduction of tumor thickness was 22% at month 3 and 31% at month 6. There were 12 tumors (40%) in the TTT treatment group and 15 (50%) in the TTT + ICG treatment group that measured 1.5 mm in thickness, with a flat ophthalmoscopic appearance. Tumor control was achieved in 55 tumors (92%). Two patients developed tumor recurrence in the TTT treatment group, and three developed recurrence in the TTT + ICG treatment group. A smaller initial tumor thickness, more TTT sessions, and a tumor location other than temporal were statistically predictive of a final tumor thickness of 1.5 mm. There was no apparent effect of ICG administration before TTT on the final tumor thickness and temporal tumor thickness regression., Conclusions: Despite the efficacy of TTT in the management of selected choroidal melanomas, adjuvant ICG administration before each TTT session does not seem to be beneficial in their regression pattern. Further research in vivo with a larger sample of patients and longer follow-up will be necessary to determine the role of ICG in TTT for choroidal melanomas.

The management of posterior uveal melanoma has evolved tremendously for the past decades and, more recently, there is a trend toward more focal conservative treatment. Transpupillary thermotherapy (TTT) with infrared diode laser (810 nm.) is the newest modality used as primary treatment or as complementary method to radiotherapy or surgical resection in very selected cases of choroidal melanoma. Plaque radiotherapy or charged-particle irradiation is particularly recommended for medium- or small-sized uveal melanoma not suitable to TTT or resection. Special custom-designed plaque radiotherapy (iodine-125) can be used for iris, ciliary body or juxta-paillary choroidal melanoma. The tumor control rate after plaque or charged-particle radiotherapy appears to be similar, but charged-particle irradiation may produce worse anterior segment complications than plaque radiotherapy. Stereotatic radiation therapy for choroidal melanomas may be effective in controlling tumor growth but the number of patients treated with the approach is too small to draw strong conclusions. Local tumor resection using trans-scleral resection is mainly suitable for selected iris, ciliary body, or anterior choroidal melanoma, particularly with smaller basal dimensions and greater thickness. Combined therapies (radiotherapy plus TTT, tumor resection plus TTT) appears to be more effective in decreasing the incidence of intraocular tumor recurrence. Enucleation is still performed for large uveal melanoma when there is no hope for useful vision. Based on the published ophthalmic literature, it seems that enucleation carries the same survival prognosis as each of the conservative treatment modalities.

The management of posterior uveal melanoma has evolved tremendously over the past decades and more recently there has been a trend toward more focal conservative treatment. Transpupillary thermotherapy (TTT) with infrared diode laser (810nm) is the newest modality used as primary treatment or as a complement to radiotherapy or surgical resection in selected cases of choroidal melanoma. Plaque radiotherapy or charged-particle irradiation is particularly recommended for medium- or small-sized uveal melanoma not suitable to TTT or resection. Special custom-designed plaque radiotherapy (iodine-125) can be used for the iris and ciliary body, or in juxtapaillary choroidal melanoma. The tumor control rate after plaque or charged-particle radiotherapy appears to be similar but charged-particle irradiation may produce worse anterior-segment complications than plaque radiotherapy. Stereotactic radiation therapy for choroidal melanoma may be effective in controlling tumor growth, but the number of patients treated with this approach is too small to draw solid conclusions. Local tumor resection using trans-scleral resection is mainly suitable for selected iris, ciliary body, or anterior choroidal melanoma, particularly with smaller basal dimensions and greater thickness. Endoresection may preserve central vision or temporal field when radiotherapy would be expected to cause optic neuropathy. Longer follow-up is necessary to establish the efficacy of tumor control. Combined therapies (radiotherapy plus TTT or tumor resection plus TTT) appear to be more effective in decreasing the incidence of intraocular tumor recurrence. Enucleation is still performed for large uveal melanoma when there is no hope of regaining useful vision. Based on the published ophthalmology literature, it seems that enucleation carries the same survival prognosis as each of the conservative treatment modalities.

Indocyanine green angiography (ICG) is a well-known ancillary test for evaluation of choroidal tumors. The authors review the different images seen in choroidal nevus, melanoma, metastasis, hemangioma, osteoma, and vortex vein varix. ICG appears to be useful for the diagnosis of non pigmented choroidal tumors. In addition, ICG provides good information on the limits of pigmented tumors, particularly for the follow-up of a growing tumor and the choice of treatment.

Purpose: To report the results of transpupillary thermotherapy (TTT) for selected posterior pole choroïdal melanomas., Material and Methods: Prospective study including 56 patients (mean age of 61 years) with choroidal melanoma treated with TTT. All treated tumors had either documented growth or clinical risk factors for future growth and for metastasis. The injection of infracyanine green (I CG) was randomized., Results: The mean initial tumor basal diameter was 7.8 mm and tumor thickness was 3 mm. Twenty-seven tumors (48%) touched the optic disc and sixteen (29%) were under the fovea. Among these 56 patients with choroidal melanoma, 47 patients (84%) presented with primary choroidal melanoma. 9 tumors (16%) were late recurrences after conservative treatment. A mean of three treatment sessions was delivered. After a mean follow-up of 30 months, tumor regrowth was documented in 4 patients (7%) and the visual acuity was the same than the pretreatment acuity in 26 eyes (47%). The mean final thickness was 1.8 mm (percent reduction of tumor thickness was 39%). Intraocular complications included retinal fibrosis and/of retinal striae in 12 eyes (22%) and vascular occlusion in 14 eyes (25%). No statistical impact of ICG administration on the tumor regression was demonstrated., Conclusions: This series confirms the efficacy of transpupillary thermotherapy in the management of selected posterior pole choroïdal melanomas.

