Nondiagnosed uveal melanomas

PURPOSE: To determine the proportion of nondiagnosed uveal melanomas after evaluation by optometrists or ophthalmologists. DESIGN: Retrospective observational cohort study. PARTICIPANTS: Four hundred thirty-three ophthalmic oncology patients with uveal melanoma. METHODS: This was a retrospective study of uveal melanoma patients from a single ophthalmic oncology center. We sent questionnaires to living patients we had treated between 1980 and 2000 for uveal melanoma. Patients were divided into those who had an examination within 1 year before diagnosis of a melanoma in which the tumor was not detected, those patients who were being observed with a known pigmented uveal tumor, and those who had not had an eye examination for at least 10 years. MAIN OUTCOME MEASURE: The detection of unsuspected melanomas. RESULTS: We determined that 37% of patients referred to us with a newly discovered uveal melanoma had been examined within a year, without a uveal melanoma being detected. Of patients whose medical records were obtained, 71% had eyes that had been dilated and the tumor not found. The patients in whom the tumors were nondiagnosed within 1 year of referral to us had a mean tumor thickness of 6 mm and a mean tumor diameter of 12 mm. Ninety percent of the tumors were partially posterior to the equator. Patients who had been observed by their outside ophthalmologist with a choroidal pigmented tumor had significantly smaller tumors (P<0.005). CONCLUSIONS: There are a notable number of patients seen by general ophthalmologists with symptomatic uveal melanomas in whom the diagnosis is not established. It is likely that screening efforts for this relatively rare condition are often not efficacious.     

Expression of HLA antigens in paraffin sections of uveal melanomas

Expression of histocompatibility (HLA) antigens on tumor cells may influence the recognition of these tumor cells by the immune system. Immunological recognition may influence tumor growth and patient survival.Although HLA class I and II antigens are known to be present on several tissues in the eye, their presence on ocular tumors had not yet been demonstrated. We studied the expression of these antigens on paraffin preparations of uveal melanomas. Most tumors carried class I and ₂m antigens on most of their cells, while class II antigens were less often expressed. No association with tumor cell type or tumor size was observed. Further studies will be necessary to determine the relevance of different levels of antigen expression with regard to patient survival.     

Echographic pseudoextension of uveal melanomas

Background: Standardized echography is routinely utilized to assess uveal melanomas. Echographic pseudoextension is defined as normal structures mimicking intrascleral or extrascleral extension of tumor on echography. Methods: The records of 151 consecutive uveal melanoma patients evaluated with standardized echography over a 6-year period (1986–1991) were reviewed to identify those in which pseudoextension or true extension was diagnosed. Results: Fourteen (9%) cases of pseudoextension were noted, with causes including juxtapapillary tumor location (seven cases), extraocular muscle insertion (five cases), vortex ampullae (one case), and post-brachytherapy changes (one case). Clinical, echographic, and/or histopathologic follow-up confirmed absence of true extension. Six (4%) cases of true extrascleral extension were identified and confirmed histopathologically. Conclusion: Differentiating extraocular tumor extension from pseudoextension is critical, and use of standardized A-scan and contact B-scan echography is integral in this assessment.     

Phototherapy of posterior uveal melanomas.

The results of phototherapy on a small series of 19 patients with uveal melanomas are presented. Laser radiation at a wavelength of 620 to 630 nm was used in conjunction with a 5 to 7.5 mg/kg dose of haematoporphyrin derivative administered 24 hours before treatment, with total doses/treatment averaging 960 J/cm2. Eleven patients received two treatments, and one received a third. The longest duration of tumour control to 30 September 1990 was 31 months. Of the 19 patients treated six had complete regression of the tumour, while another five had minor to significant regression. A strong correlation between degree of regression and degree of tumour pigmentation was found, the lighter tumours responding much better than darker tumours. There were also strong indications that if a tumour did not respond to the initial phototherapy it was very unlikely that subsequent phototherapy would provide any further benefit.     

Internal resection of posterior uveal melanomas

AIMS—To evaluate the safety and efficacy of internal resection in the treatment of malignant melanoma of the choroid.
METHODS—32 consecutive patients with histopathologically proved malignant choroidal melanomas were treated with internal resection. 29 of the 32 (90.6%) tumours were within 2 disc diameters of the optic nerve or fovea. The surgery was performed at two university centres by one of the authors. Follow up was between 1 and 85 months (mean 40.1 months).
RESULTS—Three patients developed distant metastases and died of malignant melanoma (metastatic and mortality rate 9.4%). In one case, distant metastases developed in association with an intraocular recurrence. There have been no other intraocular recurrences. The most common postoperative complication was vitreous haemorrhage, which occurred in 12 patients (37.5%); cataract occurred in eight eyes; and three patients developed retinal detachment postoperatively. Three of the operated eyes have been enucleated (9.4%); a total of four (12.5%) have lost light perception. 10 patients (31.2%) had visual acuities of 6/60 or better and 18 of 32 (56.3%) were between 6/120 and light perception.
CONCLUSION—These data suggest that the internal resection of posterior uveal melanomas is a reasonable globe saving management option. This treatment modality is particularly well suited to elevated tumours in close proximity to the optic nerve or fovea.

