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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.)

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.

A high-grade diffuse T cell lymphoma, initially simulating bilateral panuveitis, was diagnosed by analysis of a vitreous biopsy specimen and a breast tumor in a 57-year-old woman. It responded favorably to aggressive chemotherapy before it relapsed in leukemic transformation. This case emphasizes the misleading initial symptoms of primary intraocular lymphoma and the role of immunophenotyping in the diagnosis and classification of lymphoproliferative ocular disorders. The presentation and management of uveal lymphoid neoplasia are discussed.

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.

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.

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.

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.

Background/purpose: Acquired neoplasms of the nonpigmented ciliary body epithelium (NPCE) are rare, and most information about them has come from single case reports. This study was undertaken to review the authors' experience with a series of patients with acquired neoplasms of the NPCE, to delineate the clinical and histopathologic features of these tumors, and show how they differ from ciliary body melanoma., Methods: A clinicopathologic review was conducted on acquired tumors of the NPCE that were evaluated by the authors and a review of the English language literature was done. The data from the authors' cases were compared with previously reported cases., Results: The authors had personal experience with nine patients with acquired tumors of the NPCE and found 18 other patients with these tumors in the literature. Of the authors' patients, all tumors were predominantly nonpigmented and were white to light-tan in color. Associated clinical findings included signs of intraocular inflammation in all patients, secondary cataract in eight (89%), and subluxation of the lens in six (67%). Eight of the tumors were managed successfully by local resection and one by enucleation. Histopathologically, the tumors showed considerable variation from patient to patient. Seven tumors were classified as benign adenoma and two as low-grade adenocarcinoma. There was no local recurrence or systemic metastases. Although tumors of the NPCE historically have been misdiagnosed clinically as ciliary body melanoma, our study suggests that they have some characteristic features that severe to differentiate them from melanoma and other ciliary body lesions. In contrast to melanoma, acquired neoplasms of the NPCE are amelanotic and are more likely to have an irregular surface, associated inflammatory signs, to transmit light well during transillumination, and show high internal reflectivity with ultrasonography., Conclusion: Acquired neoplasms of the NPCE have characteristic clinical and histopathologic features that should suggest the diagnosis. Due to their anterior location in the ciliary body, local resection (rather than enucleation) is usually the treatment of choice. The visual prognosis is fair, and the systemic prognosis is excellent.

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.

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.

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.

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.

Background: Carcinoid tumor is a low-grade malignancy that usually arises in the gastrointestinal tract or bronchus and rarely metastasizes to the eye. Metastasis of carcinoid tumor to the uvea can be confused clinically with other primary and metastatic uveal tumors., Methods: The authors reviewed the records of 410 consecutive patients with uveal metastases referred to the Ocular Oncology Service at Wills Eye Hospital to identify those in whom carcinoid tumor was the primary neoplasm. The authors evaluated the clinical features of these metastases., Results: Of 410 consecutive patients with uveal metastases, the primary neoplasm was a carcinoid tumor in 9 (2.2%). There were four men and five women. The mean age at ocular diagnosis was 50 years. In five patients (56%), the primary tumor was undiagnosed at ocular presentation. In the other four patients, the mean time interval from diagnosis of the primary carcinoid tumor to uveal metastasis was 89 months (range, 55-180 months). The site of the primary carcinoid tumor was the bronchus in seven patients, the esophagus in one, and the thymus in one. The site of intraocular metastasis was the choroid in six patients, the ciliary body in two, and the iris in one. All choroidal tumors had a characteristic orange color. Initial ocular treatment included external beam radiotherapy in five patients, plaque radiotherapy in two, argon laser photocoagulation in one, and local resection in one. Ocular tumor control was achieved in each patient. After a mean follow-up of 34 months, four patients (44%) are still alive. Five patients have died, with a mean survival of 34 months (range, 2-104 months) after the diagnosis of uveal metastasis., Conclusions: Uveal metastasis from carcinoid tumor is rare and tends to arise from the bronchus. Clinically, it has a distinctive orange color and may be associated with a longer systemic survival, compared with uveal metastasis from other primary sites.

A review of seven cases of intraocular leiomyoma personally managed by the authors disclosed clinical and histopathologic characteristics that serve to differentiate this uncommon tumor from uveal melanoma. Leiomyoma generally occurs in younger patients and has a definite predilection for females. It tends to affect the ciliary body and peripheral choroid rather than the posterior choroid. In contrast to melanoma, which is located in the uveal stroma, leiomyoma usually is located in the supraciliary or suprachoroidal space. During transillumination, leiomyoma usually transmits light readily, whereas most melanomas cast a shadow. If intraocular leiomyoma is suspected clinically, the best management seems to be removal by a modified lamellar sclerouvectomy. In contrast to melanoma, leiomyoma shows positive immunoreactivity for muscle markers and negative immunoreactivity for melanoma-specific antigen and neural markers.

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.

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.