Purpose: To report the results of primary transpupillary thermotherapy (TTT) for selected posterior pole choroidal melanomas., Material and Methods: Prospective non randomized study including 34 patients with choroidal melanoma treated with TTT using near-infrared radiation (810 nm) delivered from the diode laser. All treated tumors had either documented growth or clinical risk factors for future growth and/or metastasis. The treatment was delivered using a specially modified infrared diode laser through a slit lamp adaptor. A contact lens was placed on the cornea to view the fundus and focus the laser beam. Treatment was initiated using a 60-second exposure and a low energy level at 300 mW with a 3.0 mm beam width. The energy was raised stepwise by 50 to 100 mW until the surface of the tumor develop a light grayish discoloration. The TTT sessions were delivered at 3-month intervals., Results: Among these 34 patients with choroidal melanoma, 29 patients presented with primary choroidal melanoma. Five tumors (15%) were late recurrences after conservative treatment. The mean initial tumor basal diameter was 7.2 mm and tumor thickness was 2.9 mm. Seventeen tumors (50%) touched the optic disc and 10 (29%) were under the fovea. After a mean of three treatment sessions and 20 months of follow-up, the mean tumor thickness gradually decreased to 2.3 mm at month 3 and 2.0 mm at month 6 after the initial TTT. The percent reduction of tumor thickness was 20% at month 3 and 29% at month 6. The mean final thickness was 1.7 mm. Treatment was successful in 33 patients (97%). Tumor regrowth was documented in one patient (3%) and required plaque radiotherapy. After treatment, visual acuity was the same or better than the pretreatment visual acuity in 21 eyes (62%) and worse in 13 eyes (38%). Intraocular complications included retinal traction in 12 eyes (34%) and vascular occlusion in 3 eyes (9%)., Conclusion: This series confirms the efficacy of transpupillary thermotherapy in the management of selected posterior pole choroidal melanomas. Longer follow-up is still required to assess late local recurrence and the impact on metastatic disease.

Purpose: The authors present the unique clinical features of cavitary uveal melanoma., Design: Retrospective chart review., Participants: Eight patients with cavitary uveal melanoma., Main Outcome Measures: The clinical, ultrasonographic, and histopathologic features of eight patients with cavitary melanoma of the ciliary body were studied., Results: In all eyes there was a brown ciliary body mass that blocked transmission of light on trans-scleral transillumination. Ocular ultrasonography revealed a large, single hollow cavity (unilocular "pseudocyst") in five cases and multiple hollow cavities (multilocular "pseudocyst") in three cases. The cavity occupied a mean of 55% of the entire mass thickness (range, 31%-79%). In five cases, a basal uveal mass was noted on ultrasonography. Four patients underwent tumor resection; one had enucleation, and three had 125I radioactive plaque treatment. In the five cases confirmed histopathologically, the cavitation was empty, contained erythrocytes, serous fluid, and/or pigment-laden macrophages. In no case was the cavity lined by necrotic tumor, endothelial cells, or epithelial cells., Conclusion: Ciliary body melanoma can develop an intralesional cavity resembling an intraocular cyst. The presence of a solid mass at the base and a thick wall surrounding the cavity can assist in the differentiation of cavitary melanoma from benign cyst.

Circumscribed conjunctival melanoma usually arises in the bulbar conjunctiva and less often in the forniceal or palpebral conjunctiva. After simple superficial removal, employed by many ophthalmologists, these tumors have an increased tendency toward local recurrence and distant metastasis. A surgical procedure designed to remove the tumors completely and minimize the changes of recurrence would be desirable. The authors employed a surgical approach to conjunctival melanoma excision, which they believe insures more complete tumor removal and decreases the chances of recurrence and metastasis. The surgical management of melanoma in the limbal region of the bulbar conjunctiva consists of localized alcohol epitheliectomy, removal of the mass by a partial lamellar scleroconjunctivectomy, and supplemental double freeze-thaw cryotherapy to the adjacent remaining conjunctiva by a specific technique. For tumors located in the forniceal or palpebral conjunctiva, wide surgical resection with alcohol treatment to the scleral base and cryotherapy to the surrounding conjunctiva is performed. A "no touch" technique is employed and direct manipulation of the tumor is strictly avoided in an effort to prevent tumor cell seeding into a new area. The technique currently employed has evolved from experience with circumscribed conjunctival melanoma excision during a 20-year period. About 80 patients had circumscribed conjunctival melanoma unassociated with appreciable primary acquired melanosis. Although it is not the purpose of this article on surgical technique to provided a detailed statistical analysis of the results, the authors currently believe that this technique should be employed in all cases of circumscribed lesions in which conjunctival melanoma is a diagnostic consideration. Incisional biopsy and frozen sections are generally not advisable. Preliminary observations suggest that this method decreases the chances of local recurrence.

Objective: In the white population, an association between oculo(dermal) melanocytosis (ODM) and uveal melanoma is well recognized. However, the lifetime prevalence of uveal melanoma in the ODM population is not known. This study was designed to determine the lifetime prevalence of uveal melanoma among patients with ocular melanocytosis., Design: Fifty-six white patients manifesting ODM with uveal melanoma formed the basis of the study., Main Outcome Measures: Published prevalence rates of ODM and uveal melanoma were used for calculations using Bayes' theorem., Results: The lifetime prevalence of uveal melanoma in white patients with ODM is estimated to be 2.6 x 10(-3). The median age at diagnosis of uveal melanoma in the ODM population was similar to a randomly selected population (60.5 years and 62.5 years, respectively). In the vast majority of patients (90%) with ODM-associated uveal melanoma, the uveal melanoma was diagnosed between the ages of 31 years and 80 years., Conclusions: One of about 400 patients with ODM followed for life is estimated to develop uveal melanoma. Excessive melanocytes in the uveal tract in ODM may provide the biologic basis for susceptibility to the development of uveal melanoma. Patients with ODM should be monitored ophthalmoscopically, especially during the susceptible period, for the development of uveal melanoma. The authors suggest that a national registry of ODM patients be created and prospective data collected to better assess the risk of developing uveal melanoma.