Keywords: choroidal melanoma; internal resection; malignant melanoma; posterior uveal melanoma     

The morphology of uveal malignant melanomas

Scanning electron microscopy (S.E.M.) has been performed on tissue cultures obtained from four choroidal malignant melanomas. The morphology of these cells has been demonstrated using this technique. Microvilli were found to present on the surfaces of all cells studied. These microprocesses often formed a connection between the cell and the cover slip, or other tumour cells. Rounded vesicles were demonstrated on the surfaces of some cells. It is possible that some of the larger vesicles contained melanosomes.     

MicroRNA在葡萄膜恶性黑色素瘤中的研究进展

恶性黑色素瘤恶性程度高,易经血流转移,是成年人中最多见的一种恶性眼内肿瘤,其发生发展涉及到多步骤的分子生物学机制,包括原癌基因和抑癌基因的遗传和表观遗传学改变。因此研究参与此过程的分子机制能为肿瘤的有效治疗提供有益的见解。微小核糖核酸（ｍｉｃｒｏＲＮＡ,ｍｉＲＮＡ）是一类长约２２个核苷酸的非编码单链小分子ＲＮＡ,在各种生理病理过程中发挥了重要作用,最新的研究发现,异常表达的ｍｉｃｒｏＲＮＡ参与了葡萄膜恶性黑色素瘤众多的病理过程。本文综述了ｍｉｃｒｏＲＮＡ的发现、形成及作用机制,葡萄膜恶性黑色素瘤中ｍｉｃｒｏＲＮＡ的异常表达及其可能机制,ｍｉｃｒｏＲＮＡ与葡萄膜恶性黑色素瘤的发生与增殖、侵袭和转移以及ｍｉｃｒｏＲＮＡ在葡萄膜恶性黑色素瘤中的临床应用价值。     

Syntactic structure analysis in uveal melanomas.

Syntactic structure analysis was carried out successfully on 92 paraffin embedded uveal melanomas, taken from patients with a minimum follow up of 5 years. This simple, fast, and reproducible method of describing the tumour architecture has been significantly correlated with malignancy in tumours from several sites. Paraffin sections 5 microns thick, were cut and stained with haematoxylin and eosin. Tumours were classified according to a modification of the Callender classification. A minimum spanning tree (MST), using the centre points of tumour nuclei, was constructed in five randomly chosen fields with an interactive digitising video overlay system. Ten syntactic structure features were derived from each MST; subsequently, the mean and standard deviation of the five fields analysed were calculated for further statistical analysis. Reproducibility was acceptable with a mean correlation coefficient of 0.70. In univariate survival analysis, the percentage of points with three neighbours yielded prognostic significance (p < 0.05). Minimum spanning tree variables were compared (chi 2 test) with classic tumour prognosticators and there was a significant correlation between Callender cell type and the following MST parameters: mean number of points (p < 0.003); MST length (p < 0.003); mean line length (p < 0.01); number of nuclei with one neighbour (p < 0.004); number of nuclei with two neighbours (p < 0.02), and number of nuclei with three neighbours (p < 0.005). Syntactic structure analysis is an evolving technique, but may be able to mathematically (and reproducibly) describe melanoma architecture across the spectrum of the Callender classes. This would also allow architectural grading of tumours within the specific Callender groups, providing more precise prognostic information. Further modifications of this technique are necessary to optimise prognostic potential when applied to uveal melanomas.     

Genetic instability in human malignant uveal melanomas

PURPOSE: The aim of the study was evaluation of genetic changes: loss of heterozygosity (LOH) and microsatellite instability (MSI) in the genome of cells of the uveal melanoma. MATERIAL AND METHODS: The incidence of MSI and LOH in cells of uveal melanomas was examined in tissue specimens obtained at surgical resection of the tumour in 14 patients. The results were related to respective MSI and LOH incidence in the genome of peripheral blood cells of the same patients. DNA was isolated with organic extraction. The fluorescent multiplex polymerase chain reaction (PCR) was used to amplify microsatellite loci included in commercially available human identification kits. Phenotyping was performed with the use of ABI Prism 310 Genetic Analyzer. RESULTS: MSI and LOH was found in 6 of 14 cases of uveal melanoma, manifested at one or more loci. MSI was present in chromosomes 3, 11 and 16. LOH was detected in chromosomes: 2, 3, 8, 13, 16 and 19. Genetic instability of the LOH/MSI type was detected in 3 patients with long anamnesis and large tumor infiltrating retrobulbar structures (pT4 feature). Two patients died within a year because of generalized cancer disease. CONCLUSIONS: 1 Loss of heterozygosity and microsatellite instability is present in uveal melanomas. 2. Genetic instability of LOH/MSI type associates with advanced size of tumour and progression of neoplastic disease.     

