Uveal melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. UMs are usually initiated by a mutation in GNAQ or GNA11, unlike cutaneous melanomas, which usually harbour a BRAF or NRAS mutation. The annual incidence in Europe and the USA is ~6 per million population per year. Risk factors include fair skin, light-coloured eyes, congenital ocular melanocytosis, ocular melanocytoma and the BAP1-tumour predisposition syndrome. Ocular treatment aims at preserving the eye and useful vision and, if possible, preventing metastases. Enucleation has largely been superseded by various forms of radiotherapy, phototherapy and local tumour resection, often administered in combination. Ocular outcomes are best with small tumours not extending close to the optic disc and/or fovea. Almost 50% of patients develop metastatic disease, which usually involves the liver, and is usually fatal within 1 year. Although UM metastases are less responsive than cutaneous melanoma to chemotherapy or immune checkpoint inhibitors, encouraging results have been reported with partial hepatectomy for solitary metastases, with percutaneous hepatic perfusion with melphalan or with tebentafusp. Better insight into tumour immunology and metabolism may lead to new treatments.

Changes in immunological markers and influx of macrophages following trans-scleral thermotherapy of uveal melanoma.

PURPOSE: In trans-scleral thermotherapy (TSTT), heat is applied through the sclera in order to target an intraocular uveal melanoma. Previously, it had been shown that in uveal melanoma, hyperthermia and transpupillary thermotherapy influenced expression of immunologically relevant proteins, such as S100, HLA and heat-shock proteins (HSPs). We investigated whether TSTT induced similar changes. METHODS: Experimental TSTT was applied on eleven uveal melanomas prior to enucleation. Each tumour sample was processed for histopathological examination; immunohistochemical analysis was performed to determine expression of S100, HLA, HSPs and macrophage markers. RESULTS: In TSTT-treated areas, expression of S100 and different HSPs was lost, while an upregulated expression of HSP GP96 was observed at the border of these areas. Expression levels of HLA-A and HLA-B varied between tumours and were not influenced by TSTT. The borders of the TSTT-treated areas showed high numbers of infiltrating macrophages, which were predominantly of the M2 phenotype. CONCLUSION: TSTT has an effect on immunological parameters with local loss of expression of HSPs and S100. The influx of M2 macrophages around the TSTT-treated areas indicates the presence of an innate immune reaction against the induced necrosis, suggesting that TSTT-treated tumour cells are removed by a macrophage-mediated tissue repair mechanism.

Intravascular presence of tumor cells as prognostic parameter in uveal melanoma: a 35-year survey.

PURPOSE: Invasion of tumor cells into blood vessels is essential for metastasis of uveal melanoma. The occurrence of ingrowth of tumor cells in blood vessels in uveal melanoma was analyzed, and this parameter was compared with the survival of the patients. METHODS: Between 1972 and 2007, 643 eyes primarily enucleated for uveal melanoma were evaluated histopathologically. Survival data were obtained from charts and from the Integral Cancer Center patient registry. RESULTS: No vascular ingrowth of tumor cells occurred in 59% of the eyes, whereas 18% had tumor cell ingrowth in vessels inside the tumor, 10% in vessels outside the tumor, and 8% in vessels inside as well as outside the tumor. The presence of any intravascular ingrowth of tumor cells correlated significantly with the diameter (P < 0.01) and prominence of the tumor (P < 0.01), as well as with non-spindle-cell type (P = 0.03) and intrascleral ingrowth (P < 0.01), and was associated with a worse survival. When extravascular matrix patterns were not included in the multivariate analysis, intravascular ingrowth came out as an independent prognostic factor, but this was not the case when extravascular matrix patterns were included in the multivariate model. CONCLUSIONS: Intravascular ingrowth of tumor cells in uveal melanoma occurs frequently in combination with well-known histopathologic factors such as large tumor size, epithelioid cell type, and intrascleral ingrowth.

Vascular endothelial growth factor a in eyes with uveal melanoma.

OBJECTIVES: To determine the presence of vascular endothelial growth factor A (VEGF-A) in the aqueous humor of eyes with uveal melanoma and to identify its source. METHODS: The VEGF-A concentrations were determined in aqueous humor samples obtained after enucleation from 74 eyes with untreated uveal melanoma and from 8 eyes with treated uveal melanoma. Patient survival and clinical and histopathological tumor variables were compared. In situ hybridization, Western blot analysis, and enzyme-linked immunosorbent assay were used to determine expression of VEGF-A in tumor tissue and in overlying retina. RESULTS: Aqueous VEGF-A concentrations ranged from 18 to 826 pg/mL in 74 untreated eyes, while concentrations in 30 control eyes were significantly lower (median, 50.1 pg/mL) (P<.001). Concentrations in 8 treated eyes were much higher (median, 364 pg/mL). In situ hybridization on tissue sections and Western blot analysis and enzyme-linked immunosorbent assay on tissue extracts revealed VEGF-A in uveal melanoma tissue and in retinal tissue. CONCLUSIONS: Uveal melanoma is associated with increased concentrations of VEGF-A in aqueous humor. Aqueous VEGF-A concentration correlates with largest basal tumor diameter and with the tumor height. In eyes with uveal melanoma, tumor and retinal tissues are sources of VEGF-A.

HLA Class I and II genotype in uveal melanoma: relation to occurrence and prognosis.

PURPOSE: To assess whether human leukocyte antigen class I and class II alleles confer susceptibility to uveal melanoma or are related to specific clinical or tumor characteristics and survival. METHODS: Between 1990 and 2004, 235 consecutive Dutch patients with diagnoses of primary uveal melanoma were typed for HLA class I and II, either by complement-dependent cytotoxicity test or by DNA-based technique. Allele frequencies were compared with those of a control group that consisted of 2440 healthy Dutch blood donors. In addition, allele frequencies of 138 patients with uveal melanoma, who underwent enucleation as primary treatment, were compared for tumor characteristics and survival. RESULTS: With regard to tumor characteristics, correlations between HLA-DR13 and tumor size, HLA-B35 and spindle cell type, and HLA-B60 and ciliary body involvement were observed before correction for the number of alleles tested. Correlation was found between the presence of HLA-B44 and decreased survival. We did not find any allele that correlated with susceptibility to uveal melanoma after correction for the number of comparisons between patients and controls. CONCLUSIONS: This study shows that HLA class I and II antigens do not contribute to an increased genetic susceptibility to uveal melanoma. This does not exclude an important role for HLA antigens in immune surveillance against uveal melanoma and their metastases.