Purpose: To report the singular case of a patient who developed three noncontiguous uveal melanomas over a 30-year period., Method: Case report., Result: Systemic evaluation of a 50-year-old man with an iris melanoma and bilateral choroidal melanomas disclosed no evidence of metastases or other primary neoplastic disease., Conclusion: Although rare, the possibility of bilateral and multifocal uveal melanoma should be recognized.

The management of intraocular tumours has come a long way since the days when enucleation was the only modality of treatment available to the ophthalmologist. Despite the fact that enucleation is still necessary in certain situations, the emphasis is currently on conservative management, thereby saving the eye and some amount of useful vision wherever possible. This review highlights the current trends in the management of adult intraocular tumours with emphasis on newer diagnostic modalities such as computed tomography, magnetic resonance imaging, and fine needle aspiration biopsy. Only those tumours that are most likely to be seen in clinical practice are included.

We conducted a phase II trial of bleomycin+vincristine+lomustine+dacarbazine (BOLD) with intercycle alpha interferon-2b in previously untreated patients with metastatic uveal melanoma. Objective tumor response and toxicity were assessed. Twenty-three patients with histologically verified metastatic uveal melanoma were enrolled into this study between November 1992 and August 1995. Chemotherapy was administered in the following fashion: dacarbazine (DTIC), 200 mg/m2 intravenously on days 1-5; vincristine, 1 mg/m2 (not to exceed 2 mg) intravenously on days 1 and 4; bleomycin, 15 mg intravenously on days 2 and 5; lomustine (CCNU), 80 mg orally on day 1; and alpha interferon-2b, 3 x 10(6) IU subcutaneously on days 8, 10, 12, 15, 17, 19. A cycle was 28 days, and patients were reevaluated after every 2 cycles. Among twenty evaluable patients, four objective responses were observed (RR = 20%). Hematologic toxicity was modest by comparison to some other combination chemotherapy regimens in common use. Neurotoxicity was frequently observed, but it was seldom severe. An unexpected and unpredictable severe pulmonary toxicity was observed in 3 patients, the etiology of which remains unclear. The regimen of BOLD+interferon is active in the treatment of metastatic uveal melanoma. The precise role of the regimen has to be defined in light of its toxicity, particularly the unpredictable pulmonary toxicity. The pattern of occurrence of these pulmonary events is most consistent with either an acquired hypersensitivity reaction or a cumulative toxic effect of 2 or more of the agents. Patients considered for treatment with this regimen must be judiciously selected. Those with no clear contraindications may benefit from a trial of this regimen, but they must be monitored closely.

Patients with primary ocular tumors are seen infrequently in the medical profession, and most of these patients are referred to specialty centers which has resulted in a good study population. In the past, ocular tumors were treated with enucleation, but the current emphasis is now on organ preservation with sparing of all or partial visual acuity. In the management of these tumors, plaque brachytherapy and particle beam therapy have been used more frequently as an alternative to enucleation. A multi-institutional study, the Collaborative Ocular Melanoma Study (COMS), is currently underway, organized by the National Eye Institute. The COMS isotope of choice is Iodine-125 (I-125). Recurrence after plaque therapy is approximately 15%, although it may be as high as 37% at 15 years for metastatic disease. In one study, nondiffuse iris melanoma has been controlled in 93% of patients by custom plaques utilizing I-125. Plaque brachytherapy also utilizes I-125 for the treatment of retinoblastoma tumors either as primary therapy or following external beam radiation. Currently, through the utilization of plaque radiation therapy, enucleation may be avoided in the majority of patients, and many patients may retrieve some visual acuity. We will review plaque brachytherapy techniques, diagnosis, staging, and some of the pertinent literature of the two most frequently encountered primary ocular tumors: choroidal melanoma, sometimes referred to as uveal melanoma, with an incidence of approximately 1,500 new cases per year in the adult population; and retinoblastoma, the most common intraocular primary malignancy found in childhood, with a frequency of approximately 250 [corrected] new cases per year.

Background: Radiotherapy is effective for the management of most uveal metastases, and standard external beam radiotherapy is generally administered during a 3-to 4-week period. For those patients in whom external beam radiotherapy or other methods fail or those patients with solitary uveal metastases, plaque radiotherapy may be an alternative method., Objective: To determine the effectiveness of plaque radiotherapy for the management of uveal metastasis., Methods: A retrospective review of 36 patients with uveal metastases who were examined at the Oncology Service at Wills Eye Hospital, Philadelphia, Pa, and treated with plaque radiotherapy. The clinical findings and follow-up data of the primary tumor and the uveal metastasis were analyzed., Results: Of the 36 patients, 27 (75%) received plaque treatment as primary therapy for the uveal metastasis and 9 (25%) received plaque treatment as secondary therapy after failure of the uveal tumor to respond to external beam radiotherapy, chemotherapy, or hormonal therapy. During treatment, 22 patients (61%) had no other systemic metastasis and 14 (39%) had controlled systemic metastasis. No patients had active metastasis elsewhere. The uveal metastasis was solitary and well circumscribed in all but 1 patient; it measured a mean of 11 mm in basal dimension and 4 mm in thickness. The mean time for treatment was 86 hours, and the mean therapeutic dose was 68.80 Gy to the tumor apex and 235.64 Gy to the tumor base. Regression of the uveal metastasis was documented in 34 patients (94%) during a mean follow-up of 11 months. As early as 3 months after treatment, the mean tumor thickness had decreased to 2 mm. Plaque radiotherapy salvaged 5 of the 6 eyes that had failed prior external beam radiotherapy. Radiation retinopathy, radiation papillopathy, or both were found in 3 patients (8%) and occurred at a mean of 8 months after treatment. At the last examination, 18 patients (50%) were alive (11 with and 7 without active systemic metastasis) and 18 (50%) were dead from systemic metastasis., Conclusions: Plaque radiotherapy is an effective method for treating selected solitary uveal metastasis. It offers a high degree of tumor control, especially for those eyes in which other methods have failed. Plaque treatment is provided during a short period, minimizing the time demand for these patients with a limited life expectancy.