Anterior chamber angle recession in uveal melanomas

Summary Sixteen uveal melanomas in celloidin sections and eight other fresh cases of melanoma were examined using different clinical and histological methods. A recession of the lateral border of the anterior chamber angle was found in most of them. The grade of this distortion varied from very deep to insignificant, but was apparent in most cases. Seven fresh cases were gonioscopically examined and some recession was seen in five of them.     

Heterogeneous expression of melanoma-associated antigens in uveal melanomas

Twenty-five uveal melanomas were stained with seven monoclonal antibodies (MoAbs) recognizing different antigens on cutaneous melanomas. A two step immuno-peroxidase procedure was used. Phenotypic heterogeneity was observed for four MoAbs (M.2.2.4, AMF-7, 225.28S, PAL-M1) while two MoAbs (NKI-beteb, CL203.4) reacted strongly with most (85%) uveal melanomas, and one MoAb (R-24) showed very low reactivity. Despite heterogeneity, co-expression of some antigens was observed. Expression of the antigen recognized by MoAb M.2.2.4. was significantly lowered by pre-enucleation irradiation while the other antigens remained unchanged. Expression of antigens on uveal melanomas differed markedly from primary cutaneous melanomas. The clinical relevance of these findings awaits further study.     

S100 immunophenotypes of uveal melanomas.

To determine whether ocular melanomas are immunophenotypically identical to cutaneous melanomas, 34 primary and metastatic choroidal melanomas representing all major histotypes defined by the Callender's classification, plus one melanoma of the iris and one conjunctival melanoma, were subjected to a panel of immunostains designed to distinguish anaplastic biopsies of cutaneous melanomas from carcinomas and lymphomas. All ocular melanomas were found to express the intermediate filament vimentin but not keratin, and all but 2 were melanotic by immunostaining. Thirty-three of 34 (97%) choroidal melanomas were strongly stained with a rabbit polyclonal antibody (P-S100) developed against the S100 protein family. In contrast, none of 14 spindle cell type primary lesions was stained with a monoclonal antibody (MAB-079) specific for both S100 alpha and S100 beta, the best-characterized S100 polypeptides. Furthermore, only 2 of 5 epithelioid and 3 of 10 mixed-cell-type melanomas were weakly reactive. Overall, 14.7% (5 of 29) were stained. In comparison, MAB079 stained 85% of all cutaneous melanomas. Five metastases of choroidal melanomas (spindle B, epithelioid, and mixed cell types) from different organ sites also were stained by P-S100 but not by MAB079. These findings were corroborated by immunostaining with another monoclonal antibody (MAB4D4) specific for S100 beta. Differential staining by the polyclonal but not the monoclonal antibodies suggests the possible presence of a variant S100 polypeptide(s) in choroidal melanomas. Since S100 alpha, S100 beta, and related proteins appear to be physiologically important, additional studies of these S100 proteins may shed light on the etiology or pathology of choroidal melanomas.     

Survival after proton-beam irradiation of uveal melanomas

PURPOSE: To evaluate the independent prognostic factors for survival, metastasis, local recurrence, and enucleation in patients who had undergone proton-beam therapy for posterior uveal melanomas. DESIGN: Interventional case series. METHODS: In this retrospective study, 224 consecutive incident cases were treated at the Biomedical Cyclotron Centre (Nice, France) from June 1991 to December 1997. Overall, metastasis-free, local recurrence-free, and enucleation-free survival rates were calculated according to the Kaplan-Meier method using the log-rank test. The multivariate prognostic analysis was performed using the Cox proportional hazards model. RESULTS: The 5-year overall survival rate was 78.1% (SE: 3.7%). A largest basal tumor diameter (LTD) below 10 mm and female sex were independently associated with a better prognosis. The 5-year metastasis-free survival rate was 75.6% (SE: 3.6%). Only an LTD above 10 mm and ciliary body involvement were independently associated with metastasis. Ten patients (4.5%) had a local recurrence, which was correlated with the risk of metastasis (P =.045). The 5-year enucleation-free survival rate was 69.6% (SE: 4.0%). Once again, an LTD below 10 mm and female sex were predictive of a better prognosis. CONCLUSION: Our results with proton-beam therapy correspond to those reported in the literature. This treatment strategy is safe and yields predictably good results. In addition to the two independent prognostic factors for survival and metastasis, namely LTD and ciliary body involvement, sex also had a significant impact in our case series, but the clinical relevance of this finding is unknown.     

Pathological and prognostic features of uveal melanomas

Uveal melanomas may arise in the iris, ciliary body or choroid. Choroidal melanomas are the most common and usually display a discoid, collar-button or mushroom-shaped growth pattern. Uveal melanomas are composed of spindle and epithelioid cells and are classified histopathologically as either spindle-cell-type or mixed-cell-type tumours.The most important factors predicting clinical behaviour and underlying biology are cell type, cytomorphometric features, largest tumour dimension, scleral invasion and mitotic figures. Other valuable prognostic factors are tumour-infiltrating lymphocytes and macrophages, and the presence of vascular loops.