A total of 116 patients, all of whom had systemic metastases from posterior uveal melanoma, were evaluated to identify potential indicators for time to systemic metastasis. In the multivariate Cox proportional hazards model with clinically available variables, the age at initial treatment for uveal melanoma, gender and diameter of the primary tumor were revealed to be independent predictive factors for time to systemic metastasis. Age older than 60 years, male gender, and diameter of the primary uveal melanoma more than 10 mm were proved to be independent unfavorable factors. The estimated median time to systemic metastasis for the most unfavorable group (age > 60, male, diameter > 10 mm) was 20.2 months in contrast with 76.1 months for the most favorable group (age < or = 60, female, diameter < or = 10 mm). Although the results of this study cannot be applied to all patients with posterior uveal melanoma, predictive factors for time to systemic metastasis in those patients who have recurred supplement the information obtained from prognostic factors for the likelihood of metastasis or survival. They contribute not only to our understanding of the biology of metastasizing posterior uveal melanoma, but also in developing appropriate strategies for follow-up and treatment.

Purpose: To report the rare occurrence of choroidal melanoma in an African-American albino., Methods: A 68-year-old African-American man with oculocutaneous albinism developed an amelanotic choroidal mass in his left eye. A transvitreal fine-needle aspiration biopsy was performed to confirm the diagnosis, and the patient was treated with iodine 125 plaque radiotherapy., Results: The cytology of the needle biopsy showed spindle cells with nuclear atypia and prominent nucleoli. The cells showed positive immunoreactivity for HMB-45, supporting the diagnosis of choroidal melanoma., Conclusion: To our knowledge, this is the first reported case of a choroidal melanoma occurring in an African-American albino.

Uveal melanoma usually occurs sporadically in the absence of obvious genetic predisposing factors. However, in rare patients, there is a suggestion that there may be genetic predisposition. Rare occurrences of familial uveal melanoma are believed to be inherited in an autosomal dominant mode. There are a few clinical conditions that can predispose to or be associated with uveal melanoma, including ocular melanocytosis, neurofibromatosis type I, and familial atypical mole and melanoma syndrome. Nonrandom cytogenetic changes in uveal melanoma are characterized by monosomy 3, trisomy 8, and structural or numerical abnormalities of chromosome 6. Alterations of chromosome 9p are less frequently observed. CDKN2 gene, a cutaneous melanoma predisposition gene, is probably not a uveal melanoma predisposition gene as evidenced by the lack of somatic mutations involving this gene in uveal melanoma samples and the absence of germline mutations in familial uveal melanoma patients. Transgenic mouse models developed using a tyrosinase promoter tagged with a mutated ras gene or SV40-Tag oncoprotein develop retinal pigment epithelium tumors that resemble uveal melanoma. We propose that uveal melanoma cases be categorized on genetic basis according to a new classification system. This classification scheme will help to identify and uniformly categorize uveal melanoma patients with genetic predisposition. Such patients offer unique opportunities for studying the genetic aspects of uveal melanoma and, therefore, appropriate tissue samples should be obtained from them for molecular genetic studies. Further studies are needed to fully understand the genetic aspects of uveal melanoma.

Most malignant melanomas in the ocular region arise in the uveal tract (iris, ciliary body, and choroid). Uveal melanoma generally has characteristic clinical features and the diagnosis can usually be made by an experienced ophthalmologist using slit lamp biomicroscopy or indirect ophthalmoscopy. Ancillary studies such as fluorescein angiography, ultrasonography, magnetic resonance imaging, and fine needle biopsy can occasionally be used to establish the diagnosis in atypical cases. Today, most affected patients are managed by specialists in ocular oncology. The management of uveal melanoma has been the subject of considerable controversy. Iris melanoma can usually be excised without enucleation of the affected eye. With regard to posterior uveal melanoma (ciliary body and choroid), enucleation of the affected eye was once the undisputed method of treatment. More recently, however, removal of the eye is performed less often and alternatives to enucleation have gained popularity. Several years ago, laser photocoagulation and plaque brachytherapy were the most popular alternatives to enucleation. Now, techniques of local tumor excision and transpupillary thermotherapy are gaining popularity in selected cases. Even more recently, various combinations of these methods have been judiciously used in many instances. The selected method of treatment in a given case depends on a number of complex clinical factors. Philosophies regarding the management of these lesions continue to change. This review covers the current diagnosis and management of uveal melanoma with emphasis on methods of management.

Objectives: To assess the effect of plaque radiotherapy on the visual acuity of patients with juxtapapillary choroidal melanoma and to determine the clinical predictive factors for radiation retinopathy, radiation papillopathy, local tumor recurrence, and distant metastasis., Design: A retrospective review of the medical records of 93 patients with juxtapapillary choroidal melanoma who were treated initially with plaque radiotherapy., Results: During a mean follow-up of 78 months, radiation retinopathy developed in 81 patients (87%) and radiation papillopathy developed in 48 patients (52%) after a mean interval of 21 and 27 months, respectively. The univariate variables that were significant predictors of radiation retinopathy were history of diabetes mellitus (P = .05) and use of a notched radioactive plaque (P = .04). The factors predictive of radiation papillopathy were age (> 45 years; P = .01), history of diabetes mellitus (P = .05), mushroom-shaped tumor configuration (P = .006), and nasal location of the tumor (P = .04). By using Kaplan-Meier survival curves, we found that the proportion of the 93 patients with radiation retinopathy was 87 (94%) at 5 years and with radiation papillopathy was 53 (57%) at 5 years. By using life-table analysis, we found that the proportion of the 93 patients who experienced a decrement of at least 3 lines of visual acuity was 67 (72%) by 50 to 60 months. Local tumor recurrence was documented in 14 patients (15%) after a mean interval of 41 months. The age of the patient (< 35 years; P = .02) and the superior (P = .004) and inferior (P = .05) locations of the tumor were predictive of local tumor recurrence. Distant metastasis developed in 11 patients (12%) after a mean interval of 44 months. The factors predictive of distant metastasis were a tumor with a basal diameter larger than 6.0 mm (P = .05), the superior location of the tumor (P = .01), and local tumor recurrence (P < .001)., Conclusion: Based on these observations, plaque radiotherapy remains a potential option vs enucleation for the management of juxtapapillary choroidal melanoma.

Objective: To assess the clinical features that predict metastasis of diffuse choroidal melanoma., Design: A review of patients who had been diagnosed clinically as having diffuse choroidal melanoma evaluated on the Oncology Service at Wills Eye Hospital, Philadelphia, Pa., Main Outcome Measure: Effect on metastasis of clinical features of the tumor., Results: Of 3500 consecutive patients with choroidal melanoma, 111 (3%) had diffuse choroidal melanoma. Of these 111 tumors, the mean tumor base was 14.7 mm and the mean overall tumor thickness was 2.1 mm. The thickness-to-base percentage averaged 14.8%. The tumor had poorly defined margins in 39 patients (35%), orange pigment on its surface in 49 (44%), and a secondary serous retinal detachment in 76 (68%). Optic nerve invasion was clinically suspected in 2 patients (2%) and transcleral extension in 3 (3%). Initial management was enucleation in 36 patients (32%), plaque radiotherapy in 60 (54%), laser photocoagulation in 3 (3%), and observation in 12 (11%). During a mean follow-up of 5.3 years (median, 3.9 years), metastasis developed in 29 patients (26%). Using Kaplan-Meier survival estimates, the probability of metastasis developing was 16% at 3 years, 24% at 5 years, and 36% at 10 years. The clinical factors predictive of metastasis by univariate analysis included tumor basal dimension 18 mm or more (P = .002), poorly defined tumor margins (P = .03), transcleral extension (P = .003), and optic nerve invasion (P = .03). The clinical factors predictive of metastasis by multivariate analysis included basal dimension of 18 mm or more (P = .01), optic nerve invasion (P = .03), and poorly defined tumor margins (P = .05)., Conclusions: Despite its relative flatness, diffuse choroidal melanoma carries a metastatic potential of 24% at 5 years. The risks for metastasis are greatest with increasing tumor base and poorly defined margins. Recognition of the clinical features of this tumor in the earliest stage and prompt treatment are encouraged.

The management of uveal melanoma has evolved tremendously for the past century, and more recently there is a trend toward more focal conservative treatment. Enucleation is still performed for large uveal melanoma when there is no hope for useful vision with conservative treatment. Plaque radiotherapy is particularly recommended for medium- or small-sized uveal melanoma. Special custom-designed plaque radiotherapy can be used for iris, ciliary body, or juxtapapillary choroidal melanoma. Charged-particle irradiation constitutes an alternative treatment modality for posterior uveal melanoma. However, charged-particle therapy is limited by the availability of appropriate therapeutic facilities. Local tumor resection using lamellar sclerouvectomy is mainly suitable for selected iris, ciliary body, or anterior choroidal tumors with smaller basal dimension and greater thickness. Ablative laser photocoagulation is indicated for very selected cases of small posterior choroidal uveal melanoma. Combined plaque radiotherapy with indirect ophthalmoscope laser therapy appears to be a more effective local tumor treatment plan than plaque radiotherapy alone. Transpupillary thermotherapy is the newest modality used as primary treatment or as complementary method to brachytherapy for treatment of selected choroidal melanomas. Hyperthermia with infrared irradiation below photocoagulation level produces tumor necrosis with few ocular complications. Based on the published ophthalmic literature, it seems that enucleation carries the same survival prognosis as each of the conservative treatment modalities.

A 67-year-old man was diagnosed as having a melanocytoma of the optic disc in the left eye. Observation during a 5-year period showed no change in the lesion. At age 72 years, he had abrupt visual loss to no light perception in the affected left eye. Clinical examination disclosed little enlargement of the papillary tumor but ultrasonographic evidence of optic nerve infiltration. Precontrast magnetic resonance imaging studies disclosed a hyperintense infiltrative lesion in the enlarged left optic nerve. Enhancement features of the lesion excluded a hemorrhagic process. The eye was removed with a 22.5-mm segment of optic nerve. Histopathologic examination showed a large, necrotic, mixed-cell malignant melanoma confined to the optic nerve. No choroidal involvement or viable melanocytoma cells were documented. This case stresses that it may be difficult to differentiate a melanocytoma from a primary malignant melanoma of the optic nerve.

Objective: To study the clinical profile and kindreds of patients with familial uveal melanoma (FUM)., Design: Retrospective case series., Setting: Tertiary referral center., Patients: Medical charts of 4500 patients with uveal melanoma were reviewed for family history of uveal melanoma. The clinical profile of these patients and their kindreds were studied to determine the incidence of FUM and pattern of inheritance. The association of FUM to cutaneous melanoma, familial atypical mole and melanoma syndrome, and other nonmelanocytic cancers was analyzed using statistical methods., Results: Of 4500 patients with uveal melanoma, 56 patients in 27 families (0.6%) had a family history of uveal melanoma. The uveal melanoma in all 56 familial patients was unilateral. In 17 cases (63%), the second affected relative was a first-degree relative. In the remainder, the second affected relative was a second- (22%) and third-degree (15%) relative. In 25 families (93%) only two members were affected, and in two families (7%) three members had uveal melanoma. Patients with FUM were four times as likely to have a second primary malignant neoplasm than were people in the general population. However, no evidence was seem that unaffected kindreds of patients with FUM were at higher risk of having a second primary malignant neoplasm., Conclusions: Familial involvement in uveal melanoma is rare. Familial uveal melanoma most often (63%) affects first-degree relatives, rarely affects more than two persons in a family, and may be associated with a generalized inherited predisposition to cancer. Further genetic studies are necessary to fully characterize FUM syndrome.

Background: The occurrence of bilateral primary uveal melanoma has been assumed to be a rare, random event . Bilaterality of a primary cancer is suggestive of an inherited cancer predisposition. The authors therefore evaluated patients with bilateral primary uveal melanoma for such cancer predisposition., Methods: The charts of 4500 patients with uveal melanoma were reviewed for the presence of bilaterality. The clinical profile of patients with bilateral primary uveal melanoma was studied. The presence of ocular melanocytosis, familial atypical mole and melanoma syndrome, neurofibromatosis type 1, cutaneous melanoma, familial uveal melanoma, Li-Fraumeni syndrome, and second primary cancers also was investigated., Results: Of 4500 patients with primary uveal melanoma, 8 (0.18%) were identified to have bilateral primary uveal melanoma. Using the annual incidence rate (Shammas and Watzke) and normal approximation to the binomial, the expected number of patients with primary bilateral uveal melanoma in the authors' series was calculated to be less than one person. Observation of eight patients with bilateral primary uveal melanoma represented greater than expected occurrence (P<0.0001). The mean age at diagnosis in the first eye was 56 years. The interval between the diagnosis of uveal melanoma in the two eyes ranged from 2 to 32 years (median, 10.5 years). Two patients had bilateral ocular melanocytosis. Ocular melanocytosis was more common (2/8, 25%) in patients with bilateral uveal melanoma compared with those with unilateral uveal melanoma (60/4492, 1.3%). This difference was statistically significant (P = 0.001). No relation to familial atypical mole and melanoma syndrome, cutaneous melanoma, neurofibromatosis type 1, familial uveal melanoma, second primary cancers, or Li-Fraumenni syndrome was observed., Conclusions: Bilateral primary uveal melanoma occurs more frequently than expected by chance, and may be associated with ocular melanocytosis. In the authors' series, there was no clinical evidence of an inherited genetic predisposition for bilateral primary uveal melanoma. Unidentified germ-line mutations may be involved in pathogenesis of bilateral uveal melanoma.

Background: The management of small melanocytic choroidal tumors is controversial. An important reason for this controversy is that the natural course and metastatic potential of these lesions are not defined clearly. Prior studies that have attempted to elucidate the natural course of these lesions have focused on selected small groups of patients with presumed small choroidal melanomas. There are no large studies investigating the growth potential and metastatic potential for the spectrum of small melanocytic choroidal tumors when considered as an unselected whole group. In addition, the clinical features of these tumors predictive of metastases have not yet been identified., Methods: A retrospective review was performed on 1329 patients with small melanocytic choroidal tumors measuring 3 mm or less in thickness. Clinical parameters of the patient and tumor were obtained and analyzed for their relation to eventual tumor growth and metastasis using a Cox proportional hazards regression model., Results: Tumor growth was documented in 18% of patients. The factors predictive of tumor growth (multivariate analysis) included greater tumor thickness (P = 0.0001), posterior tumor margin touching optic disc (P = 0.0001), symptoms of flashes, floaters (P = 0.002), and blurred vision (P = 0.003) relative to no symptoms, orange pigment on the tumor surface (P = 0.004), and the presence of subretinal fluid (P = 0.05). The relative risk (RR) was greatest for initial tumor thickness 2.1 to 3.0 mm (RR = 5.2) and tumor thickness 1.1 to 2.0 mm (RR = 4.3) relative to tumors 1 mm or less in thickness, as well as posterior margin touching the optic disc (RR = 2.6). After adjusting for significant tumor variables, the effect of interventional tumor treatment showed a decreasing risk for tumor growth compared with continued observation without treatment. Of 1329 patients, metastases developed in 35 (3%). The factors predictive of metastases (multivariate analysis) included posterior tumor margin touching the optic disc (P = 0.003), documented growth (P = 0.003), and greater tumor thickness (P = 0.004). The relative risk for metastases was greatest for tumor thickness 1.1 to 3.0 mm (RR = 8.8) and growth (RR = 3.2)., Conclusion: Of small choroidal melanocytic tumors measuring 3 mm or less in thickness at the time of initial examination, 18% demonstrated growth and 3% metastasized during the period of follow-up. Based on this analysis, the clinical features of these tumors can be used to estimate the risk for tumor growth and metastases and assist the clinician with patient management.

We conducted this study to determine whether occurrence of primary uveal melanoma in the setting of familial atypical mole and melanoma (F A M-M) syndrome (an autosomal dominant cutaneous preneoplastic syndrome) follows a pattern of a hereditary cancer predisposition syndrome. A retrospective review of 4600 consecutive patients with primary uveal melanoma revealed eight patients with biopsy-proven F A M-M syndrome. The clinical profile of these patients was studied and their kindreds analyzed. In patients with F A M-M syndrome, the uveal melanoma occurred at a relatively young age (mean 40 years; range 10-52 years). The diagnosis of F A M-M syndrome preceded or followed the diagnosis of uveal melanoma by as much as 10 years. None of the patients had an associated nonmelanocytic malignancy. Three of the eight patients had a positive family history of melanoma (cutaneous melanoma (2) and uveal melanoma (1). The authors conclude that the occurrence of primary uveal melanoma in the setting of F A M-M syndrome does not follow a clear pattern of a hereditary cancer predisposition syndrome.

Purpose: Metastatic cancer to the iris is rare, and the best approaches to clinical recognition and treatment of this neoplasm are not widely known. We reviewed a series of patients with metastatic cancer to the iris and elucidated the clinical variations, diagnostic approaches, and treatment of this neoplasm., Methods: The files of the Wills Eye Hospital Ocular Oncology Service were surveyed, and cases of metastatic cancer to the iris were extracted for further analysis. General data, systemic data, tumor characteristics, diagnostic methods used, treatment, and prognosis were tabulated., Results: Of 512 patients with uveal metastasis, the iris was involved in 40 (7.8%). The metastasis originated from breast carcinoma in 16 cases, lung carcinoma in 11, carcinoid tumor in three, melanoma in three, colonic carcinoma in two, and esophageal, laryngeal, prostate, and kidney carcinoma in one case each. In one case the primary tumor was never identified. There was no history of primary cancer in 13 (32%) of 40 patients. All iris metastases were unilateral, and secondary glaucoma was present in 15 (38%). Fine-needle aspiration biopsy of the iris lesion helped to establish the diagnosis in 11 cases. Treatment with chemotherapy, radiotherapy, or both, achieved local tumor control in all patients. The overall mean survival was 20 months and the median survival was 13 months after diagnosis of the iris metastasis., Conclusions: Iris metastasis can show a spectrum of clinical variations, but its features are generally distinctive enough to differentiate it from other intraocular neoplasms and inflammations. Treatment consists of chemotherapy, which was sometimes combined with ocular irradiation. The visual prognosis was good but the systemic prognosis was generally poor.

Background: Plaque radiotherapy is the most common method of managing posterior uveal melanoma but its use for iris melanoma and iris metastases has not yet been evaluated., Methods: Fourteen patients with non-resectable iris melanoma and four with iris metastasis were treated with plaque radiotherapy. The tumour response to treatment and the local side effects of the radioactive plaque were evaluated., Results: In the iris melanoma group over a mean follow up of 26 (range 6-75) months, the tumour regressed in 13 of the 14 patients (93%) and recurred as diffuse seeding in one patient (7%). Despite large doses of radiation given transcorneally, the cornea developed epitheliopathy, abrasion, and oedema in only one case each. The major radiation side effects were localised iris vasculopathy without glaucoma in two cases, posterior synechiae in five cases, and cataract in six cases. In the iris metastasis group, tumour regression was observed in all four patients (100%) and radiation side effects were not evident over the relatively short mean follow up period of 8 (range 4-9) months. All of the 14 patients with irradiated iris melanoma have remained systemically healthy without metastasis while three of the four patients with irradiated iris metastases have died of metastases from the primary neoplasm., Conclusion: Custom designed plaque radiotherapy appears to be an effective alternative method of controlling non-resectable diffuse iris melanoma and solitary iris metastasis and has relatively few side effects.

Purpose/methods: A 64-year-old man with a history of maxillary antrum melanoma had abrupt-onset night blindness and photopsia., Results/conclusions: Ophthalmologic examination and electroretinogram suggested melanoma-associated retinopathy. Serum produced a weak but specific labeling of human bipolar cells by indirect immunofluorescence. Complete excision of melanoma may have contributed to low levels of circulating autoantibodies. The identity of the retinal bipolar antigen recognized by melanoma-associated retinopathy autoantibodies is needed for more accurate diagnosis.

A ten-year-old boy was referred with an enlarging amelanotic iris tumor and secondary glaucoma in the left eye. After excisional biopsy it proved histopathologically to be an iris melanoma. The patient also had multiple nevi on his trunk, scalp, and buttocks suggestive of familial atypical mole melanoma (FAM-M) syndrome and confirmed histopathologically. To the authors' knowledge, this is the first report of iris melanoma in association with FAM-M syndrome. The young age at tumor onset is suggestive of a predisposing condition such as FAM-M syndrome. The association of uveal melanoma with FAM-M syndrome is discussed.

The records of 265 consecutive patients with juxtapapillary choroidal melanoma were reviewed and a statistical non-randomised retrospective study was performed to evaluate the risk for metastasis and compare the survival rate of patients treated with plaque radiotherapy or enucleation. To obtain sufficient overlap between the enucleation and plaque radiotherapy, the statistical analysis was limited to an adjusted subgroup of 127 patients who met eligibility criteria for plaque radiotherapy and who had a minimum of 3 years of follow up after treatment. In the adjusted subgroup of 127 patients, 92 patients (72%) were initially treated with enucleation and 35 (28%) with plaque radiotherapy. In both univariate and multivariate logistic analysis models, the age of the patient (> 50 years), tumour thickness (> 3 mm), and treatment by age interaction were found to be significant factors for development of distant metastasis. In patients younger than 50 years, the method of treatment (enucleation versus plaque radiotherapy) did not significantly affect the risk of metastasis. For those older than 50 years, there was a non-significant trend for patients in the enucleation group to be at a higher risk for metastasis than those in the plaque group. In the enucleation group, patients older than 50 years had a significantly higher incidence of distant metastasis than those younger than 50 years. In the plaque radiotherapy group, there was no significant higher incidence of metastasis in patients younger than 50 years than in those older than 50 years. When a Cox proportional hazards model was used to evaluate the survival rate, there was the same statistically significant effect of treatment by age interaction as was found in the multivariate logistic model on survival time. Moreover, there was a significant effect of treatment by tumour thickness interaction on survival time. Patients in the enucleation group had a better survival rate when the thickness of the tumour was less than 3 mm compared with a tumour of more than 3 mm. There were no apparent effects of tumour thickness on survival for patients treated with plaque radiotherapy. From these results, the authors currently recommend plaque radiotherapy as a viable option to enucleation in patients with juxtapapillary choroidal melanoma.

We analyzed cytogenetic abnormalities in 10 cases of primary uveal melanoma. Clonal chromosomal abnormalities were present in nine cases. Chromosome 6 was most commonly affected (seven cases) and included gain of material from 6 and/or loss of material from 6q. Trisomy of chromosome 8 or gain in material from 8q, mostly in the form of an i(8q) resulting in three to five copies of the 8q segment was seen in six cases. Monosomy of chromosome 3 and rearrangements of chromosome 9 were less frequent and were altered in three cases each. Clinical, histopathologic, and cytogenetic abnormalities are correlated.

Sixty eight cases of histologically proved conjunctival melanoma were reviewed in order to determine the clinical factors that were predictive of local recurrence and distant metastasis. All patients were treated with surgical excision and most had supplemental cryotherapy. The mean follow up was 7.5 years. Histopathologically, the conjunctival melanoma arose from primary acquired melanosis in 56%, from naevus in 26%, and de novo in 18%. Of the 68 patients, 38 (56%) developed at least one local tumour recurrence and 22 (32%) developed more than one recurrence. The method of initial treatment and the eventual development of metastasis were the two parameters statistically associated with tumour recurrence. Those patients treated initially with tumour excision alone had a statistically significant higher recurrence rate than those treated initially with excision and supplemental cryotherapy (p = 0.001). Fourteen patients (21%) developed metastasis and the mean period between treatment and metastasis was 3.6 years. Twelve (18%) died from metastatic melanoma with a mean interval of 4.4 years from the time of initial surgery until death. The only clinical parameter that was statistically associated with distant metastasis was local tumour recurrence (p = 0.015). Based on these observations, the authors make recommendations regarding the treatment of conjunctival malignant melanoma. It appears that initial complete excision of the tumour with supplemental cryotherapy offers the patient the best chance of remaining free of recurrence and metastasis.

A 76-year-old man with compressive optic neuropathy secondary to a retrobulbar mass was managed by orbitotomy and removal of the mass. The lesion proved histopathologically to be an unusual orbital melanoma with massive central necrosis. There was no histopathological evidence of congenital melanocytosis. Dermatological and systemic evaluation before and after orbital surgery revealed no evidence of primary melanoma elsewhere. The patient developed hepatic metastasis 2 years after excision of the orbital tumour. It appears that the melanoma was a primary orbital tumour and not a metastatic melanoma from an occult primary lesion.

We report two cases of choroidal melanoma with massive orbital extension that were managed by modified enucleation by way of a lateral orbitotomy. In both cases, the orbital component of the tumor was removed intact along with the globe. This approach allows placement of an orbital implant and avoids the long healing process associated with orbital exenteration.

A review of 3706 consecutive patients with uveal melanoma revealed that 40 patients (1.1%) were age 20 years or younger at the time of diagnosis. The youngest patient was age 6 years but the majority of patients (78%) were between 15 and 20 years old. The tumor occurred in the iris in 5 cases (12%) and in the posterior uvea in 35 cases (88%). The mean largest tumor dimension and thickness was 10 mm and 5 mm, respectively. In all cases, the diagnosis of uveal melanoma was suspected before referral, and misdirected treatment was avoided. The tumor was initially treated by enucleation in 24 cases (60%), local resection in 7 (18%), plaque radiotherapy in 3 (8%), and observation in 6 (15%). Secondary treatment was required in 7 cases in the form of enucleation (4 cases), ablative laser (1 case), plaque radiotherapy (1 case), and exenteration (1 case). The mean follow-up period was 68 months (median, 48 months) from the time of treatment, and only one patient died of metastases (from a massive ciliochoroidal melanoma 33 months after treatment). The remainder of the group of young patients are alive and healthy. Cumulative survival rates show that 96% of young patients with uveal melanoma survive at the 5-year period.

A review of 3706 consecutive patients with uveal melanoma over a 17-year period revealed that 16 patients (0.4%) were pregnant women at the time of diagnosis. The mean age at presentation in this group was 30 years and the mean months of gestation at the time of diagnosis of the posterior uveal melanoma was 6 months. Seven of the sixteen tumors were active uveal melanomas at the initial examination and were treated immediately, while the remaining nine tumors were initially diagnosed as suspicious choroidal nevi or dormant choroidal melanomas, seven of which grew into active melanomas during the course of the pregnancy, necessitating therapy. The tumors were managed by enucleation in 10 cases, plaque radiotherapy either during or after pregnancy in 4 cases, and observation in 2 cases. Histopathologically, the melanomas did not differ appreciably in cell type, mitotic activity, and other features when compared with a matched group of tumors in nonpregnant women. All of the patients who elected to carry the pregnancy to term (14 cases) delivered healthy babies with no placental or infant metastases. The 5-year survival rate using the life table method in these pregnant women with posterior uveal melanoma is 71% and is similar to the survival of nonpregnant women with posterior uveal melanoma reported in other series.

We studied the feasibility of using the surface coil probe technique for the noninvasive in vivo study of ocular tumors by phosphorus 31 magnetic resonance spectroscopy. The characteristic organophosphate metabolites of suspected uveal melanomas before proton beam irradiation were determined qualitatively by phosphorus 31 magnetic resonance spectroscopy in vivo using a three-turn surface coil. Spectra of choroidal hemangioma, osteoma, and metastasis were also obtained in vivo and compared with those of uveal melanomas. Analysis of spectra performed at 1.5 T showed significant peaks of phosphomonoesters, inorganic phosphate, phosphodiesters, phosphocreatine, and adenosine 5'-triphosphates. The unusually high concentration of phosphodiesters may be considered as a marker for uveal melanomas and other choroidal tumors. By analyzing the ratio of phosphocreatine to phosphodiesters spectral area values, we interpreted qualitatively spectra of intraocular tumors to differentiate malignant tumors from benign lesions. Nevertheless, the main limitation of interpreting the spectra was their contamination by signals from surrounding tissues.